Sugar, Uric Acid, and the Etiology of Diabetes and Obesity

By electricdiet / May 13, 2021


Abstract

The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.

Fructose-induced weight gain and metabolic syndrome

Experimental studies from the 1950s showed the peculiar ability of fructose to induce insulin resistance in laboratory rats. Today, fructose intake has been shown to induce all features of metabolic syndrome in rats, as well as oxidative stress, endothelial dysfunction, fatty liver, microalbuminuria and kidney disease (rev. in 1). Similar findings can be shown when animals are fed sucrose or high-fructose corn syrup (HFCS), both which contain fructose (2,3). In contrast, administration of glucose or starch results in fewer features of metabolic syndrome when provided equivalent intake (4,5).

Fructose may increase the risk for obesity by altering satiety, resulting in increased food intake. The intake of fructose is not effective in stimulating insulin and leptin secretion in humans, and hence may not induce a satiety response (6). Other mechanisms may also be operative. For example, a high intake of fructose induces leptin resistance in rats (7). Fructose also encourages food intake due to stimulation of dopamine in the mesolimbic system and effects on the hypothalamus (8,9). Food intake is also stimulated by hepatic ATP depletion (10), which occurs in animals and humans administered fructose (11). Fructose may also affect metabolic rate. A recent study in humans documented a reduction in resting energy expenditure in overweight and obese subjects fed fructose but not glucose (12).

Fructose-induced metabolic syndrome does not require increased energy intake

The ability for fructose (and sucrose, which contains fructose) to stimulate food intake and to lower metabolism provides a mechanism for how a high fructose intake may encourage weight gain and visceral fat accumulation. However, fructose or sucrose also alters fat stores and metabolism independent of excessive energy intake. Although weight gain is largely controlled by overall energy intake, other features of metabolic syndrome can occur independent of weight gain. For example, rats fed fructose develop fatty liver, hypertriglyceridemia, and insulin resistance when compared with rats fed isocaloric glucose or starch-enriched diets (4,5). Indeed, hypertriglyceridemia, fatty liver, and type 2 diabetes can be induced in metabolic syndrome–prone rats with caloric restriction provided the diet is high (40%) in sucrose (which contains fructose) (5). A recent epidemiological analysis in humans also found an association of diabetes prevalence with sugar availability that was independent of total energy intake (13).

A role for uric acid in fructose-induced fat accumulation

The observation that fructose-fed rats develop fatty liver and metabolic syndrome without requiring increased energy intake suggests that the metabolism of fructose may be different from that of other carbohydrates. Fructose is distinct from glucose only in its initial metabolism. The first enzyme to metabolize fructose is fructokinase (also known as ketohexokinase [KHK]). The metabolism of fructose to fructose-1-phosphate by KHK occurs primarily in the liver, is rapid and without any negative feedback, and results in a fall in intracellular phosphate and ATP levels (1416). This has been shown to occur in the liver in humans with relatively small doses of oral fructose (60 g fructose alone or 39 g fructose with 39 g glucose) (11). The decrease in intracellular phosphate stimulates AMP deaminase (AMPD), which catalyzes the degradation of AMP to inosine monophosphate and eventually uric acid (15) (Fig. 1). The increase in intracellular uric acid is followed by an acute rise in uric acid in the circulation likely due to its release from the liver (14). Fructose also stimulates uric acid synthesis from amino acid precursors, such as glycine (17).

FIG. 1.
FIG. 1.

Fructose-induced nucleotide turnover. Fructose is rapidly phosphorylated in the hepatocyte by KHK to fructose-1-phosphate (F-1-P), which uses ATP as a phosphate donor. Intracellular phosphate (PO4) levels decrease, stimulating the activity of AMP deaminase 2 (AMPD2). AMPD2 converts AMP to inosine monophosphate (IMP). IMP is metabolized to inosine by 5′ nucleotidase (5′NT), which is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO), ultimately generating uric acid.

Recent studies suggest that this “side event” in fructose metabolism may be critical for how fructose induces metabolic syndrome. First, there are actually two KHK isoforms, and they differ in their ability to activate this pathway. KHK-C phosphorylates fructose rapidly, consuming ATP with the generation of uric acid. In contrast, KHK-A phosphorylates fructose slowly and consumes minimal ATP (18). When both KHK-C and KHK-A are deleted, mice are fully protected from fructose-induced metabolic syndrome and fatty liver (18); however, when KHK-A is selectively deleted, there is increased fructose available for metabolism by KHK-C, and the metabolic syndrome and fatty liver are worsened compared with wild-type mice despite the same intake of total calories and fructose (18). These studies suggest that differences in nucleotide turnover might influence the metabolic response.

To examine the purine nucleotide pathway in the metabolic response, we silenced aldolase B in a hepatocyte line (HepG2 cells) (19). Aldolase B is the second enzyme in fructose metabolism, and the genetic loss of aldolase B is the cause of hereditary fructose intolerance. When aldolase B is inhibited, fructose is phosphorylated by ATP but cannot be further metabolized, nevertheless fructose can be metabolized by other routes such as hexokinase. In this regard, subjects with hereditary fructose intolerance, are known to have hyperactive KHK and show enhanced ATP depletion and uric acid generation in response to fructose. As such, this is an interesting condition in which marked nucleotide turnover and ATP depletion occur but without the ability to be further metabolized by this primary enzymatic pathway to glucose, glycogen, or triglycerides (20). Nevertheless, the feeding of fructose to HepG2 cells lacking aldolase B resulted in a rapid accumulation of triglycerides, consistent with our findings that uric acid itself can induce triglyceride accumulation (19). These experiments explain why fatty liver and hyperuricemia are common complications of this disease (21) and also why fatty liver and diabetes are complications in subjects with glycogen storage disease I, in which hepatic intracellular ATP depletion and hyperuricemia also occur (2225). Finally, it provides an explanation for why fructose is lipogenic (based on acetate labeling studies) despite little of the fructose molecule being incorporated into the triglyceride molecule itself (19).

We next addressed how the degradation of nucleotides might lead to fat accumulation. Specifically, our group and others have shown that AMPD counters the effects of AMP-activated protein kinase (AMPK) (26,27). Whereas activation of AMPK in hepatocytes induces oxidation of fatty acids and ATP generation, AMPD has opposite effects. Overexpression of AMPD in HepG2 cells blocks fatty acid oxidation and increases fat accumulation, whereas silencing AMPD blocks fructose-induced fat accumulation. The mechanism is mediated in part by the generation of uric acid, which inhibits AMPK (27).

In addition to inhibiting AMPK, uric acid may stimulate hepatic lipogenesis (28). The mechanism appears to be mediated by uric acid–dependent intracellular and mitochondrial oxidative stress (28). Although uric acid is a potent antioxidant in the extracellular environment, when uric acid enters cells via specific organic anion transporters, it induces an oxidative burst that has been shown in vascular smooth muscle cells, endothelial cells, adipocytes, islet cells, renal tubular cells, and hepatocytes (2931). Uric acid–induced oxidative stress appears to be mediated by the stimulation of NADPH oxidase, which translocates to mitochondria (28,29,32). Uric acid can also generate triuretcarbonyl and aminocarbonyl radicals as well as alkylating species upon reaction with peroxynitrite and can also directly inactivate nitric oxide (NO) to 6-aminouracil (33,34).

The induction of oxidative stress in the mitochondria causes a reduction in aconitase-2 activity in the Krebs cycle, resulting in citrate accumulation that is transported into the cytoplasm where it activates ATP citrate lyase, acetyl CoA carboxylase, and fatty acid synthase, leading to fat synthesis (19). Uric acid also causes a reduction in enoyl CoA hydratase-1, a rate-limiting enzyme in β-fatty acid oxidation (35). The consequence is fat accumulation in the hepatocyte (19,35).

Recently, we identified another mechanism by which uric acid may increase the risk for hepatic fat accumulation and metabolic syndrome. Fructose (or sucrose) ingestion is known to increase hepatic KHK levels (5). The increased expression of KHK is driven in part by the production of uric acid from fructose (35) A rise in intracellular uric acid activates the nuclear transcription factor, carbohydrate responsive element–binding protein (35). When KHK expression is increased in HepG2 cells by uric acid exposure, the triglyceride accumulation in response to fructose is enhanced (35).

This is relevant to subjects with nonalcoholic fatty liver disease (NAFLD). Subjects with NAFLD ingest more fructose-containing soft drinks than age, sex, and BMI-matched control subjects and have increased KHK expression in their liver (36). Subjects with NAFLD who have the highest fructose intake also show the greatest ATP depletion in response to a fructose load, and those subjects with the highest uric acid levels show a greater nadir in the ATP depletion (37). These data are consistent with an induction of KHK in the liver with subsequent increased sensitivity to the effects of fructose via a uric acid–dependent mechanism.

Rodents have lower serum uric acid than humans due to the presence of uricase in their liver, and hence show a lesser rise in serum uric acid in response to fructose (38). Nevertheless, lowering uric acid has also been found to block the development of hepatic steatosis in fructose-fed rats (35). Lowering uric acid also reduces hepatic steatosis in the desert gerbil (which spontaneously develops fatty liver on a normal diet) (39), in alcoholic fatty liver (in which increased intrahepatic uric acid occurs) (40), and in the Pound mouse (a mouse model of metabolic syndrome manifesting fatty liver, obesity, insulin resistance, and hypertension caused by a leptin receptor mutation) (28). These studies supported the tight association of hyperuricemia with fatty liver; prospective studies have also reported that an elevated uric acid independently predicts the development of NAFLD (41). The ability of hyperuricemia to predict fatty liver is independent of obesity. Hyperuricemia is even associated with NAFLD in hemodialysis subjects who have a BMI below 20 (19). A summary of how fructose and uric acid induce fatty liver is shown in Fig. 2.

FIG. 2.
FIG. 2.

Classic and alternative lipogenic pathways of fructose. In the classical pathway, triglycerides (TG) are a direct product of fructose metabolism by the action of multiple enzymes including aldolase B (Aldo B) and fatty acid synthase (FAS). An alternative mechanism was recently shown (30). Uric acid produced from the nucleotide turnover that occurs during the phosphorylation of fructose to fructose-1-phosphate (F-1-P) results in the generation of mitochondrial oxidative stress (mtROS), which causes a decrease in the activity of aconitase (ACO2) in the Krebs cycle. As a consequence, the ACO2 substrate, citrate, accumulates and is released to the cytosol where it acts as substrate for TG synthesis through the activation of ATP citrate lyase (ACL) and fatty acid synthase. AMPD2, AMP deaminase 2; IMP, inosine monophosphate; PO4, phosphate.

Fructose-induced hyperuricemia, insulin resistance, and diabetes

The observation that inhibition of uric acid synthesis prevented metabolic syndrome and hepatic steatosis leads to the question of how uric acid might contribute to insulin resistance and diabetes.

Hepatic effects.

The observation that uric acid can induce mitochondrial oxidative stress and fatty liver may explain how fructose induces insulin resistance. Mitochondrial oxidative stress has a role in driving insulin resistance (42). In turn, the development of fatty liver is also linked with insulin resistance (43).

Effects in the white adipose tissue.

Uric acid may also induce insulin resistance via effects on adipocytes. Uric acid is taken up in adipocytes by an organic anion transporter where it induces oxidative stress via activation of NADPH oxidase, generating oxidized lipids and inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) (29,44). Adiponectin synthesis is also inhibited (44). In the hyperuricemic Pound mouse, the inhibition of uric acid synthesis by allopurinol attenuates the local inflammatory response in the visceral fat, reduces the expression of inflammatory cytokines, and enhances circulating levels of adiponectin in association with an improvement in insulin resistance (44). Likewise, the reduction of uric acid by either allopurinol or benzbromarone in the fructose-fed rat results in less insulin resistance and decreases the leptin overexpression that occurs in the visceral fat (4,45).

Vascular effects.

Fructose may also induce insulin resistance via effects on the vasculature. One of the major effects of insulin is to stimulate the release of NO from endothelial cells, where it causes vasodilation that aids delivery of glucose to the skeletal muscle. Mice that cannot generate endothelial NO develop features of metabolic syndrome and insulin resistance (46). In this regard, uric acid inhibits endothelial NO generation, including in response to insulin (32). Uric acid reduces endothelial NO via several mechanisms, including blocking the uptake of the substrate, l-arginine (47), stimulating the degradation of l-arginine by arginase (48), and scavenging NO by uric acid or by uric acid–generated oxidants (32,34,49). Hyperuricemic rats have impaired endothelial function and hypertension that can be reversed by lowering uric acid or treating with l-arginine or antioxidants (5052). Hyperuricemia is also associated with endothelial dysfunction in humans, and lowering uric acid with allopurinol improves endothelial dysfunction in asymptomatic hyperuricemia, congestive heart failure, diabetes, chronic kidney disease, obstructive sleep apnea, and with smoking (rev. in 53).

Islet cell effects.

Chronic administration of fructose or sucrose to animals not only causes insulin resistance but may also result in type 2 diabetes (5,54). Histologically, the islets show hyalinosis and macrophage infiltration, similar to what is observed in humans with type 2 diabetes. The mechanism by which fructose induces these changes is not known because the islet does not express GLUT5, which is the primary fructose transporter. However, we reported an upregulation of the urate transporter URAT-1 in islet cells of sucrose-fed rats in association with increased expression of MCP-1 (5). Incubation of cultured insulin-secreting islet cells with uric acid also causes oxidative stress and synthesis of MCP-1 (5). Oxidative stress in islets is considered to have a major role in causing the islet dysfunction of type 2 diabetes.

Evidence that fructose mediates fatty liver and insulin resistance in humans

The major source of fructose in the Western diet is from soft drinks and fruit drinks, and this accounts for approximately 7% of caloric intake in the adult, and upward to 15% of total caloric intake in adolescents. Intake of sugar and soft drinks are higher in populations at increased risk for insulin resistance and diabetes, including the African Americans, Hispanics, Native Americans, and subjects with lower income. A meta-analysis concluded that the intake of sugary soft drinks is an independent predictor for the development of metabolic syndrome and/or diabetes (55). Genetic factors enhance the risk for developing diabetes from soft drinks (56).

Clinical studies have documented the metabolic effects of fructose. Studies from the 1960s through the 1980s showed that sucrose, or fructose, can worsen hypertriglyceridemia and insulin resistance, especially if subjects were hyperinsulinemic (57,58). More recently Stanhope et al. (59) fed 25% of diet as fructose or glucose to overweight individuals for 10 weeks. Although some features of metabolic syndrome were induced with glucose, the fructose-fed subjects showed worse postprandial hypertriglyceridemia, increased hepatic de novo synthesis of fatty acids, a decrease in insulin sensitivity (noted by elevations in fasting glucose and insulin levels), increased total and visceral fat (among men), higher 24-h uric acid levels, increased systemic inflammatory mediators (MCP-1), and lower resting energy expenditure (12,59,60). In another study, Maersk et al. (61) randomized overweight adults to drink 1 L of a sugary soft drink daily for 6 months, with control subjects receiving equivalent amount of diet soft drink, milk, or water. At the end of 6 months, the subjects receiving the sugary soft drinks displayed more visceral, skeletal muscle, and liver fat and higher serum triglycerides and cholesterol compared with the group drinking milk, with a trend toward significance in the other two groups. Tappy and colleagues (62) have also shown the ability of fructose to induce insulin resistance, hepatic lipid accumulation, and hypertriglyceridemia. Similarly, our group administered 200 g fructose to overweight men for 2 weeks and documented higher blood pressure, higher triglycerides, and lower HDL cholesterol compared with baseline, with 25% of the subjects developing de novo metabolic syndrome at 2 weeks (63). Another study showed that the administration of one 8-oz soft drink per day to adolescents results in increased body weight at 18 months compared with subjects given diet soft drinks (64).

Intervention studies have also been performed to evaluate the effect of reducing sugar intake on metabolic syndrome. For example, the Atkins diet and other low carbohydrate diets tend to improve features of the metabolic syndrome more than typical low fat diets (65). A randomized study in school children reported that reducing soft drink intake, resulting in a difference of 175 mL/day between treatment and control subjects, led to a reduction in overweight or obesity by 0.2% in the treated group compared with a 7.5% increase in the control subjects at 12 months (66). A study in California showed that the banning of soft drinks in schools resulted in a reduction in overall soft drink intake with a decrease in obesity in children 6 to 11 years of age (67). Less effect was observed in older children, possibly because the overall reduction in soft drink intake in this latter group was less effective (67). Soft drink intake in the U.S. has decreased since peaking in 1999, and this is also associated with a leveling of the rates of obesity.

Role of uric acid in insulin resistance and fatty liver in humans

As mentioned, fructose increases intracellular and circulating uric acid levels due to increased nucleotide turnover and nucleotide synthesis. Initially the rise in serum uric acid is best shown shortly (30–60 min) after fructose ingestion (or ingestion of HFCS or sucrose), but total 24-h levels are also elevated (60,68). Over time, fasting serum uric acid levels increase (58). Intake of soft drinks is also associated with increasing risk for hyperuricemia (69).

An elevated serum uric acid is also one of the best independent predictors of diabetes and commonly precedes the development of both insulin resistance and diabetes (Table 1). An elevated uric acid also independently predicts the development of fatty liver (41), obesity (70), hypertension (rev. in 71), and elevations in C-reactive protein (72). Furthermore, metabolic syndrome is associated with a high frequency of hyperuricemia, and similarly, hyperuricemia is associated with metabolic syndrome (73,74). Though hyperinsulinemia may contribute to hyperuricemia by blocking uric acid excretion, it cannot be the primary reason for the association because hyperuricemia has been reported to precede the development of hyperinsulinemia and/or diabetes (Table 1).

TABLE 1

Serum uric acid predicts the development of diabetes

A number of conditions associated with hyperuricemia are also associated with increased risk for insulin resistance or diabetes, including chronic lead intoxication and gestational diabetes mellitus. Many drugs associated with insulin resistance are also associated with hyperuricemia, such as calcineurin inhibitors and thiazide diuretics. Indeed, lowering uric acid improves the insulin resistance induced by thiazides in rats (75).

Evidence that lowering uric acid can improve insulin resistance in humans is limited. One small study showed that lowering uric acid with benzbromarone improves insulin resistance in subjects with congestive heart failure (76). Another study reported that lowering uric acid improves HbA1c levels in normotensive diabetic subjects (77). In contrast, we were not able to show an improvement of insulin resistance with allopurinol in subjects administered fructose (63), but the doses of fructose were exceptionally high (200 g/day) raising the possibility that the doses of allopurinol we used might not have been able to block intracellular uric acid. Clearly, more studies are indicated before any definitive conclusions can be made with regards to the benefit of lowering uric acid for the treatment of insulin resistance.

Problems with the fructose and uric acid hypothesis

Concerns with animal studies.

The fructose-induced hyperuricemia hypothesis has been challenged. First, animal studies using fructose typically use pure fructose as opposed to sucrose or HFCS, which is the primary source of fructose in humans, and the dose of fructose administered to rodents is usually higher (50–60% of the diet) compared with humans (where it is typically 10–15% of the diet). Purified fructose is used, however, so one can separate the effects of fructose from glucose. Indeed, animals are more sensitive to the combination of fructose and glucose because both sugars accelerate the absorption of the other (78). Combinations of free fructose and glucose, or sucrose, induce features of metabolic syndrome with levels of fructose of 20–30% dietary intake (5,79).

Furthermore, rodents are relatively resistant to fructose in part because they generate less uric acid in response to fructose due to the presence of the uricase gene in their liver (38). Uricase degrades uric acid to allantoin, and as a consequence, rats degrade uric acid rapidly after it is formed in their liver. When uricase is inhibited, rats show a greater metabolic response to fructose with worse fatty liver and higher blood pressure (79). Indeed, there is evidence that the loss of uricase may have provided a survival advantage to ancestral apes living in Europe in the mid-Miocene and therefore may have acted like a thrifty gene (80). The subsequent rise in sugar intake over the last centuries may have acted in concert with the loss of uricase to predispose us to obesity and diabetes (80).

Clinical studies: the importance of the control group.

Recently, a number of investigators have presented meta-analyses that suggest fructose does not have a causal relationship with obesity or metabolic syndrome (8183). Before we analyze these studies, it is important to understand the complexity related to their interpretation. First, many clinical studies use fructose alone—and often at relatively high doses—in order to evaluate the effects of fructose per se. This allows one to directly address the effects of fructose, and the use of high doses is a common experimental approach to allow one to identify metabolic effects that could otherwise take much longer periods to show. Indeed, the fact that metabolic syndrome could be induced de novo in 25% of healthy men with high doses of fructose in just 2 weeks is a statement of how strong this approach can be (63). Although studies involving HFCS or sucrose might be clinically more relevant, these types of studies will have trouble distinguishing whether the metabolic effects observed are from the fructose or the high glycemic content of these added sugars.

Nevertheless, the administration of fructose alone can be very difficult to interpret because the absorption of fructose when given alone is quite variable. As many as two-thirds of children and one-third of adults malabsorb fructose (84,85). This is likely because of variable expression of the fructose transporter GLUT5 in the gut. Expression of GLUT5 and the enzyme KHK, however, are enhanced with repeated exposure to fructose. It is interesting that studies in children have found an inverse relationship between fructose malabsorption and obesity (86). Consistent with this data, the metabolic response to fructose in children with NAFLD is greater compared with lean control subjects (87). The importance of fructose absorption has recently been highlighted in African Americans because they commonly malabsorb fructose and also have a lower frequency of NAFLD (88). The observation that NAFLD subjects may absorb fructose more efficiently is further supported by our observation of higher KHK expression in liver biopsies of NAFLD compared with other liver disease (36) and could be the reason why ATP depletion in response to fructose is greater in NAFLD subjects with a higher prior exposure to dietary fructose (37). Our observation that hyperuricemia may regulate KHK (35) also provides an explanation for why studies in which fructose is given to young athletic lean individuals are often negative and why they may not carry over to older and heavier individuals.

Another key issue is whether studies evaluating fructose should include fructose from natural fruits. One can argue that fructose is fructose regardless of source, but natural fruits also contain numerous substances that block fructose effects, including potassium, vitamin C, and antioxidants such as resveratrol, quercetin, and other flavonols. We found, for example, that whereas fructose from added sugars is associated with hypertension, fructose from natural fruits is not (89). We further showed that caloric restriction involving a reduction in fructose intake from added sugars could markedly improve metabolic syndrome in obese Mexican adults, and that this occurred even if natural fruits were administered (90).

Another important issue is whether glucose itself is the right control for fructose. Outwardly it would seem true, but we recently discovered that glucose may act to induce obesity and insulin resistance by being converted to fructose in the liver (91). Specifically, high concentrations of glucose, such as occurs in soft drinks, can induce the activation of the polyol pathway in the liver, resulting in the generation of fructose. In turn, the fructose is then metabolized by KHK, resulting in fructose-dependent effects. Indeed, glucose-induced weight gain, fat accumulation, fatty liver, and insulin resistance are all dependent on KHK. While some visceral fat and weight gain occur in glucose-fed mice lacking KHK, the development of fatty liver and hyperinsulinemia are almost entirely dependent on glucose-induced fructose metabolism (91). Hence, although fructose itself will have more metabolic effects than glucose, the glucose itself may also be inducing metabolic changes via fructose.

Meta-analyses that argue fructose is not a risk factor for metabolic syndrome

Weight gain.

A meta-analysis recently reported that fructose intake does not cause weight gain compared with other sugars in short-term studies if both groups are given the same number of total calories (isocaloric diets) (81). However, no food will cause weight gain under these conditions, as weight gain is driven primarily by increased energy intake as opposed to a reduction in metabolic rate, at least in the short-term. Indeed, the mechanism by which fructose increases weight is likely via its ability to stimulate hunger and block satiety responses (7,9), so if food intake is controlled this would not be observed.

Blood pressure.

It is a scientific fact that the administration of clinically relevant doses (60 g) of fructose acutely raises blood pressure in humans (92), and similar increases in blood pressure have been observed following ingestion of 24 ounces of HFCS or sucrose-containing beverages (68). It has also been reported that high doses of fructose raises 24-h ambulatory blood pressure in humans and can be blocked by lowering uric acid with allopurinol (63). However, the recent meta-analysis by Ha et al. (82) addressed whether short-term isocaloric fructose diets can increase blood pressure after an overnight fast. Since the acute effects of fructose to raise blood pressure occur during the ingestion of fructose (and are likely mediated by uric acid), it is not surprising that the authors did not show an effect on blood pressure; indeed, a similarly designed study would conclude that glucose-rich diets do not increase insulin levels.

An important question is whether chronic fructose ingestion may be responsible for persistent elevations in blood pressure. It is known that the greatest risk for persistent hypertension is borderline hypertension in which intermittent blood pressure elevations occur. There is also evidence that fructose causes microvascular disease in the kidney, which is known to predispose to persistent salt-sensitive hypertension. Indeed, persistent hypertension can be induced with fructose and high-salt diet in rats. Furthermore, chronic fructose ingestion over time is associated with elevations in fasting uric acid levels (58,93), in part because fructose also stimulates uric acid synthesis. Epidemiological studies have also linked fructose intake with hypertension and elevated serum uric acid levels (94). Reduction in sugar intake is also strongly associated with a reduction in blood pressure (95). Indeed, the DASH (Dietary Approaches to Stop Hypertension) diet is in essence a diet low in fructose from added sugars (while containing natural fruits, see above).

Uric acid.

Wang et al. (83) also reported that short-term isocaloric trials do not show an effect of fructose on fasting uric acid levels. Again, the design of the study would not be expected to show a rise in uric acid because the initial rise in uric acid is transient and occurs within minutes of the ingestion of fructose. However, as mentioned, there is some evidence that over time continued ingestion of fructose will result in chronic elevations of uric acid. A more detailed discussion is provided elsewhere.

Another issue with all three metanalyses is that they included control groups that ingested sucrose, which can be questioned because sucrose is a disaccharide that contains fructose (8183).

Other issues related to uric acid.

Other aspects of the uric acid studies have also been questioned. One paradox is that the acute elevation of serum uric acid by infusion often results in an improvement in endothelial function (96). However, while uric acid is an antioxidant in the extracellular environment, it has prooxidative effects inside the cell (28,29). Several investigators have also suggested that it is not uric acid that is driving metabolic syndrome, but rather xanthine oxidase, since this enzyme generates oxidants in addition to uric acid, and it may be the former that is responsible for the metabolic syndrome. For example, high-dose allopurinol improves endothelial dysfunction in subjects with heart failure whereas the lowering of uric acid with probenecid was ineffective (97). However, this could simply relate to the relative superiority of allopurinol to lower intracellular uric acid as it blocks synthesis. Although xanthine oxidase–induced oxidants could be important, the observation that raising intracellular uric acid, even in the presence of allopurinol, can increase hepatic fat suggests that it is the uric acid that is responsible (35).

Genetic studies.

A final argument relates to the genetics of uric acid and fructose metabolism. While some genetic polymorphisms in various enzymes involved in fructose metabolism and urate transport have been linked with metabolic syndrome and hypertension (98100), several genome-wide association studies (GWAS) could not show such associations (101,102). However, the primary polymorphism driving serum uric acid in the GWAS studies is SLC2A9; this polymorphism mediates the transport of uric acid out of tubular cells, and so it may not predict the development of diabetes because it is likely to dissociate the serum from intracellular uric acid levels, the latter of which may be more important in driving insulin resistance.

Conclusions

Searching for the cause of type 2 diabetes has been a prime area of research since Etienne Lancereaux described fat diabetes (diabetes gras) in 1880. Though more studies are needed, the evidence that fructose-induced hyperuricemia may have a contributory role is gaining ground. While it still remains a hypothesis (103), increasing evidence suggests uric acid may have a fundamental role in the manifestations of metabolic syndrome (Fig. 3). Given that hyperuricemia is a remediable risk factor, we recommend both basic and clinical studies to address this important possibility.

FIG. 3.
FIG. 3.

Uric acid: potential mechanisms for insulin resistance and diabetes. Uric acid may contribute to insulin resistance in the liver by inducing mitochondrial oxidative stress and steatosis (28). Uric acid also blocks the ability of insulin to stimulate vasodilation of blood vessels, which is important for the delivery of glucose to the skeletal muscle (4,32). Uric acid also induces local inflammation in the adipose tissue with a reduction in the production of adiponectin (44). Finally, uric acid may also have direct effects on the islet cells leading to local oxidative stress and islet dysfunction (5). Mt, mitochondria; PO4, phosphate.

ACKNOWLEDGMENTS

Support for this study was provided by ADA Basic Science Award 7-12-BS-16 to Y.Y.S.

R.J.J. has patent applications related to lowering uric acid as a means to prevent or treat insulin resistance and features of metabolic syndrome; holds stock in XORT Pharma Corp.; and is on the Scientific Board of Amway. T.N. has patent applications related to lowering uric acid as a means to prevent or treat insulin resistance and features of metabolic syndrome and holds stock in XORT Pharma Corp. No other potential conflicts of interest relevant to this article were reported.

R.J.J. wrote the first draft of the manuscript. T.N., L.G.S.-L., M.S., S.S., M.L., T.I., Y.Y.S., and M.A.L. improved the manuscript with their comments and suggestions. In addition, all of the authors have made scientific contributions that provided the groundwork for this Perspective.

  • Received February 1, 2013.
  • Accepted June 17, 2013.



Sell Unused Diabetic Strips Today!

Low-Carb Breakfast Burrito – Diabetic Foodie

By electricdiet / May 11, 2021


For a healthy, delicious way to energize your morning, treat yourself to a low-carb breakfast burrito! They’re so simple to make and great for meal-prep.

Low-carb breakfast burrito cut into two halves and stacked on a white plate

Looking for a healthy and delicious way to start the day? A low-carb breakfast burrito is sure to energize your morning!

These tasty wraps are also great for meal-prep. Store in the refrigerator or freezer for a nutritious grab-and-go breakfast.

How to make a low-carb breakfast burrito

Start to finish, this tasty meal can be ready in less than 30 minutes!

Individual burrito ingredients in separate ramekins and bowls, as seen from above

Step 1: In a medium mixing bowl, whisk together 6 large eggs and milk. Season to taste with pepper.

Step 2: Heat a pan over medium heat and add the butter. Once melted, pour in the egg mixture. Continue to cook, stirring occasionally, until eggs are scrambled.

Step 3: Add the spinach to a pot of boiling water until completely wilted, about 3-5 minutes. Remove from water, drain well, and set aside.

Step 4: To assemble the burritos, add layers of scrambled egg, chopped bacon, spinach, and peppers to a low-carb tortilla. Top with shredded cheese.

Ingredients on a tortilla on a plate next to three ramekins of ingredients

Step 5: Add any desired sauce, then wrap the burrito and serve.

That’s it! You can sit down and enjoy your burrito as a leisurely breakfast, or take it on-the-go to fuel you up for the day.

Burrito cut into two halves and stacked on a white plate

Variations for this recipe

There are so many delicious ways to make a healthy breakfast burrito! While I love the option outlined in this recipe, I’ll share a few alternatives to help you find your own perfect combination.

To start, feel free to use another protein based on your taste, preference, or convenience. To reduce the fat, try replacing the pork bacon with turkey bacon. You could also crumble up some lower sodium breakfast sausage.

Want to add or substitute veggies? Go for it! Try adding raw or sautéed onions or mushrooms, or swap the spinach out for Swiss chard. If you ask me, you can never go wrong with veggies.

Not worried about carbs? Add some black or pinto beans for extra fiber and bulk. To keep sodium low, I recommend making your own beans.

On the other hand, if you want to lower the carbs, you could eliminate the tortillas and enjoy this dish as a burrito bowl instead. This also gives you some room to add even more of your favorite toppings!

There’s no right or wrong way to make a burrito. So go ahead and have some fun experimenting with this tasty and healthy recipe.

Storage

You can store these burritos in an airtight container in the refrigerator for up to 3 days. They’re a great option for a healthy grab-and-go breakfast!

For longer storage, you can also freeze your burritos for up to 3 months. Simply wrap each one in parchment paper, place in a sealable plastic gallon bag, and store in the freezer.

Ingredients on a tortilla on a plate next to three ramekins of ingredients

Other low-carb breakfast recipes

I love starting my morning with low-carb and keto-friendly dishes. They keep my blood sugar stable while giving me the energy I need to tackle the day! Here are a few of my favorite breakfast options I think you’ll enjoy:

For even more delicious inspiration, check out this round-up of my favorite diabetic smoothie recipes!

When you’ve tried this recipe, please don’t forget to let me know how you liked it and rate the recipe in the comments below!

Recipe Card

Low-carb breakfast burrito cut into two halves and stacked on a white plate

Low-Carb Breakfast Burrito

For a healthy, delicious way to energize your morning, treat yourself to a low-carb breakfast burrito! They’re so simple to make and great for meal-prep.

Prep Time:15 minutes

Cook Time:10 minutes

Total Time:25 minutes

Author:Diabetic Foodie

Servings:6

Instructions

  • In a medium mixing bowl, whisk together 6 large eggs and milk. Season to taste with pepper.

  • Heat a pan over medium heat and add the butter. Once melted, pour in the egg mixture. Continue to cook, stirring occasionally, until eggs are scrambled.

  • Add the spinach to a pot of boiling water until completely wilted, about 3-5 minutes. Remove from water, drain well, and set aside.

  • To assemble the burritos, add layers of scrambled egg, chopped bacon, spinach, and peppers to a low-carb tortilla. Top with shredded cheese.
  • Add any desired sauce, then wrap the burrito and serve.

Recipe Notes

This recipe is for 6 breakfast burritos.
To reduce the fat and sodium, substitute turkey bacon in place of the pork bacon.
Leftovers can be stored in an airtight container in the refrigerator for up to 3 days.
For longer storage, wrap each burrito in parchment paper, place in a sealable plastic gallon bag, and keep in the freezer for up to 3 months.

Nutrition Info Per Serving

Nutrition Facts

Low-Carb Breakfast Burrito

Amount Per Serving (1 burrito)

Calories 401
Calories from Fat 286

% Daily Value*

Fat 31.8g49%

Saturated Fat 6.9g43%

Trans Fat 0g

Polyunsaturated Fat 1.1g

Monounsaturated Fat 2.6g

Cholesterol 259.2mg86%

Sodium 642.6mg28%

Potassium 171mg5%

Carbohydrates 17.5g6%

Fiber 13.2g55%

Sugar 1g1%

Protein 21.2g42%

Net carbs 4.3g

* Percent Daily Values are based on a 2000 calorie diet.

Course: Breakfast, Brunch

Cuisine: American

Diet: Diabetic, Gluten Free

Keyword: breakfast burrito, gluten-free, keto burrito, low-carb burrito



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Hominy Macaroni and Cheese – My Bizzy Kitchen

By electricdiet / May 9, 2021






Hominy Macaroni and Cheese – My Bizzy Kitchen







































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Homemade Keto Tortillas | Diabetes Strong

By electricdiet / May 7, 2021


Have you been missing Taco Tuesdays on a low-carb diet? Thanks to these easy homemade keto tortillas, you can get back to enjoying tacos, burritos, wraps, and so much more!

Closeup of tortillas on a blue plate next to ramekins with cheese and cilantro

When taco night comes around, following a low-carb or keto diet doesn’t mean you have to miss out on the fun. Just whip up a batch of easy homemade keto tortillas.

They’re simple to make, cost less than store-bought versions, and don’t contain any unwanted ingredients or fillers. In fact, these low-carb tortillas are also dairy-free, gluten-free, and vegan!

How to make homemade keto tortillas

This recipe takes less than 30 minutes to come together. That leaves more time to focus on the most important part: figuring out your perfect toppings!

Step 1: Add the coconut flour, almond flour, salt, psyllium husk, and xanthan gum to a food processor. Process until fine and well-combined.

Dry ingredients in the food processor, as seen from above

Step 2: Put the processor on low and slowly pour in the oil and water.

Step 3: Once the ingredients start to form a rough dough, turn off the food processor.

Dough forming in food processor, as seen from above

Step 4: Remove the dough, shape into a ball, then place on a flat surface.

Step 5: Knead the dough for 1-2 minutes, then roll into an even ball.

Step 6: Flatten the dough into a thick disk about 6 inches wide. Using a sharp knife, cut the dough into 6 equal pieces.

Dough ball cut into six equal pieces

Step 7: Roll each piece into small balls. One at a time, place a small ball of dough between two sheets of baking paper or parchment paper. Roll out into a thin tortilla.

Raw tortilla, rolled out and ready to be fried

Step 8: Repeat with the remaining dough.

Step 9: Heat a non-stick pan over medium-high heat. Once hot, fry each tortilla for 2-3 minutes per side. They will puff up slightly.

5 homemade keto tortillas on a blue plate next to a striped dish towel, as seen from above

Once cooked, I recommend keeping the tortillas warm in the oven until you’re ready to serve.

What to eat with low-carb homemade tortillas

I absolutely love how versatile these tortillas are! I never run out of ways to use them.

For something quick and healthy, these tortillas go so well with my 15 minute beef fajitas. You’ll get a delicious, low-carb meal that’s bursting with color and flavor.

They’re also perfect for taco night. I never get tired of serving them with Instant Pot chicken chili as the base. From there, just add all your favorite low-carb toppings!

Need a quick low-carb lunch? Fill homemade tortillas with keto tuna salad, or use them in these smoked salmon and cream cheese wraps.

Of course, if you’re craving some cheesy comfort food, you can always use them to whip up low-carb quesadillas. After a long day, sometimes, a simple meal like that can really hit the spot.

Closeup of tortillas on a blue plate next to ramekins with cheese and cilantro

Storage

Another great thing about these tortillas is that they keep well in the refrigerator. Whether you have leftovers or you decide to make extras, you can enjoy them throughout the week!

You can store cooked tortillas in an airtight container in the refrigerator. I recommend eating them within 5 days.

When you’re ready to enjoy, you can gently reheat them in a pan or the oven. You could also eat them chilled if you’re in a hurry.

Finished tortillas on a blue plate next to a striped dish towel, as seen from above

Other quick and tasty keto recipes

Looking for more low-carb foods you can whip up in a flash? I’ve got you covered! Here are a few of my favorite keto recipes that can be ready in 30 minutes or less:

You can also check out this roundup of my favorite low-carb cauliflower recipes for even more inspiration!

When you’ve made this dish, please don’t forget to let me know how you liked it and rate the recipe in the comments below!

Recipe Card

Homemade Keto Tortilla

Have you been missing Taco Tuesdays on a low-carb diet? Thanks to these easy homemade keto tortillas, you can get back to enjoying tacos, burritos, wraps, and so much more!

Prep Time:10 minutes

Cook Time:20 minutes

Total Time:30 minutes

Servings:6

5 homemade keto tortillas on a blue plate, as seen from above

Instructions

  • Add the coconut flour, almond flour, salt, psyllium husk, and xanthan gum to a food processor. Process until fine and well-combined.

  • Put the processor on low and slowly pour in the oil and water.

  • Once the ingredients start to form a rough dough, turn off the food processor.

  • Remove the dough, shape into a ball, then place on a flat surface.

  • Knead the dough for 1-2 minutes, then roll into an even ball.

  • Flatten the dough into a thick disk about 6 inches wide. Using a sharp knife, cut the dough into 6 equal pieces.

  • Roll each piece into small balls. One at a time, place a small ball of dough between two sheets of baking paper or parchment paper. Roll out into a thin tortilla.

  • Repeat with the remaining dough.

  • Heat a non-stick pan over medium-high heat. Once hot, fry each tortilla for 2-3 minutes per side. They will puff up slightly.

Recipe Notes

This recipe is for 6 tortillas.
Leftover tortillas can be stored in an airtight container in the refrigerator for up to 5 days.

Nutrition Info Per Serving

Nutrition Facts

Homemade Keto Tortilla

Amount Per Serving (1 tortilla)

Calories 99
Calories from Fat 77

% Daily Value*

Fat 8.5g13%

Saturated Fat 0.9g5%

Trans Fat 0g

Polyunsaturated Fat 1g

Monounsaturated Fat 2g

Cholesterol 0mg0%

Sodium 365mg15%

Potassium 0mg0%

Carbohydrates 14g5%

Fiber 12.5g50%

Sugar 0.5g1%

Protein 2.3g5%

Net carbs 1.5g

* Percent Daily Values are based on a 2000 calorie diet.

Course: Appetizer, Side Dish

Cuisine: Mexican

Diet: Diabetic, Gluten Free, Low Lactose

Keyword: dairy-free, gluten-free, keto, keto tortilla, low carb, vegan



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Fresh Salsa Recipes: Fiesta Salsa Perfect Update To Avocado Salsa Recipes

By electricdiet / May 5, 2021


Update Your Salsa with Fiesta Salsa with Fresh Salsa Recipes

Who doesn’t like chips and dip? Looking for a salsa makeover? Fresh salsa recipes especially with avocado is our favorite. Avocados are a delectable addition to pretty much anything! Tomato Corn Avocado Salsa recipe with around 5 ingredients is the best of avocado salsa recipes.  Fresh and convenience items combined together for this Fiesta Salsa from Holly Clegg’s Eating Well To Fight Arthritis cookbook  gives you the flavors of fresh salsa recipes effortlessly. Whether it is summer time or you are looking for salsa tailgating recipes, this quick fresh salsa recipe tops our list so keep the ingredients handy in your pantry. You can even use this as a side salad!

Fiesta Salsa

Simple Avocado Salsa Recipes with Garden Ingredients

With the tomatoes, corn, green chilies and green onions, you have a quick salsa recipe.  Your family will request this healthy easy recipe as this simple salsa recipe is a great way to enjoy chips and dip. Perfect to serve for game days, holidays or for an afternoon snack. Get creative and serve as a salad or a dip. Try using bell pepper squares and cucumber rounds for your chips to add veggies and lower simple carbohydrate intake! You can even serve this delicious salsa with avocado recipe on a bed of mixed green and top it with leftover grilled chicken and then you have another meal! Versatile and add whatever other garden ingredients you have. Nutritious and delicious! Doesn’t get better than that!

Fiesta Salsa
If you want fresh salsa recipes that are simple, this fresh tomato corn avocado salsa recipe makes a quick refreshing snack and also is an easy diabetic recipe. Just a few ingredients with a burst of lime. This salsa goes well with any meal. It’s so quick to make.

    Servings20 (1/4 cup) servings

    Ingredients

    • 2


      avocadospeeled, pitted, and chopped

    • 1pint


      cherry tomatoesquartered, or grape tomatoes, halved

    • 1cup


      frozen cornthawed

    • 1(4-ounce) can


      chopped green chiliesdrained

    • 1


      bunch green onionschopped

    • 3tablespoons


      lime juice



    • salt and pepper to taste

    Instructions
    1. In large bowl, carefully combine all ingredients.

    Recipe Notes

    Calories 42, Protein (g) 1, Carbohydrate (g) 5, Fat (g) 2, Calories from Fat (%) 46, Saturated Fat (g) 0, Dietary Fiber 2 (g), Cholesterol (mg) 0, Sodium (mg) 26, Total Sugars (g) 1, Diabetic Exchanges: 1 vegetable, 1/2 fat

    Terrific Tidbit: Mash leftover avocado with lemon or lime juice and this helps with discoloration. Use the ratio of 1/2 teaspoon per half mashed avocado. Cover with plastic wrap and refrigerate.

    Top Fresh Salsa Recipes

    This quick salsa recipe makes a great snack or salad. Try serving with chicken or fish as a side salad. Easy to make and great versatility!  Fiesta Salsa from Holly Clegg’s arthritis cookbook will become a favorite fresh salsa recipe while it also doubles as a condiment.

    Sometimes you need a quick fresh dip with minimal preparation.  Pick up these few ingredients.  You truly whip up this favorite fresh tomato salsa recipe in minutes. If you are an avocado addict like we are, the avocado makes the recipe!

    Best Diabetic Salsa Recipe for Salsa with Avocados

    This Fiesta Salsa recipe is also an easy diabetic recipe to put on your diabetes diet! Sometimes it can be difficult to find diabetic salsa recipes that have that “wow” factor too and are easy salsa recipes.  So easy to throw together and everyone thinks you made a gourmet appetizer! Remember, color equals nutrition!

    Corn Stripper Gadgets-Easy Way To Remove Corn Off The Cob

    You might be thinking do these corn gadgets really work?  Yes, they do and it makes fresh corn on the cob easier to include in this tomato avocado corn salsa.  Once you make the switch to fresh corn on the cob, you will taste the difference!  Or, if you have leftover corn on the cob, strip the corn off the cob to toss in other recipes.

    Corn Stripper Hand ProtectorCorn Stripper Hand ProtectorCorn Stripper Hand ProtectorOXO Good Grips Corn StripperOXO Good Grips Corn StripperOXO Good Grips Corn StripperChef'n Cob Corn Stripper (Yellow)Chef’n Cob Corn Stripper (Yellow)Chef'n Cob Corn Stripper (Yellow)

    Chili Con Queso Makes Popular Simple Healthy Dip and Chips Recipe!

    Who doesn’t like chips and dips? Another out-of-this-world classic and popular appetizer is this Chili Con Queso from KITCHEN 101. No Velveeta cheese but still with rich, cheesy taste! There’s easy ways to serve a warm dip. Serve dips in a fondue pot or slow cooker. Fix and forget it! Start cooking trim and terrific for the most delicious and good for you recipes!

    SHOP: Serve Dips in Fondue Pot to Keep Warm

    Love this Fondue Pot to keep a dip warm. Queso Dip makes the perfect entertaining recipe because who doesn’t like this southwestern cheesy dip! The Chili Con Queso Dip is a super simple healthy queso.

    Queso and Fiesta Salsa are two dips you can whip up easily and everyone always loves them.

    Get All of Holly’s Healthy Easy Cookbooks

    The post Fresh Salsa Recipes: Fiesta Salsa Perfect Update To Avocado Salsa Recipes appeared first on The Healthy Cooking Blog.



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    SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

    By electricdiet / May 3, 2021


    Introduction

    This Perspective focuses on providing an overview of recent studies describing the impact of the coronavirus disease 2019 (COVID-19) pandemic on individuals with diabetes and several possible mechanisms for why individuals with diabetes represent a particularly at-risk population. In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for the outbreak that began in Wuhan, China, and rapidly spread throughout China, Europe, and the U.S. Currently, the SARS-CoV-2 virus has infected more than 12 million individuals worldwide, with more than 555,000 COVID-19 cases resulting in death, and the number of individuals becoming infected is increasing. Thus far, SARS-CoV-2 mechanisms of infectivity remain incompletely understood. Some insight, however, has been provided by the previous pandemic of SARS-CoV in 2002, but the brutality of COVID-19 has raised many unanswered questions and the pace of science needs to increase. Here, we put forth the argument that a dysregulated renin-angiotensin system (RAS), typically seen in individuals with diabetes, increases the risk of a poor clinical outcome following COVID-19 infection.

    Clinical Burden of COVID-19 in Patients With Diabetes

    Conditions associated with increased morbidity and mortality in individuals infected with SARS-CoV-2 are the presence of diabetes, hypertension, cardiovascular disease, and severe obesity (BMI ≥40 kg/m2) (13). Considering the high prevalence of hypertension, cardiovascular disease, and obesity in individuals with diabetes, it is difficult to know how diabetes alone directly contributes to the increased risk of adverse outcomes following SARS-CoV-2 infection. Studies indicate that 12–16% of individuals with severe infections have diabetes (1,2). However, a recent meta-analysis of six clinical studies involving 1,687 COVID-19 patients provided evidence that individuals with diabetes exhibited a similar prevalence of being infected with SARS-CoV-2 as the overall population, but presence of diabetes was a critical comorbidity that increased the risk of a poor outcome (4). Certain racial groups such as African Americans and Native Americans are highly prone to developing diabetes and experience disparities in health care making them particularly vulnerable to COVID-19 (5). However, to date there is a paucity of data regarding comorbidities, COVID-19 outcomes, and mechanisms that modulate viral pathogenesis. In this Perspective, we bring attention to specific factors that may complicate COVID-19 in individuals with diabetes including 1) the presence of bone marrow changes (myeloidosis) that predispose those with diabetes to an excessive proinflammatory response (cytokine storm) and contribute to insulin resistance and reduced vascular repair, and worsening function of the heart, kidney, and systemic vasculature as a whole; 2) increased circulating furin levels that could cleave the spike protein and increase infectivity of SARS-CoV-2; 3) dysregulated autophagy that may promote replication and/or reduce viral clearance; and 4) gut dysbiosis that leads to widespread systemic inflammation, increased gut glucose and sodium absorption, and reduced tryptophan and other key amino acid absorption needed for incretin secretion and glucose homeostasis. Central to each of these dysfunctions is the dysregulated RAS, in particular, the global loss of ACE2, which we propose is a unifying mechanism that could lead to the increased risk of morbidity and mortality in individuals with diabetes presenting with COVID-19.

    Biochemistry and Physiology of RAS

    The RAS is a key hormonal circuit tasked in regulating extracellular fluid volume and blood pressure in mammals. If blood pressure falls, the juxtaglomerular cells in the kidneys produce and secrete renin, which cleaves serum angiotensinogen to produce angiotensin I (Ang-I). Then, angiotensin-I converting enzyme (ACE) further converts Ang-I into angiotensin II (Ang-II) in the lungs by removing the C-terminal dipeptide from Ang-I (Fig. 1). Ang-II in turn activates the G-protein–coupled angiotensin type 1 receptor (AT1R) on adrenal zona glomerulosa cells to produce aldosterone, which causes sodium retention, an increase in blood volume, and blood pressure stabilization. Besides its beneficial function in regulating extracellular fluid volume, a dysregulated RAS, as seen in diabetes, could lead to an increase in serum levels of Ang-II that could cause a plethora of potentially harmful effects including vasoconstriction, inflammation, and increased oxidative stress. ACE2 converts Ang-II into Ang-1-7, and Ang-1-7 acts through the Mas receptor (MasR) to oppose the effects of Ang-II. This ability of ACE2 to convert the serum vasopressor Ang-II into the vasodilating Ang-1-7 identifies it as a “negative” regulator of RAS. Notably, COVID-19 patients exhibit increased serum levels of Ang-II (6), which would support less cleavage by ACE2 and thus potentially less ACE2 activity. In addition to systemic RAS, “local” RAS exists within each tissue including a lung RAS, intestinal RAS, and bone marrow RAS. Interestingly, the RAS system in the intestinal mucosa significantly contributes to the regulation of glucose, salt, and water uptake. Emerging COVID-19 gastrointestinal disturbances implicate a central role of intestinal pathophysiology in exacerbation of hyperglycemia and blood pressure in individuals with diabetes infected with SARS-CoV-2.

    Figure 1
    Figure 1

    The biochemical pathways of the RAS and the beneficial ACE2/Ang-1-7 arm of RAS. The amino acid sequences of hormones are colored in blue and enclosed in parentheses. Renin is produced and secreted in the juxtaglomerular cells of the kidney when plasma NaCl decreases or blood pressure falls. Renin cleaves angiotensinogen to produce Ang-I, which is further converted into Ang-II by ACE in the lungs. Ang-II induces aldosterone secretion from adrenal zona glomerulosa cells, which in turn promotes sodium and water retention in the kidneys, increasing blood pressure. Thus, initial serum Ang-II levels are set by renin. However, the steady-state serum Ang-II level is also markedly affected by the rate of its conversion to Ang-1-7 by ACE2. Therefore, ACE2 activity contributes to regulating the steady-state levels of Ang-II. If we consider an example of a rainwater barrel and assume that renin is the actual rainfall amount, Ang-II is the rainwater, and ACE2 activity is the barrel’s outlet spigot, then the rainfall amount (renin) would always determine the rainwater (Ang-II) inflow rate and level into the barrel. But if we would keep the barrel outlet spigot always open (ACE2 is active) during and after rainstorms, the final level of rainwater would not be as high as in the case if the barrel’s outlet spigot were closed (ACE2 is inactive). Aldo, aldosterone; ZG, zona glomerulosa.

    ACE2 Protein: Function, Interaction Between ACE2 and ADAM17, and ACE2 as the Receptor for SARS-CoV and SARS-CoV-2

    ACE2 was discovered in 2000 (7), just 2–3 years before the first wave of SARS-CoV coronavirus pandemic, when ACE2 was identified as the major SARS-CoV “receptor” on host cells. ACE2 functions as a metallocarboxypeptidase, a plasma membrane–bound proteolytic enzyme (Fig. 2A) that removes a single carboxy-terminal amino acid from specific bioactive oligopeptides, such as Ang-I and Ang-II to form Ang-1-9 and Ang-1-7, respectively (Fig. 1). Unlike ACE, which is a peptidyl dipeptidase removing two carboxy-terminal amino acids from Ang-I and Ang-1-9, ACE2 is not inhibited by typical ACE inhibitors, such as captopril.

    Figure 2
    Figure 2

    A: Block diagram of the hACE2 protein segments and the structure of its soluble domain, which is shed from the full-length hACE2 after cleavage with endopeptidases, such as ADAM17. The cyan segment depicts the location of the endopeptidase cleavage sites. The amino acids at the borders of the segments are shown in black. The structure depicts the locations of zinc (catalytic) and chloride (regulatory) binding sites. The Cl binding site, coordinating a single Cl anion, regulates the efficacy of ACE2 to cleave its substrates (Ang-I and Ang-II). Specifically, ACE2-mediated removal of the terminal leucine from Ang-I is potentiated, whereas the cleavage of the terminal phenylalanine from Ang-II is inhibited in the presence of extracellular chloride anions. The structure of the hACE2 was replotted from pdb ID: 1R42 (50). CD, cytosolic domain; TMD, transmembrane protein. B: The interface of the SARS-CoV-2 virus (brown) and the N-terminal domain of hACE2 (green). The open red circles show the interaction hotspots similar to those identified for the SARS-CoV virus. The catalytic site of hACE2 is visible in the left upper corner. The structure of the hACE2 bound to SARS-CoV-2 receptor binding domain (RBD) was replotted from pdb ID: 6M0J (19).

    The ectodomain of ACE2 can be shed into the systemic circulation as a soluble protein, preserving the catalytic activity of ACE2 (soluble ACE2) and its ability to generate in the circulation the vasoprotective peptide, Ang-1-7. Shedding of the ACE2 ectodomain occurs after proteolytic cleavage by plasma membrane–anchored endopeptidases, enzymes capable of breaking nonterminal peptide bonds, such as a disintegrin and metallopeptidase domain 17 protein (ADAM17) (8) or the type II transmembrane serine proteases (TMPRSS2) (9).

    Human ACE2 (hACE2) is predominantly expressed in the nasal epithelium, airways, lungs, heart, adipose tissue, kidneys, small intestine, and colon (7,1012). The high density of hACE2 is found in human nasal epithelium goblet cells, human ciliated cells of the airways, the type 2 alveolar (AT-2) epithelial cells, and bronchial transient secretory cells (10,11). High hACE2 expression in the nasal epithelium is consistent with clinical observations that symptomatic individuals with COVID-19 present with a higher viral load in the nasal cavity compared with the throat (10) and that some COVID-19 patients complain of inability to smell (13). The hACE2-expressing nasal epithelium may provide an “intermediate site” for viral replication before its invasion of the lungs to cause symptomatic COVID-19 and may serve as a sanctuary niche for SARS-CoV-2 survival without spreading to the lungs in human subjects, thus perhaps permitting asymptomatic human-to-human transmission. Notably, the SARS-CoV-2–positive individuals may shed the virus for up to 37 days (3).

    The ACE2 protein contains two cofactors: Zn2+ and Cl ions (Fig. 2A). The zinc binding site, coordinating Zn2+, is critical for the catalytic activity of ACE2 and consists of H374-E375-X-X-H378 in hACE2. The Cl binding site regulates the efficacy of ACE2 to cleave its substrates (Ang-I and Ang-II) in an extracellular Cl-dependent manner (7).

    The spike proteins of SARS-CoV and SARS-CoV-2 bind the membrane-bound ACE2 to enter the host cells (1416). The interface of the SARS-CoV-2 receptor binding domain located on the S1 subunit of the spike protein and the N-terminal segments of hACE2 was mapped using cryo-EM and X-ray crystallography (Fig. 2B) (1719), and the structure data shed light on the underlying mechanisms. There are several virus binding hotspots on the surface of hACE2 that are critical for virus infectivity; these include hotspot 31 (lysine 31), hotspot 353 (lysine 353), and the hydrophobic interaction site (tyrosine Y83) (17). Compared with SARS-CoV, SARS-CoV-2 forms additional hydrogen bonds, dipole-dipole interactions, and salt bridges (19), suggesting stronger interaction. The affinity binding data indicate that the receptor binding domain of SARS-CoV-2 has a greater affinity to hACE2 compared with that of the SARS-CoV virus (17), potentially explaining the enhanced ability of SARS-CoV-2 to quickly spread and infect a great number of hosts. While membrane-bound hACE2 is the major cellular receptor for SARS-CoV-2 binding and internalization, the soluble form of hACE2 is efficient at preventing the coronaviruses attachment to the membrane-bound hACE2 (20).

    Proteolytic cleavage of the homotrimeric spike protein ectodomains at the S1/S2 subunit junction is critical for entry of coronaviruses into host cells. The ectopeptidase TMPRSS2 and endosomal peptidases cathepsin B/L are the major cellular enzymes that mediate coronavirus “priming” in SARS-CoV-2 (14) by cleaving the spike protein at the S1/S2 cleavage site (IAY↓TMS) (Fig. 3). The SARS-CoV-2 spike protein has an additional canonical furin cleavage site (PRRAR↓SV) located upstream of the conserved IAY↓TMS cleavage site (15,21). This is a unique property of SARS-CoV-2 because the furin site is not present in SARS-CoV (15,21). The presence of a furin-like cleavage site in viral spike-shaped hemagglutinin proteins has been associated with an increased virulence and pathogenicity in avian and human influenza viruses. Consistently, the current pandemic epidemiological data confirm the increased transmissibility and pathogenicity of SARS-CoV-2 as compared with SARS-CoV (22).

    Figure 3
    Figure 3

    Block diagram of the homotrimeric SARS-CoV-2 spike protein assembly. “RBD” stands for receptor binding domain, “FP” stands for fusion peptide, and the IPF block depicts the location of internal fusion peptide. S1 and S2 are two segments of SARS-CoV-2 ectodomain that can be cleaved with the indicated endopeptidases. The cryo-EM structure (15) of the spike protein is shown in the center of the figure. The proteolytic sites are shown in green. In the structure, the residues preceding and following the furin cleavage site are colored in brown. The inset shows a magnifying view of the TMPRSS2/cathepsin cleavage site. The structure of the homotrimeric SARS-CoV-2 spike protein complex was replotted from pdb ID: 6VYB (15). Each spike protein in the homotrimer is color coded for better identification.

    The structure of the SARS-CoV-2 spike protein provides insight on why the addition of the furin cleavage site may increase transmissibility of the virus. According to the structure, the TMPRSS2 cleavage site (IAY↓TMS) is located in a shallow pocket on the lateral surface of the SARS-CoV-2 spike protein (Fig. 3), whereas the short solvent-exposed protein loop harboring the furin-cleavage site (not solved in the structure and shown as the dotted lines in Fig. 3) appears to hang over the TMPRSS2 cleavage site, obstructing access. The newly biosynthesized SARS-CoV-2 viral particles are likely released by budding in a Golgi compartment–dependent manner. Since furin is a Ca2+-dependent endopeptidase, which is present and active only in the Golgi compartment (Fig. 4), the complete cleavage of the furin site is expected in Golgi compartment–processed SARS-CoV-2 spike proteins and is experimentally confirmed (15). Furin-cleaved S1/S2 subunits remain noncovalently bound in the homotrimeric spike protein assembly. It is possible that in the furin precleaved SARS-CoV-2 spike protein, the TMPRSS2 cleavage site is no longer obstructed and is more accessible for TMPRSS2 and/or cathepsins. However, experimental confirmation will be needed for this hypothesis. The SARS-CoV-2 spike protein can be in the closed (folded) or open conformation when the viral receptor binding domain unfolds and extends above the trimeric spike protein structure (Fig. 3). Whether furin cleavage affects the equilibrium between the two spike protein conformations also remains unclear and awaits experimental evidence.

    Figure 4
    Figure 4

    Diagram of the SARS-CoV-2 virus life cycle. SARS-CoV-2 is a member of the Coronaviridae subfamily and belongs to the genus of β-coronaviruses. This is a positive-sense single-stranded RNA virus. SARS-CoV-2 viral RNA serves to code the viral genome and as mRNA for direct protein translation by the host cell ribosomes. Indeed, viral RNA contains a poly-A tail at the 3′ end and a typical mRNA cap structure at the 5′ end. SARS-CoV-2 viral RNA is nonsegmented. Viral RNA genome translation starts with the production of two replicase polyproteins, pp1a and pp1ab, which consist of 11 or 16 covalently linked nonstructural proteins (nsp), respectively. These two large polyproteins are subject to proteolytic cleavage by proteases resulting in the formation of individual nsp1–nsp16. Viral nsp3 functions as a papain-like protease and is important for cleaving the interdomain junctions between nsp1 and nsp4, whereas nsp5 is a chymotrypsin-like protease, which is also named “main protease” because it is responsible for cleaving interdomain junctions between nsp4 and nsp16. Nsp6 can induce small-diameter autophagosome formation in infected cells. Nsp12 (RdRp) is an RNA-dependent RNA polymerase, which is critical for a large-scale replication of viral RNA. Nsp12 requires several cofactors, such as nsp7 and nsp8. The RNA helicase nsp13 (Hel) is important for replication. Nsp14 is a viral N7-methyltransferase ensuring the fidelity of replication. The viral RNA also encodes four structural proteins: the spike protein (S), envelop protein (E), membrane protein (M), and nucleocapsid protein (N). In SARS-CoV-2 virions, viral RNA is enveloped with a membrane that is stabilized by the imbedded structural proteins, including S, E, M, and N proteins. The S or spike protein is a homotrimer that gives the viral particles a characteristic appearance of spiky corona. The S protein is critical for the viral entry into the host cells. The S1 subunit of the SARS-CoV-2 spike protein utilizes the hACE2 protein as its cellular receptor. The TMPRSS2 protein is the key endopeptidase that is important for priming the spike protein of SARS-CoV-2, allowing viral entry into host cells. Cathepsin B/L is an endosomal protease that can substitute TMPRSS2 activity during spike protein priming before viral RNA gains access into the cellular cytosolic compartments. SARS-CoV-2 replication takes place in double membrane vesicles (DMV) that are associated with the specific areas of the rough endoplasmic reticulum or other intracellular membranes, including autophagosomal membranes. The M, E, and N structural proteins together with the S protein are important for formation and stabilization of the SARS-CoV-2 viral particles. Viral structural protein modification takes place in the Golgi compartment before viral particles are ready for budding. Furin is a Ca2+-dependent endopeptidase enriched in the Golgi compartments that precleaves the spike protein at a specific cleavage site in the Golgi compartments, with S1 and S2 subunits remaining noncovalently bound in budding virions. ADAM17 proteolytic activity generates soluble hACE2.

    As COVID-19 progresses, SARS-CoV-2 may also involve the lytic release pathway for newly produced viral particles, bypassing the budding process utilizing the furin-containing Golgi compartments (Fig. 4). In such cases, the spike protein of SARS-CoV-2 may remain at least partially uncleaved by intracellular furin. At this stage of COVID-19, extracellular furin may be utilized to complete the cleavage of spike protein’s furin cleavage sites, facilitating the virus spread in the infected host. Notably, circulating levels of furin are elevated in patients with diabetes (23), and patients with diabetes infected with SARS-CoV-2 present with increased mortality (4) and delayed recovery from SARS-CoV-2 infection. Also, individuals with high plasma furin concentration typically have a pronounced dysmetabolic phenotype and elevated risk of diabetes.

    RAS Modulates Autophagy

    There is increasing evidence that dysregulated autophagy contributes to the pathogenesis of diabetes and its complications. Autophagy is primarily recognized for its essential role in cellular housekeeping and homeostasis through the sequestration and transfer of intracellular components to lysosomes for degradation. However, the endocytic pathway and autophagy are key processes affecting virus infection and replication, including the coronavirus family (24). Viral RNA replication in coronavirus-infected cells occurs in double membrane vesicles that resemble autophagosomes (Fig. 4). Additionally, nonstructural protein 6 (nsp6) of SARS-CoV-2 can generate autophagosomes, and an associated mutation in nsp6 is identified in COVID-19 patients (4,24). Interestingly, inhibition of the canonical autophagy pathway, using in vitro approaches, does not appear to have an effect on SARS-CoV replication, suggesting a noncanonical process. However, a key autophagy protein, LC3, colocalizes with viral replication-transcription complexes, and an S-phase kinase-associated protein 2 (SKP2) reduces autophagy protein Beclin1 levels in coronavirus infections (24,25). In both cases, fusion between autophagosomes and lysosomes is blocked, leading to an accumulation of autophagosomes favoring replication of the virus. Inhibiting SKP2 or enhancing autophagy flux has been shown to reduce the replication of coronaviruses (24,25). RAS can be an important regulator of autophagy. Ang-II activation of angiotensin type 2 receptor (AT2R) attenuates autophagy, whereas Ang-II activation of AT1R induces autophagy through AMPK/mTOR signaling. Ang-1-7 induces autophagy via the cofilin receptor (26). Activation of intestinal RAS promotes Paneth cell autophagy leading to bowel inflammation and arrested release of antimicrobial factors including defensin 5, which inhibits SARS-CoV-2 infection by cloaking ACE2 (27). Given the strong association between the RAS and autophagy, both may serve as therapeutic targets to ablate SARS-CoV-2 infection and replication, and this may further explain the possible beneficial effects of ACE inhibitors/ATR blockers in the treatment of COVID-19, discussed further below.

    A Dysregulated RAS May Increase Adverse Outcomes in Individuals Infected With SARS-CoV-2

    Several mechanisms may contribute to increased severity of COVID-19 progression in subjects with diabetes. Individuals with diabetes are more vulnerable to most infections and may exhibit decreased viral clearance due to reduced neutrophil chemotaxis, phagocytosis, and intracellular killing of microbes. Under noninfectious conditions, chronic diabetes in both human and rodent models was associated with myeloidosis (7), with monocytes expressing higher levels of proinflammatory cytokines that may, in patients with acute respiratory distress syndrome (ARDS), contribute to cytokine storm.

    Once bound to ACE2, SARS-CoV was shown to downregulate cellular expression of ACE2, and the unopposed action of Ang-II was deemed responsible for worsening lung injury (28). Whether this is the case with SARS-CoV-2 is not known. Ang-II receptor blockers, ACE inhibitors, thiazolidinediones, incretin GLP-1 agonists, and statins are typical medications for diabetes that are known to increase ACE2 expression. Lack of evidence regarding the risk or benefit of ACE inhibitors and angiotensin receptor blockers (ARBs) has resulted in the American College of Cardiology, American Heart Association, American Society of Hypertension, and European Heart Association recommendations that patients should continue treatment with their usual antihypertensive therapy (29). However, we would propose that drug-induced increases in ACE2 expression would potentially be beneficial in subjects with diabetes by increasing Ang-1-7 and shifting the RAS axis away from the profibrotic, proinflammatory arm of RAS. Thus, in subjects with diabetes, infection with SARS-CoV-2 would potentially result in additional loss of ACE2 expression in blood vessels and could exacerbate the already compromised vasculature (29).

    Implications of COVID-19 Infection on Bone Marrow Dysfunction and Increasing Severity of Diabetic Vascular Complications

    The existence of specific RAS systems in organs including the bone marrow has been well established. Local RAS is active in primitive embryonic hematopoiesis (30) and continues to regulate each stage of physiological and pathological blood cell production in the adult via autocrine, paracrine, and intracrine pathways. Local RAS peptides directly regulate myelopoiesis, erythropoiesis, thrombopoiesis, and the development of other cellular lineages (31).

    The bone marrow plays a critical role in the pathogenesis of diabetic complications. Individuals with diabetes with vascular complications typically have reduced numbers and migratory function of bone marrow–derived vascular reparative cells, called circulating angiogenic cells (CACs or CD34+ cells). Ang-1-7 improved migration, restored bioavailable nitric oxide, and reduced reactive oxygen species in diabetic CACs. Ang-1-7 gene modification of CACs restored the cells in vivo vasoreparative function (32). A unique set of individuals with diabetes that remained free of microvascular complications, despite >40 years of poor glycemic control, had higher mRNA levels for ACE2 and MasR in their CACs compared with age-, sex-, and glycemia-matched individuals with diabetes with microvascular complications (32). In Akita mice, global loss of ACE2 (ACE2−/y–Akita mice) was associated with a reduction of hematopoietic stem/progenitor cells (HS/PC), a shift of hematopoiesis toward myelopoiesis in bone marrow, and an impairment of HS/PC migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to Ang-1-7 (33). These data support that activation of the protective RAS is beneficial for the dysfunctional diabetic bone marrow.

    Diabetes-associated bone marrow dysfunction and loss of vascular reparative cells, such as CACs, may contribute to vascular dysfunction in COVID-19 patients that can be manifested as cardiac disease including arrhythmias, viral myocarditis, heart failure, and cardiac arrest (3436). The impact of global loss of ACE2 in cardiac dysfunction is supported by preclinical studies showing that hearts from Akita mice exhibit marked systolic dysfunction and that ACE2−/y-Akita mice show impaired flow-mediated dilation of the femoral artery in response to ischemia/reperfusion injury, indicative of endothelial dysfunction. In contrast, gain-of-function studies using ACE2 overexpression, via adenoviral gene delivery, in type 1 diabetic rats decreased collagen accumulation and improved left ventricular remodeling and function (7).

    The impact of dysregulated RAS is seen in obesity and type 2 diabetes models. Heart failure with preserved ejection fraction (HFpEF) is a proinflammatory state closely linked to obesity-related cardiovascular dysfunction. Loss of ACE2 increases epicardial adipose tissue macrophage polarization to proinflammatory M1-like phenotype and worsens HFpEF in response to diet-induced obesity. Ang-1-7 has potent anti-inflammatory effects in adipose tissue of obese type 2 diabetic mice and protects against diabetic cardiomyopathy and nephropathy. Importantly, Ang-1-7 decreased macrophage M1 polarization and preserved cardiac function in diet-induced obese ACE2 knockout mice (7).

    In COVID-19 patients, the prevalence of kidney disease on admission and the development of acute kidney injury during hospitalization is high and associated with in-hospital mortality (37). Patients with diabetes with nephropathy have reduced ACE2. Global loss of ACE2 exacerbates diabetic kidney injury while potentiating Ang-II–mediated cardiorenal fibrosis and oxidative stress in the heart and kidney (7). In Akita mice, recombinant hACE2 (rhACE2) treatment for 4 weeks resulted in decreased glomerular mesangial matrix expansion, which was associated with increased Ang-1-7 levels and lowered Ang-II levels, along with reduced NADPH oxidase activity. The loss of ACE2 via ADAM17 proteolytic cleavage, which is strongly activated in COVID-19 patients, will likely promote further injury to the cardiovascular system and kidneys in patients with diabetes (7,38). Importantly, ACE2 overexpression increases the antihypertensive components of the RAS and pretreatment with rhACE2 prevents Ang-II–induced hypertension in preclinical experimental models. However, these results have yet to be validated in human hypertension.

    While the lung is not considered a target tissue for diabetic complications, COVID-19 patients with diabetes experience worse pulmonary disease than those without diabetes. ACE2 knockout mice exhibit ARDS pathology. ARDS triggers multiple pulmonary diseases and is observed in COVID-19 patients. Importantly, ACE deficiency or treatment with AT1R blockers of ACE2−/y mice rescues them from ARDS (38). Taken together, these studies support that in individuals with diabetes with vascular complications, the loss of the protective RAS would serve to intensify SARS-CoV-2–induced pathology.

    SARS-CoV-2 Hijacks Gastrointestinal ACE2, Local RAS, and Transporters

    The recent demonstration of SARS-CoV-2 actively infecting human enterocytes and the mounting gastrointestinal symptomology implicate gastrointestinal tract pathophysiology in COVID-19 infection (12,39). The digestive system possesses the body’s site of greatest relative expression of ACE2, which in the gut exists as a tetramer with B0AT1 (Fig. 5). While B0AT1 is not expressed in lung pneumocytes, ACE2:B0AT1 complex in the gut acts as a central player in local gut RAS and regulates uptake of glucose, sodium, water, and amino acids (4042). However, ACE2:B0AT1 complex internalization by SARS-CoV-2 (Fig. 6) destabilizes the gastrointestinal tract’s role in diabetes and blood pressure regulation (Fig. 7).

    Figure 5
    Figure 5

    Atomic structure of human B0AT1/ACE2 ternary complex bound to spike protein region of SARS-CoV-2. A: The complex comprises a dimer of heterodimers formed by two B0AT1 subunits (red) contacting with two ACE2 subunits (green), with each ACE2 interfacing with a single SARS-CoV-2 spike (brown). The complex was stabilized using Na+ cotransporter B0AT1 transport substrate leucine within the center membrane-spanning domain, known to serve tryptophan, glutamine, and other neutral amino acids in addition to leucine. Intestinal apical membranes express the B0AT1:ACE2 complex, which does not occur in lung pneumocytes (40). B: Side view showing charged moiety interactions in the extracellular region of the gut lumen (top inset) and also hydrophobic interactions of B0AT1 TM3 and TM4 interacting with the single long transmembrane domain of ACE2 within the apical membrane (bottom inset). Data coordinates were obtained from pdb ID: 6M17 (18).

    Figure 6
    Figure 6

    Intestinal epithelial cell RAS and B0AT1 govern glucose, sodium, and inflammation. All RAS components are recapitulated locally in the gut (41). Luminal agonist and antagonist bioactive peptides are derived from interactions of gut digestive enzymes intertwined with microbiome metabolism. Oral ARBs and ACE inhibitor drugs impact gut RAS. Gut RAS governs sodium and glucose uptake via NHE3, SGLT1, and GLUT2. The ACE2:B0AT1 complex dimer of heterodimers (18) serves the Na+-coupled transport of neutral amino acids, including tryptophan. In enteroendocrine L cells, basolateral tryptophan stimulates GLP-1 and GIP secretion. These incretins maintain gut tight junctions, preventing dysbiosis, stimulate pancreatic β-cells, and blunt α-cells, thereby modulating plasma glucose levels. SARS-CoV-2 binding to ACE2 disrupts this homeostasis.

    Figure 7
    Figure 7

    Dysregulated RAS in lung and gut epithelium of individuals with diabetes with COVID-19. ACE2, a pleiotropic regulator of the RAS, is hijacked as a receptor for SARS-CoV-2 to promote viral infection. Loss of ACE2 indirectly via proteolytic processing, autophagy, and ADAM17-mediated shedding (not shown) partly drives not only lung but also gut disease in individuals with diabetes with COVID-19. SARS-CoV-2 S1 binding to ACE2 initiates internalization of ACE2:B0AT1 complex (gut) or ACE2 (outside of gut). Thus, SARS-CoV-2 by downregulating intestinal ACE2-B0AT1 would promote leaky gut syndrome with elevated plasma bacterial lipopolysaccharides and/or peptidoglycans enhancing systemic inflammation. In the lung, virus internalization also promotes a reduction in ACE2 that results in pulmonary pathology. Careful targeting of the RAS axis will likely optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2. WBC, white blood cell.

    B0AT1 (SLC6A19) is the intestine’s primary epithelial apical membrane transporter serving Na+-coupled uptake of neutral amino acids, such as tryptophan. B0AT1 was originally discovered and functionally characterized by Stevens et al. (43), and the transporter was initially named NBB, B, B0, or B(0) in the literature but was subsequently called B0AT1. ACE2 chaperones the trafficking of B0AT1 to form the stabilized dimer of ACE2:B0AT1 (18) in the apical membrane (Fig. 5). Importantly, B0AT1 substrates, notably tryptophan and glutamine, signal downregulation of lymphoid proinflammatory cytokines, promote tight junction formation, activate the release of antimicrobial peptides, and modulate mucosal cell autophagy as defense mechanisms. In the models shown in Figs. 6 and 7, binding of SARS-CoV-2 S1 to ACE2 (18) (Fig. 6) results in downregulating both intestinal ACE2 and B0AT1, with consequences of disrupting sodium and glucose transport, promoting leaky gut syndrome, elevating plasma bacterial lipopolysaccharide, and enhancing inflammation (Figs. 5 and 7).

    Intestine, lumen-facing ACE, and ACE2 participate in the food digestion process but are also intertwined in cross talk with gut microbiome metametabolomics of bioactive peptides. Such peptides include a balance of agonists and antagonists of enterocyte apical membrane MasR and AT1R, which are physiologically tasked with regulating uptake of dietary Na+ via NHE3 and glucose absorption via SGLT1 and GLUT2 (Fig. 6).

    SARS-CoV-2 Modulation of Insulin and Glucose

    Intestinal ACE2:B0AT1 dimer of heterodimers promotes enterocyte Na+-coupled uptake of phenylalanine, glutamine, tryptophan and its microbiome-generated metabolites, and other neutral amino acid agonists of nutrient-sensing receptors. These stimulate release of GLP-1 and GIP into the blood from gut mucosal enteroendocrine L cells (Fig. 6) (44). These incretins circulate to activate pancreatic β-cells, suppress α-cells, and afford brain satiety. SARS-CoV-2 infection of gut mucosa results in endocytosis of apical ACE2, thereby downregulating its activity (45), resulting in gut luminal accumulation of AT1R agonist peptides and disrupting all functions of B0AT1.

    Gut–Bone Marrow Connection in Individuals With Diabetes Infected With COVID-19

    The dysregulated RAS in the bone marrow with its accompanying myeloidosis promotes chronic inflammation that can contribute to both lung and gut pathology (Fig. 7). An extensive literature supports the concept of communication between the gut and bone marrow. The gut microbiota is a critical extrinsic regulator of hematopoiesis (46), as very low concentrations of microbial antigens set the size of the bone marrow myeloid cell pool, and the size of this pool correlates strongly with the complexity of the intestinal microbiota. In turn, bone marrow cells migrate to the gut and impact gut function via changes in blood flow, gut immunity, and epithelial and endothelial tight junction integrity. Recruitment of bone marrow–derived immune cell to the gut is necessary for host defense and contributes to inflammation resolution and tissue healing. Loss of ACE2 in diabetes results in phylogenetic differences in the gut bacterial community composition with increases in bacteria that have been associated with peptidoglycan generation, which promotes systemic inflammation (47). Overactivation of bone marrow–derived immune cells including proinflammatory monocytes results in secretion of a large number of harmful cytokines into the circulation that promotes insulin resistance. In the patient with diabetes infected with COVID-19, developing pneumonia can be devastating, as preexisting systemic inflammation can rapidly lead to multiple organ failure. Inflammatory cytokine storm is a notable cause of death in critically ill COVID-19 patients and may be driven as much by gut-induced inflammation as lung injury. Thus, imbalance in the bone marrow RAS system (Fig. 7) may represent a central mechanism to not only initiate but also propagate lung and gut injury.

    Possible Therapeutics That Modulate RAS

    From the perspective of gut enterocyte local RAS, orally delivered ACE inhibitors upregulate expression of both intestinal ACE2 and B0AT1 with their attending nutrient-signaled release of GLP-1, GIP, and mucosal antimicrobial peptides (40) (Fig. 6). In a preclinical colitis model, the ARB irbesartan restored intestinal B0AT1 and ACE2 expression and tryptophan homeostasis with concurrent reduction of intestinal inflammasome activity through an mTOR S6 kinase pathway (48). Irbesartan further shifted the gut microbiota composition toward favorable taxa and away from stress-related dysbiosis (48). Activation of enterocyte AT1R signaled apoptosis with reduced mucosal villus height, while losartan-mediated blockage of gut AT1R resulted in increased mucosal cell proliferation and reduced apoptosis.

    Increasing gut ACE2 by engineering probiotic species such as Lactobacillus paracasei (LP) to express this recombinant protein was a strategy used to prevent microvascular complications in diabetic mice. LP expressing the secretable ACE2 fused with the nontoxic subunit B of cholera toxin (which acts as a carrier to facilitate transmucosal transport), showed increased ACE2 activities in serum and tissues, and reduced diabetic complications (49). These results provide proof of concept for feasibility of using engineered probiotic species as a live vector for delivery of decoy hACE2 for possible treatment of enteric COVID-19 infection.

    rhACE2 given as intravenous medication may be explored as beneficial to COVID-19 patients with pulmonary complication, as it increases pulmonary blood flow and oxygenation in a pig model of lipopolysaccharide-induced ARDS. Supplementation with ACE2 or inhibition of Ang-II improves outcomes in acute lung injury. A pilot trial demonstrated that rhACE2 is well-tolerated in ARDS patients and showed the anticipated changes in RAS peptides. Taken together, evidence unequivocally supports the concept that ACE2 is critical in pulmonary function and its imbalance in COVID-19 infection contributes to the devastating lung consequences.

    An ACE2 activator, diminazene aceturate (DIZE) is a known antiprotozoal drug used in humans, but it has additional benefits including potent anti-inflammatory and antifibrotic activity. DIZE has been used in type 1 diabetes to prevent nephropathy and gastric inflammation. DIZE modulated the RAS by reducing serum Ang-II and the expression of AT1R, but it increased Ang-1-7 (7). DIZE not only increased ACE2 activity but also increased the expression of ACE2 in select cell types where DIZE inhibited the expression of IL-6, IL-8, and MCP-1 at both mRNA and protein levels following stimulation with lipopolysaccharide. Collectively, these results show that DIZE downregulates proinflammatory cytokine production by many distinct cell types and suggest that this drug may provide benefit to COVID-19 patients by reducing pulmonary inflammation and fibrosis, gut inflammation, and cytokine storm.

    Conclusion

    As the global pandemic unfolds and rapidly spreads, there is an urgent need for basic and clinical studies to address the many unanswered questions posed by COVID-19. This Perspective has directed attention to the disruption of RAS in the lung, gastrointestinal tract, and bone marrow as possible mechanisms of SARS-CoV-2 disease pathogenesis. The dysregulated RAS can potentially impact clinical outcomes in individuals with diabetes resulting in increased morbidity and mortality. ACE2 has emerged as the pleiotropic regulator of the RAS, by metabolizing Ang-II into the beneficial peptide Ang-1-7, while being harmful as the SARS-CoV-2 receptor. Loss of ACE2 indirectly via proteolytic processing, autophagy, and shedding partly could not only drive lung pathology but also gut disease in individuals with diabetes infected with COVID-19. SARS-CoV-2, by downregulating intestinal ACE2-B0AT1, could promote leaky gut syndrome with elevated plasma bacterial lipopolysaccharides and/or peptidoglycans enhancing systemic inflammation. Careful targeting of the RAS axis may represent a strategy for improving clinical outcomes in subjects with diabetes infected with COVID-19.



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    Eggplant Zucchini Bake – Diabetic Foodie

    By electricdiet / May 1, 2021


    This eggplant zucchini bake is inspired by eggplant parmigiana. Dig in to layers of crispy veggies, hearty tomato sauce with turkey, and delicious melty cheese!

    Eggplant Zucchini Bake on a white plate on marble table

    Do you ever get so excited by all the fresh produce at the store or farmers’ market, then get home and realize you bought way too much?

    We can’t let all those tasty veggies go to waste. So when I found myself craving eggplant parmigiana, I decided to make this eggplant zucchini bake using zucchini slices in place of the noodles!

    The tomato sauce for this dish includes ground turkey because I wanted to add some lean protein. If you prefer a meatless dish, feel free to leave it out.

    This bake is packed with tasty veggies in a hearty sauce, then topped with delicious melted cheese for a low carb twist on eggplant parmigiana. What better way to use up your produce?

    How to make eggplant zucchini bake

    This tasty bake is such a great way to add more veggies to your weekly menu. Here is what you need:

    All the ingredients for the recipe laid out on a marble surface

    And here’s how the recipe comes together:

    Step 1: Slice the eggplant into rounds and place them on a platter in a single layer with minimal overlap.

    Eggplant rounds on a platter being sprinkled with salt

    Step 2: Sprinkle with kosher salt, place another platter on top of the eggplant slices, then add something with a bit of weight (like a cast iron pan) on top. Let the slices sit for 30 minutes to an hour.

    Step 3: Meanwhile, cook the ground turkey in a skillet over medium heat. Once browned, remove the turkey to a plate lined with paper towels and wipe out the skillet.

    Step 4: Return the turkey to the skillet over medium heat, then add the tomato sauce and oregano leaves. Once the sauce is heated through, turn off the heat.

    Turkey and tomato sauce in a skillet

    Step 5: Remove the weighted item and platter from the eggplant slices, then drain off the liquid that has accumulated in the bottom platter. Rinse the eggplant and pat dry.

    Step 6: Heat the oil in a large skillet. One hot, add as many eggplant slices as you can fit in one layer and cook for 2-3 minutes per side until golden. Transfer the eggplant slices to paper towels to drain.

    Eggplant slices being cooked in a skillet

    Step 7: Repeat until all the eggplant slices are cooked.

    Step 8: Preheat the oven to 375°F. Place a few tablespoons of the tomato and ground turkey sauce in the bottom of a 13 x 9-inch baking dish.

    Step 9: Layer in half of the eggplant and half of the zucchini, then spread about half of the remaining tomato and ground turkey sauce on the vegetables.

    Eggplant zucchini bake being assembled

    Step 10: Tear the basil leaves and sprinkle half of them on top of the sauce, then cover with half of the mozzarella and half of the Parmesan.

    Step 11: Repeat the layers.

    Eggplant bake ready to go in the oven

    Step 12: Place in the oven and bake for 25-30 minutes until the cheese has melted.

    Finished dish after coming out of the oven

    Cut your pasta-free eggplant parmigiana into six slices and serve!

    Reducing the fat

    This vegetable bake is a bit higher in fat than the majority of my recipes. This is mostly due to the oil used to fry the eggplant slices.

    If you want to reduce the fat, you have a few options. First, you could use the eggplant raw instead of fried. Make sure you still extract the moisture from the eggplant so it gets nice and crispy while baking!

    If you have an air fryer, you could use that to crisp up the eggplant instead. An air fryer uses much less oil, which will reduce the fat content.

    Finally, you could cut back on the amount of cheese or only use it on the top layer.

    Plate of eggplant zucchini bake next to the baking dish, seen from above

    Storage

    If you have any leftovers of your eggplant bake, you can store them covered in the refrigerator for 3-4 days.

    Before reheating, be sure to cut your dish into slices so they’ll be easier to heat all the way through.

    The finished dish seen from above

    Other delicious eggplant recipes

    Looking for more ways to add some eggplant to your weekly menu? Here are a few of my favorite ways to use up this fresh ingredient:

    When you’ve tried this bake, please don’t forget to let me know how you liked it and rate the recipe in the comments below!

    Recipe Card

    Eggplant Zucchini Bake on a white plate on marble table

    Eggplant Zucchini Bake

    This eggplant zucchini bake is inspired by eggplant parmigiana. Dig in to layers of crispy veggies, hearty tomato sauce with turkey, and delicious melty cheese!

    Prep Time:40 minutes

    Cook Time:30 minutes

    Total Time:1 hour 10 minutes

    Author:Diabetic Foodie

    Servings:6

    Instructions

    • Slice the eggplant into rounds and place them on a platter in a single layer with minimal overlap.

    • Sprinkle with kosher salt, place another platter on top of the eggplant slices, then add something with a bit of weight (like a cast iron pan) on top. Let the slices sit for 30 minutes to an hour.

    • Meanwhile, cook the ground turkey in a skillet over medium heat. Once browned, remove the turkey to a plate lined with paper towels and wipe out the skillet.

    • Return the turkey to the skillet over medium heat, then add the tomato sauce and oregano leaves. Once the sauce is heated through, turn off the heat.

    • Remove the weighted item and platter from the eggplant slices, then drain off the liquid that has accumulated in the bottom platter. Rinse the eggplant and pat dry.

    • Heat the oil in a large skillet. One hot, add as many eggplant slices as you can fit in one layer and cook for 2-3 minutes per side until golden. Transfer the eggplant slices to paper towels to drain.

    • Repeat until all the eggplant slices are cooked.

    • Preheat the oven to 375°F. Place a few tablespoons of the tomato and ground turkey sauce in the bottom of a 13 x 9-inch baking dish.

    • Layer in half of the eggplant and half of the zucchini, then spread about half of the remaining tomato and ground turkey sauce on the vegetables.

    • Tear the basil leaves and sprinkle half of them on top of the sauce, then cover with half of the mozzarella and half of the Parmesan.

    • Repeat the layers.

    • Place in the oven and bake for 25-30 minutes until the cheese has melted.

    Recipe Notes

    This recipe is for 6 servings of eggplant and zucchini bake.
    To reduce the fat, cook the eggplant rounds in an air fryer or leave them raw. You could also reduce the amount of cheese used.
    Leftovers can be stored covered in the refrigerator for 3-4 days.

    Nutrition Info Per Serving

    Nutrition Facts

    Eggplant Zucchini Bake

    Amount Per Serving (1 slice)

    Calories 318
    Calories from Fat 193

    % Daily Value*

    Fat 21.4g33%

    Saturated Fat 5.2g33%

    Trans Fat 0g

    Polyunsaturated Fat 7.7g

    Monounsaturated Fat 4g

    Cholesterol 65.4mg22%

    Sodium 454.2mg20%

    Potassium 501.2mg14%

    Carbohydrates 10.1g3%

    Fiber 1.3g5%

    Sugar 5.7g6%

    Protein 24.7g49%

    Vitamin A 0IU0%

    Vitamin C 0mg0%

    Calcium 0mg0%

    Iron 0mg0%

    Net carbs 8.8g

    * Percent Daily Values are based on a 2000 calorie diet.

    Course: Main Course

    Cuisine: Italian

    Diet: Diabetic

    Keyword: easy dinner recipes, eggplant zucchini bake



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    Pasta with Zucchini and Corn

    By electricdiet / April 29, 2021






    Pasta with Zucchini and Corn – My Bizzy Kitchen







































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    Keto Cheese Crackers | Diabetes Strong

    By electricdiet / April 27, 2021


    Looking for an easy snack you can enjoy with your favorite dip? These keto cheese crackers are simple to whip up for an oh-so-satisfying crunch!

    Crackers on a white serving tray next to a ramekin of dip

    I love snacks that pack in a good crunch. They’re a great way to tide me over between meals.

    These keto cheese crackers are one of my favorite options when it comes to crispy, delicious little bites! They remind me of Cheez-Its, but with a hint of rosemary that really takes them to the next level.

    Best of all, they’re so easy to make! You just melt together the cheese and the flour, add the egg and spices, roll out the dough, cut into squares, and throw it in the oven.

    25 minutes later, you’ll have crispy, crunchy, cheesy crackers ready for all your snacking needs! They’re perfect for dipping, making low-carb platters, or enjoying all on their own.

    If low-carb, grown-up Cheez-Its sounds like something you’d enjoy, I highly recommend you whip up a batch. You’ll love having them on-hand!

    How to make keto cheese crackers

    This simple recipe comes together in just 10 easy steps.

    Recipe ingredients separated into individual bowls, as seen from above

    Step 1: Preheat the oven to 425°F (220°C) and cut two sheets of baking paper to about 18in x 13in (46cm x 33cm).

    Step 2: In a large microwave-safe bowl, add the cream cheese, parmesan, mozzarella, and almond flour.

    Step 3: Cook in the microwave in 30-second increments, stirring between each one, until the mixture is melted and very soft. Remove from the microwave and mix until smooth.

    Step 4: Add the egg, rosemary, onion powder, garlic powder, and sea salt. Mix well and shape into a rough ball.

    Batter mixed together in a large glass bowl with a wooden spoon

    Step 5: While the dough is still warm, place it in the middle of one sheet of baking paper. Lay the other sheet on top, then roll out the dough evenly to the edges of the sheet.

    Dough rolled out in an even layer on a piece of parchment paper

    Step 6: Remove the top sheet of baking paper and transfer the dough to a large baking sheet. Trim any rough edges or overhanging dough.

    Step 7: Using a pie crust cutter, cut the dough into 1in x 1in squares. If using, sprinkle coarse sea salt on top.

    Dough cut into squares on a baking sheet

    Step 8: Bake the crackers for 25 minutes, checking them at 20 minutes to make sure they aren’t getting too dark. If they’re browning too much, cover with a sheet of foil for the rest of the baking time.

    Step 9: Remove from the oven and allow to cool for 10 minutes on the baking tray.

    Finished crackers cooling on the baking sheet

    Step 10: Use a spatula to transfer the crackers to a wire cooling rack to finish cooling.

    That’s it! Once the crackers have reached room temperature, you can break them apart and serve.

    Close-up of crackers on a white serving platter

    What to serve with low-carb crackers

    These cheesy bites are great all on their own whenever you’re looking for a crunchy bite. But they’re also wonderful to serve as part of a larger tray or platter!

    If you’re a fan of meat and cheese boards, why not include low-carb crackers that are also made of cheese? You can slather on soft cheeses, layer on hard cheeses, and throw in some salami or prosciutto to top it all off.

    These crackers are also excellent for dipping. I love serving them with a simple sour cream and onion, but they’d also be great with salsa or guacamole.

    Of course, you can always serve them alongside your lunch or dinner when you just want to add some crunch to your meal. They’ll go perfectly with dishes like low-carb beanless chili or keto tuna salad!

    Storage

    Because these crackers are made with cheese, they are perishable. You’ll want to store them in an airtight container in the refrigerator, where they’ll stay fresh for up to 3 days.

    When you’re ready to enjoy, feel free to let them sit out for 20 minutes or so to come up to room temperature. You can also eat them chilled straight from the fridge.

    Crackers on a white serving tray next to a ramekin of dip

    Other keto-friendly snack recipes

    Looking for more low-carb snacks to hold you over between meals? There are so many tasty options! Here are a few of my favorite recipes I know you’ll love:

    You can also check out my roundup of 10 delicious keto fat bomb recipes for even more low-carb inspiration!

    When you’ve tried this recipe, please don’t forget to let me know how you liked it and rate the recipe in the comments below!

    Recipe Card

    Keto Cheese Crackers

    Looking for an easy snack you can enjoy with your favorite dip? These keto cheese crackers are simple to whip up for an oh-so-satisfying crunch!

    Prep Time:10 minutes

    Cook Time:25 minutes

    Cooling Time:10 minutes

    Total Time:45 minutes

    Servings:25

    Keto cheese crackers on a white serving tray next to a ramekin of dip

    Instructions

    • Preheat the oven to 425°F (220°C) and cut two sheets of baking paper to about 18in x 13in (46cm x 33cm).

    • In a large microwave-safe bowl, add the cream cheese, parmesan, mozzarella, and almond flour.

    • Cook in the microwave in 30-second increments, stirring between each one, until the mixture is melted and very soft. Remove from the microwave and mix until smooth.

    • Add the egg, rosemary, onion powder, garlic powder, and sea salt. Mix well and shape into a rough ball.

    • While the dough is still warm, place it in the middle of one sheet of baking paper. Lay the other sheet on top, then roll out the dough evenly to the edges of the sheet.

    • Remove the top sheet of baking paper and transfer the dough to a large baking sheet. Trim any rough edges or overhanging dough.

    • Using a pie crust cutter, cut the dough into 1in x 1in squares. If using, sprinkle coarse sea salt on top.

    • Bake the crackers for 25 minutes, checking them at 20 minutes to make sure they aren’t getting too dark. If they’re browning too much, cover with a sheet of foil for the rest of the baking time.

    • Remove from the oven and allow to cool for 10 minutes on the baking tray.

    • Use a spatula to transfer the crackers to a wire cooling rack to finish cooling.

    Recipe Notes

    This recipe is for 25 servings. If you cut the dough into 50 crackers, each serving will be 2 crackers.
    These crackers should be stored in an airtight container in the refrigerator.
    Enjoy within 3 days.

    Nutrition Info Per Serving

    Nutrition Facts

    Keto Cheese Crackers

    Amount Per Serving (2 crackers)

    Calories 41
    Calories from Fat 30

    % Daily Value*

    Fat 3.3g5%

    Saturated Fat 1.5g8%

    Trans Fat 0g

    Polyunsaturated Fat 0.1g

    Monounsaturated Fat 0.6g

    Cholesterol 14mg5%

    Sodium 95.5mg4%

    Potassium 14.5mg0%

    Carbohydrates 1.1g0%

    Fiber 0.3g1%

    Sugar 0.2g0%

    Protein 2.2g4%

    Net carbs 0.8g

    * Percent Daily Values are based on a 2000 calorie diet.

    Course: Appetizer, Snack

    Cuisine: American

    Diet: Diabetic, Gluten Free

    Keyword: gluten-free, Keto cheese crackers, low carb



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    Easy Chicken Lettuce Wraps Recipe – Quick Chicken Dinner with Pizzaz

    By electricdiet / April 25, 2021


    Type 2 Diabetes and Easy Chicken Lettuce Wraps Recipe

    These easy Chicken Lettuce Wraps recipe from Holly Clegg’s KITCHEN 101 cookbook makes a great diabetic chicken dinner! Did you know that 8% of our population has diabetes and 6.2 million people are unaware they have the disease? With Team Holly, even these healthiest recipes are delicious. If you have diabetes, don’t fret as we promise, with these easy, delicious recipes, you won’t feel deprived, you will feel fortunate that you can eat healthier, enjoy all your favorite foods, and feel better! One of Holly’s favorite ever email was from a gentleman who said, “I wish the word diabetes wasn’t on the cover of a book, so more people would use the book.” After that, Holly created KITCHEN 101 and Eating Well to Fight Arthritis cookbook both with a “D” throughout the book to indicate diabetic-friendly recipes!

    Chicken Stir Fry Lettuce Wraps

    Chicken Stir-Fry Lettuce Wraps
    Fast and fantastic, this enjoyable light meal of  easy chicken lettuce wraps recipe with Asian flavors comes together easily with cooked chicken, bell pepper, edamame and sweet mango with a super sauce.

      Servings8 wraps

      Ingredients

      • 1


        onionhalved and thinly sliced

      • 1


        red bell pepperseeded and thinly sliced

      • 1teaspoon


        minced garlic

      • 1 1/2teaspoons


        grated fresh ginger



      • Hearty dash red pepper flakes

      • 1/2cup


        shelled edamame

      • 1tablespoon


        low sodium soy sauce

      • 3tablespoons


        seasoned rice vinegarI love the garlic flavored kind!

      • 1tablespoon


        teaspoon cornstarchmixed with 1water

      • 2cups


        chopped skinless rotisserie chicken breast

      • 1cup


        chopped mango

      • 2tablespoons


        chopped peanuts



      • Boston or red tip lettuce leaves



      • hoisin sauceoptional

      Instructions
      1. In large nonstick skillet, sauté onion and bell pepper, cooking until onion is almost tender, about 5 minutes.

      2. Add garlic, ginger, red pepper flakes and edamame; stirring, about 1 minute.

      3. Stir in soy sauce, vinegar, and cornstarch mixture, heating mixture until thickens.

      4. Remove from heat and add chicken, mango and peanuts. Spoon mixture onto lettuce and wrap. Serve with hoisin sauce, if desired.

      Recipe Notes

      Per Serving: Calories 104 kcal Calories from Fat 24% Fat 3 g Saturated Fat 0 g Cholesterol 32 mg Sodium 172 mg Carbohydrates 8 g Dietary Fiber 2 g Total Sugars 5 g Protein 13 g Diabetic Exchanges: 1/2 other carbohydrate, 1 1/2 lean meat

      Terrific Tip: I serve my wraps with hoison sauce. 1/2 teaspoon ground ginger may be used for fresh ginger.

      Chicken Lettuce Wraps

      Best Rotisserie Chicken Recipe from KITCHEN 101 Cookbook

      Who doesn’t like stopping at the grocery to pick up a Rotisserie chicken?! Rotisserie chicken is one of our all-time favorite time-saving tips. In fact there is a whole chapter of Rapid Rotisserie Chicken Recipes in Holly Clegg’s KITCHEN 101 cookbook. You won’t believe how many healthy shredded diabetic chicken recipes in this chapter. During the Thanksgiving/Christmas holiday season use that leftover turkey in place of chicken to turn it into a new quick, easy and healthy recipe.

      Stock Your Pantry with Healthy Recipe Ingredients

      Kikkoman Light Soy Sauce, 10 Ounce (Pack of 2)Kikkoman Light Soy Sauce, 10 Ounce (Pack of 2)Kikkoman Light Soy Sauce, 10 Ounce (Pack of 2)Nakano Seasoned Rice Vinegar with Garlic, 12 oz.Nakano Seasoned Rice Vinegar with Garlic, 12 oz.Nakano Seasoned Rice Vinegar with Garlic, 12 oz.Dynasty Hoisin Sauce, 7 oz, 2 pkDynasty Hoisin Sauce, 7 oz, 2 pkDynasty Hoisin Sauce, 7 oz, 2 pk

      Get All of Holly’s Healthy Easy Cookbooks

      The post Easy Chicken Lettuce Wraps Recipe – Quick Chicken Dinner with Pizzaz appeared first on The Healthy Cooking Blog.



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