Diabetes & Kidney Stones | Diabetes Strong

By electricdiet / February 4, 2020


If you’ve never developed kidney stones yourself, you probably have a friend or two who have. And they are no picnic for approximately half a million Americans who visit the emergency room each year due to kidney stones.

As a person with diabetes, you definitely face a higher risk of developing kidney stones — especially if your blood sugars are chronically high.

Kidney stones can be incredibly painful, but they are also fortunately relatively easy to treat.

In this article, we’ll discuss what kidney stones are, why having diabetes increases your risk of developing them, causes and symptoms, how they are treated, and how you can prevent them from developing in the first place!

Diabetes & Kidney Stones

What are kidney stones?

Also referred to as “uric acid stones” or “renal stones,” kidney stones are small, hard objects that develop from chemicals in your urine, explains the National Kidney Foundation (NKF).

There are actually several different types of kidney stones and different chemicals that contribute to their development, including calcium, oxalate, urate, cystine, xanthine, and phosphate. 

In general, the formation of calcium oxalate or uric stones comes down to an imbalance: too much waste in your urine and not enough fluid. 

One purpose of our body’s need to urinate is to pass excessive amounts of chemicals, so the development of a kidney stone is a clear sign that your diet may need some improvements and/or you’re not drinking enough water.

According to the NKF, the four types of kidney stones are:

Calcium oxalate: This is the most common type of kidney stone and it develops when calcium mixes with oxalate in your urine. A diet lacking in calcium and adequate water is the number one cause of this type of kidney stone, which means it’s also easily preventable by drinking fluids and getting enough dark leafy greens in your diet! 

Uric acid: This type of kidney stone is common in people with diabetes (more on this later), as well as in those who consume a diet high in organ meats and shellfish. The high amount of purines found in those foods can lead to stones. This type of stone is also likely to “run in your family.” 

Struvite: These stones are generally a direct result of urinary tract infections. If you’re prone to developing UTIs, you may also struggle with this regularly, too. 

Cystine: The rarest type of kidney stone, these also likely “run in the family” and in people who have “cystinuria.” Cystinuria is a rare condition in which high levels of cystine (an amino acid) build-up in your urine and form crystals that become stones.

Some stones stay put in the kidney, but others may actually make its way through your urinary tract and pass without much effort or pain. If you drink adequate amounts of water, that fluid helps to constantly flush these crystals from your system.

The problem arises when those crystals continue to grow too quickly instead of being eliminated by your kidneys. Instead of passing naturally, they build-up in your kidneys or get stuck in your urinary tract and eventually create a blockage. 

This blockage prevents your body to even pass urine properly and creates tremendous pain as the urine begins to get backed-up in your kidneys, bladder, or urinary tract.

Symptoms of kidney stones

While you’ve likely passed smaller kidney stones and crystals throughout your life, the symptoms of kidney stones develop when the stones become too large to pass.

According to the NKF, the most common symptoms of kidney stones include:

  • Intense and severe pain on the side of your lower back
  • Generalized pain in your stomach and torso
  • Blood in your urine
  • Sudden nausea or vomiting
  • Sudden fever and chills
  • Cloudy urine
  • Strong odor in your urine

If you suspect you have some or all of these symptoms, visit an emergency room or urgent care clinic immediately.

Your healthcare team will likely do a “high-resolution CT scan” or “KUB x-ray” in order to see the exact size, shape, and location of your stone.

Causes of kidney stones

The most common causes of “calcium oxalate” or “uric acid” kidney stones are fairly simple — which means preventing them is doable, but for those with diabetes, it can be a bit trickier.

A combination of just a few of these not-so-healthy habits can significantly increase your risk of kidney stones. 

Why people with diabetes have a higher risk of developing kidney stones

Well, you already know that consistently high blood sugars can lead to nephropathy (kidney disease), but kidney stones are an additional issue that people with diabetes can develop.

High blood sugars lead to higher acidity in your urine

The higher your blood sugars are, the more acidic your blood and urine become. This acid leads to the development of “uric acid stones.”

Research from European Urology found that patients with type 2 diabetes whose HbA1c levels were over 6.5 percent had a 92 percent higher risk of developing kidney stones. 

Additionally, patients with type 2 diabetes taking insulin with an HbA1c between 5.7 and 6.4 percent faced a 34 percent higher risk of kidney stones. 

In general, patients in the study with fasting blood sugar levels consistently over 126 mg/dL, were 28 percent more likely to develop kidney stones compared to patients with normal fasting blood sugar levels.

The study also reported a significant finding that the main ingredient in kidney stones of people with type 2 diabetes was uric acid compared to the most common type of stone in the non-diabetic population, calcium oxalate.

Insulin resistance increases the likelihood of kidney stones

Other research has found a direct relationship between insulin resistance and kidney stones. 

“Insulin resistance plays a key role in type 2 diabetes mellitus,” explains a study published in Reviews in Urology, “and it has been linked to uric acid stone formation. Insulin resistance might result in a deficit in ammonium production in the kidney, which lowers urinary pH, thus generating a favorable milieu for uric acid stone formation.”

Another study, published Advanced Biomedical Research, came to the same conclusion.

“Insulin resistance, characteristic of the metabolic syndrome and type 2 diabetes, results in lower urine pH through impaired kidney ammoniagenesis,” explains the study. 

Insulin resistance and high blood sugars seem to significantly lower the pH in the urine, which is the main influencer of the development of a uric acid stone. This makes the urine in some people with type 2 diabetes an ideal environment for the formation of kidney stones.

Treatment options

Fortunately, kidney stones are treatable, but the right treatment for you will depend on the type, location, and size of your stones.

Here are the common treatment options for calcium oxalate and uric acid kidney stones, according to the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK):

Meet with a urologist 

A urologist specializes in the health and treatment of conditions involving your bladder and urinary tract.

Since kidney stones are largely related to your urine, you’ll likely meet with a urologist rather than a nephrologist (who specializes in kidney health). Your urologist will use the KUB x-ray mentioned earlier to assess the size and location of your stone to then determine the best treatment path.

Shock wave lithotripsy 

This painless treatment “blasts” the kidney stone into smaller pieces so they can be more easily passed through your urine. They may be small enough to pass without much pain or effort.

Even though the shock wave treatment itself isn’t painful, some patients still receive anesthesia during the procedure. The recovery period for this treatment is also brief. You’ll be walking on your own immediately after the procedure, and need a day or two to recuperate at home before resuming your normal physical activity. 

Cystoscopy and ureteroscopy 

This treatment involves a “cystoscope” to look inside your urethra and bladder in order to locate the stone. Then your doctor will break it into smaller pieces to pass through your urine, or they’ll remove the stone entirely right then.

This outpatient procedure can be uncomfortable and you will be under anesthesia, but able to go home the same day.

Percutaneous nephrolithotomy

Similar to a cystoscopy, this treatment uses a nephroscope to locate and then remove the kidney stone.

This process is more invasive because the device is inserted directly into your kidney through a small cut in your back. For larger stones, a laser can be used to break them into smaller pieces, making them more passable.

This procedure definitely requires anesthesia and staying in the hospital for a couple of days after the procedure.

Ureteral stent

After any of these treatment options, your urologist may decide to place a thin, flexible tube in your urinary tract. This “ureteral stent” helps your urine and any remaining stones pass more easily.

Your urologist will also likely want to collect the stone in order to examine it and determine what it’s made of. This helps diagnose exactly which type of kidney stone you developed. 

Don’t be surprised if your doctor also asks for a 24-hour urine collection after your stones have been removed. This is to assess how much urine you’re producing during a normal day and to measure the chemicals and minerals present in your urine.

Again, too little fluid and too many minerals can both easily lead to the formation of stones.

Prevention

If you’ve experienced kidney stones before, chances are high that you’ll develop them again — unless you make an effort to prevent them. 

“Those who have developed one stone are at approximately 50% risk for developing another within 5 to 7 years,” explains the NKF.

Here are a few things anyone can do to prevent the development of kidney stones:

Improve your blood sugars

Easier said than done, but it’s the most impactful thing you can do to protect your kidneys — let alone the rest of your body. If you don’t work with your healthcare team to bring your blood sugar levels down to a healthy range, you’ll continue to struggle with uric acid kidney stones.

Drink more water

This one is easy — but if you aren’t used to drinking plain water, the pain of a kidney stone may finally motivate you. Skip the diet soda and other chemical-laden beverages, and get more real water into your body every single day. Eventually, you’ll start to crave it.

Eat more vegetables and fruit

Low pH and high acidity levels in your urine can be easily improved by eating more vegetables and fruits. These wholesome real foods are critical to maintaining a healthy balance of pH and acidity in your bloodstream and your urine. As if you need another reason to eat more veggies.

Dark green vegetables also contain a great deal of calcium — which helps to prevent the calcium oxalate type of stones.

Reduce your sodium intake

“Everyone thinks of salty potato chips and French fries,” says the NKF. “Those should be rarely eaten. There are other products that are salty: sandwich meats, canned soups, packaged meals, and even sports drinks.”

How much of your diet consists of highly-processed sodium-laden foods? Adding salt to whole vegetables isn’t nearly as big of a problem as a diet full of these processed foods that rely on excessive sodium to give and maintain its flavor. 

Watch your animal protein intake

Animal protein has its place in the human diet, but too much of it can increase the acidity in your blood and urine tremendously.

In fact, low-carb and ketogenic diets are common causes of ketones because of their focus on animal protein. At the end of the day, it comes back to balance

Get enough calcium

While the most common type of kidney stone is referred to as a “calcium oxalate” stone, that doesn’t mean it’s the result of eating too much calcium. 

“Dairy products have calcium, but they actually help prevent stones, because calcium binds with oxalate before it gets into the kidneys,” explains the NKF. 

“People with the lowest dietary calcium intake have an increased risk of kidney stones. A stone can form from salt, the waste products of protein, and potassium.” 

Once again, good habits lead to good health! 

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Easy Spinach Artichoke Dip Recipe in Bread Bowl -Diabetic Spinach Dip

By electricdiet / February 2, 2020


Easy Spinach Artichoke Dip Recipe Served in a Bread Bowl

Who doesn’t love a good and easy Spinach Artichoke Dip Recipe? This is Team Holly’s go to recipe for many reasons. Creamy and delicious, but also because it’s easy clean-up!  Have you ever used a bread bowl? When served in a bread bowl, there are less dishes to clean while also built in dipping bread to accompany the savory snack. This healthy Spinach Dip knocks it out of the park as it’s  vegetarian and even a diabetic spinach dip. Holly had so many requests for a gluten free spinach dip, she was excited to include this Spinach Dip recipe in the men’s health cookbook, Guy’s Guide To Eating WellEating healthy is easy even with your favorite dips!  Try serving the dip with cut up veggies.

Easy Spinach Artichoke Dip
What’s best about this recipe is it doubles as delicious dip or side-I’ve served it both ways. One bite and this recipe was a slam dunk winner boasting flavors of rich, creamy Brie.

    Servings20 (1/4-cup) servings
    Prep Time15 minutes
    Cook Time5-10 minutes

    Ingredients

    • 1/2cup


      chopped onion

    • 112-ounce


      can evaporated skimmed milk

    • 2tablespoons


      cornstarch

    • 1/2teaspoon


      minced garlic

    • 4ounces


      brie cheeserind removed and cubed

    • 210-ounce


      packages frozen chopped spinachthawed and well drained

    • 114-ounce


      can quartered artichoke heartsdrained and coarsely chopped

    • 2/3cup


      skim milk



    • salt and pepper to taste

    Instructions
    1. In nonstick pot, combine onion, evaporated milk and cornstarch over medium heat, stirring, until comes to a boil and thickens, about 5 minutes. Add, Brie and garlic, stirring until Brie melts.

    2. Add milk, stirring until heated and bubbly. Stir in spinach and artichokes, heating well. Season to taste.

    Recipe Notes

    Nutritional information per serving: Calories 52, Calories from fat (%) 29% Fat (g) 2, Saturated Fat (g) 1, Cholesterol (mg) 7, Sodium (mg) 119, Carbohydrate (g) 6, Dietary Fiber (g) 1, Sugars (g) 3, Protein (g) 4, Diabetic Exchanges: 1/2 carbohydrate, 1/2 lean meat

    Terrific Tip: Skip the chips and try serving with assorted vegetables such as red pepper squares, cucumber, squash, and zucchini rounds. Serve in a hollowed out bread for easy clean up.

    Nutritional Nugget: I had so many requests for a gluten-free spinach dip so here it is!

    Easy Spinach Artichoke Dip Recipe with Health Benefits from Guy’s Guide To Eating Well

    Brie and Parmesan added to this easy spinach artichoke dip recipe make it the most amazing creamy dip. From Holly’s  men’s cookbook, this  healthy Spinach Dip is a gluten-free spinach dip and diabetic Spinach Dip. Holly’ included this recipe in my Cancer: The Hidden Sniper Chapter in Guy’s Guide To Eating Well because of all the health benefits. Easy to make and easy to eat.  Also, with spinach, milk and cheeses, this is a calcium rich dish and spinach is a super food! Guy’s Guide To Eating Well is divided into chapters of common ailments that plague men – Heart Disease, Diabetes, Cancer, GERD – with food for everyone.

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    Amazing Gluten Free Spinach Dip Steals The Show

    When asked, “Do you have a gluten free Spinach Dip recipe?” Holly did not so she immediately started testing recipes to include this yummy recipe in her men’s health cookbook. Of course, don’t use the bread bowl and serve the dip with all fresh veggies.  We actually like to do that anyway as the creamy delicious dip complements the mellow veggies.  Great for the holidays and use red and green bell peppers.  Who doesn’t like a fabulous gluten free Spinach Dip that’s also a diabetic Spinach Dip. Best of all, it is SO AMAZING!!!

    Serve Great Gluten Free Spinach Dip in Fondue Pot

    6-Cup Stainless Steel Electric Fondue Pot6-Cup Stainless Steel Electric Fondue Pot6-Cup Stainless Steel Electric Fondue Pot

    This is a great Fondue pot to serve dips because it’s the perfect size, plus it is electric. If you always struggle to keep my dips warm then this is your solution.  Set them out and serve so you don’t have to attend to them.

    Easy to use and affordable, you will be surprised how often you will pull this out as your new favorite serving piece. Serve best healthy spinach artichoke dip recipe with options.  Keep it gluten-free with fresh veggies and put a basket of chips or crackers for others.

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    Team Holly is so excited to give you Holly’s 25 Favorite Football Tailgating Recipes available for only $1.99! Included are dips, pick-ups, hearty food and the best of Holly’s sweet treats.  Best of all, it comes with a SHOPPING LIST so all the work is done for you from your menu to your grocery run!

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    The post Easy Spinach Artichoke Dip Recipe in Bread Bowl -Diabetic Spinach Dip appeared first on The Healthy Cooking Blog.



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    Sodium–Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease

    By electricdiet / January 31, 2020


    Abstract

    Diabetic kidney disease (DKD) is now the principal cause of chronic kidney disease leading to end-stage kidney disease worldwide. As a primary contributor to the excess risk of all-cause and cardiovascular death in diabetes, DKD is a major contributor to the progressively expanding global burden of diabetes-associated morbidity and mortality. Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a newer class of antihyperglycemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials of SGLT2 inhibitors have consistently demonstrated reduction of albuminuria and preservation of kidney function. In particular, SGLT2 inhibitors lower risk of congestive heart failure, a major cardiovascular complication in DKD. This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD. The American Diabetes Association/European Association for the Study of Diabetes Consensus Report published online in October 2018 recommends SGLT inhibitors as preferred add-on therapy for patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, if kidney function is adequate. Results of the ongoing and just completed clinical trials conducted in patients with established DKD will facilitate further refinement of current guidelines.

    Introduction

    The impact of the current diabetes pandemic is rapidly approaching that of the Great Plague (1,2). Its prevalence has nearly quadrupled since the 1980s, and 1 in 10 adults, or 642 million people worldwide, are now projected to have diabetes by the year 2040 (3). As the number of people living with diabetes rises, the prevalence of diabetic complications is also rapidly escalating. Approximately half of individuals with type 2 diabetes (T2D) and one-third of people with type 1 diabetes (T1D) develop diabetic kidney disease (DKD), a microvascular complication that is now the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the world (46).

    For people with diabetes, development of kidney disease increases the risk of death by five- to sixfold (79). Tragically, approximately 90% of patients with DKD die before requiring kidney replacement therapy (KRT). Among those who reach ESKD, the risk of death is 10- to 100-fold higher than for individuals with normal kidney function (10). Depending on the country, only 10%–50% of those who need KRT will ever receive it (10). Thus, in many parts of the world, ESKD equates to a virtual death sentence (1012). Although survival rates for patients receiving KRT have improved modestly over the past few decades, the increased risk of death remains unacceptably high, as one-third of those treated by maintenance dialysis die within 3 years of initiation (13).

    Achieving glycemic control with conventional blood glucose–lowering therapies early in the course of T1D or T2D reduces, but does not eliminate, the risk of developing DKD (11,14,15). Therefore, agents that control hyperglycemia safely while also preventing or treating DKD are urgently needed. Over the past three decades, discovery and elucidation of the role of sodium symporters in glucose reabsorption, and thereby glucose homeostasis, have pointed to sodium–glucose cotransporter 2 (SGLT2) inhibition as a viable therapeutic target (1619). In cardiovascular disease (CVD) outcomes trials conducted for safety, SGLT2 inhibitors actually have demonstrated clear benefits on CVD and CKD. This Perspective highlights postulated mechanisms that may underlie clinical effects of SGLT2 inhibition and provides guidance for use of these antihyperglycemic agents in patients with T2D and CKD.

    The Role of the Kidney in Glucose Homeostasis: Sodium–Glucose Cotransporters

    Under normoglycemic to mildly hyperglycemic conditions, the kidney reabsorbs almost all glucose in the glomerular filtrate (19). Glucose reabsorption occurs against its concentration gradient and is driven by sodium symporters expressed in the proximal tubule (20). Of these, SGLT2 and sodium–glucose cotransporter 1 (SGLT1) are the principal known contributors. The complementary glucose transport kinetics of these two transporters permit almost complete resorption of filtered glucose (21). Experimental data indicate that SGLT2 is expressed on the luminal surface of the epithelial cells of the proximal convoluted tubule and is a low-capacity, high-affinity glucose transporter (Km ∼1–4 mmol/L for glucose) with 1:1 Na+/glucose stoichiometry. As such, SGLT2 is responsible for the reabsorption of ∼90% of filtered glucose (Fig. 1). SGLT1 is expressed on the luminal surface of the epithelial cells of the late proximal tubule and reabsorbs most of the remaining ∼10% of filtered glucose (2123).

    Figure 1
    Figure 1

    A and B: Glucose reabsorption via SGLT1 and SGLT2 in normal and diabetic kidney. Expressed apically in the epithelium of the proximal convoluted tubule, SGLT2 reabsorbs about 90% of glucose from the urinary filtrate. The remaining 10% is reabsorbed by SGLT1, a high-affinity and low-capacity transporter expressed apically in the epithelium of the straight descending proximal tubule.

    In humans, glycosuria occurs when blood glucose reaches a threshold of about 180 mg/dL (10 mmol/L). However, this threshold can range approximately 100–240 mg/dL (5.5–13 mmol/L) (2427). Diabetes increases the glycosuric threshold to 200–240 mg/dL (11–13 mmol/L) and, in this way, exacerbates hyperglycemia. The exact mechanism behind this response is unclear but most likely includes increased expression of SGLTs. In studies of mouse and rat models of T2D, SGLT1 and SGLT2 expression are increased in the diabetic kidney (2830). Correspondingly, tubular epithelial cells freshly isolated from the urine of humans with T2D exhibit increased expression of SGLT2, and kidney tissue from patients with T2D displays higher expression of SGLT1 protein and mRNA (31, 32). In sum, higher glucose reabsorptive capacity of the diabetic kidney likely results from increased expression of SGLTs (33) (Fig. 1).

    SGLT2 Inhibition and DKD

    The BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program were the original large studies that demonstrated improvements in both CVD and CKD outcomes in over 17,000 participants with T2D at high CVD risk (34–38). EMPA-REG OUTCOME enrolled approximately 7,000 participants and followed them for a mean duration of 3.1 years. Study participants were randomized to empagliflozin (10 mg or 25 mg) or placebo. The empagliflozin group experienced significantly lower rates of hospitalization for heart failure (35% relative risk reduction), death from CVD (38% relative risk reduction), and death from any cause (32% relative risk reduction) compared with the placebo group (34). Importantly, these observed risk reductions were maintained across estimated glomerular filtration rate (eGFR) and albuminuria categories in more than 2,000 participants with eGFR <60 mL/min/1.73 m2 and/or macroalbuminuria (35).

    EMPA-REG OUTCOME also examined secondary kidney disease outcomes of incident or worsening nephropathy: new-onset albuminuria or progression to urine albumin-to-creatinine ratio (UACR) >300 mg/g (macroalbuminuria), doubling of serum creatinine, initiation of KRT, and death from kidney disease as a composite outcome and individual outcomes (36). The relative risk of developing incident or worsening nephropathy was 39% lower in the empagliflozin group compared with placebo (13% vs. 19%, P < 0.001) (36). A comparable relative risk reduction for nephropathy was observed in participants with CVD who underwent coronary artery bypass graft surgery (37). Notably, most participants in EMPA-REG OUTCOME also received treatment with ACE inhibitors or angiotensin receptor blockers, agents that have been shown to reduce DKD progression and prevent ESKD.

    The CANVAS Program integrated data from two CVD outcome trials enrolling over 10,000 participants with T2D, randomized to either canagliflozin or placebo and followed for a mean duration of 3.6 years (38). The primary composite outcome of death from CVD causes, nonfatal myocardial infarction, and nonfatal stroke occurred at a significantly lower rate in the canagliflozin group compared with placebo (14% relative risk reduction, P < 0.001). The risk of progression to albuminuria was decreased by 27%, and the composite kidney disease outcome (40% eGFR decline, KRT, or death from kidney causes) occurred 40% less frequently in the canagliflozin group relative to placebo (38). The secondary analysis of the CANVAS Program showed that cardiovascular and kidney outcomes were consistent across the different levels of kidney function (eGFR 30–45, 45–60, 60–90, and ≥90 mL/min/1.73 m2); however, canagliflozin treatment had greater benefits on fatal/nonfatal strokes in groups with eGFR <60 mL/min/1.73 m2 (hazard ratio compared with placebo was 0.56 in the 45–60 mL/min/1.73 m2 group and 0.32 in the 30–45 mL/min/1.73 m2 group) (39). Ongoing cardiovascular outcomes trials with two other SGLT2 inhibitors, dapagliflozin and ertugliflozin, will also report major CKD outcomes (40).

    Although the findings from the EMPA-REG OUTCOME and CANVAS trials provide a strong signal that SGLT2 inhibition preserves kidney function and improves overall and kidney survival in T2D, results from two clinical trials primarily designed to evaluate CKD outcomes with SGLT2 inhibition are keenly awaited. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) (ClinicalTrials.org identifier NCT02065791) and A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With CKD (Dapa-CKD) (ClinicalTrials.org identifier NCT03036150) trials are evaluating effects of canagliflozin or dapagliflozin on composite primary outcomes including ESKD, doubling of serum creatinine (CREDENCE), ≥50% sustained decline in eGFR (Dapa-CKD), and kidney disease or CVD death in participants with established DKD (41). CREDENCE concluded early due to positive efficacy findings, and results are expected to be publicly released in early 2019 (42). Dapa-CKD is expected to report in 2021 (Table 1).

    Table 1

    Summary of clinical trials evaluating kidney outcomes with SGLT2 inhibition

    Preservation of eGFR and albuminuria reduction are class effects of SGLT2 inhibitors. An initial effect observed within the first few weeks of SGLT2 inhibition is the reduction of eGFR by approximately 5 mL/min/1.73 m2, followed by stabilization over time (36,4349). This phenomenon has been observed in patients with eGFR as low as 30 mL/min/1.73 m2 (50). Compared with glimepiride, canagliflozin resulted in slower mean eGFR decline (0.5 mL/min/1.73 m2 per year for canagliflozin 100 mg daily, 0.9 mL/min/1.73 m2 per year for canagliflozin 300 mg daily, and 3.3 mL/min/1.73 m2 per year with glimepiride, P < 0.01 for between-group comparisons), despite achieving a similar level of glycemic control (46). Albuminuria reduction is also observed across levels of albuminuria and eGFR. Although it did not have a significant effect on development of new-onset albuminuria in EMPA-REG OUTCOME, empagliflozin produced a 38% relative risk reduction in progression to severely increased albuminuria (11% vs. 16%, P < 0.001) compared with placebo (36). Similarly, in the CANVAS Program, canagliflozin produced a 27% reduction in progression to severely increased albuminuria and 1.7-fold higher rate of albuminuria regression (38). Among patients with baseline UACR >100 mg/g, treatment with dapagliflozin decreased 24-h urine albumin excretion by 36% (P < 0.001), and among those with eGFR 30–60 mL/min/1.73 m2, it decreased frequency of severely increased albuminuria (UACR >1,800 mg/g) compared with placebo (44, 51). Among patients with eGFR ≥30 to <50 mL/min/1.73 m2, treatment with canagliflozin was associated with greater decrease in UACR compared with placebo (median percent reduction −30%, −21%, and −8% in canagliflozin 100 mg daily, 300 mg daily, and placebo groups, respectively) (48). When compared with glimepiride treatment with canagliflozin 100 mg or 300 mg daily in patients with at least moderately increased albuminuria (UACR ≥ 30 mg/g), decreased UACR by 32% (P = 0.01) and 50% (P < 0.001), respectively, despite similar glycemic control (46).

    Direct Effects of SGLT2 Inhibition on the Diabetic Kidney

    Knowledge of the biological mechanisms behind the kidney-protective effects of SGLT2 inhibition is evolving. Although blood glucose lowering is central to DKD prevention, there are also likely direct effects independent of glycemia.

    One putative mechanism is normalization of glomerular hemodynamics through restoration of tubuloglomerular feedback. Hyperfiltration with resulting hypertension in the glomerular capillary circulation is an early hemodynamic change observed in at least 75% of patients with T1D and 40% of those with T2D (Fig. 1) (52,53). Glomerular hyperfiltration is driven by metabolic derangements including hyperglycemia and hyperaminoacidemia, as well as increased proximal tubular reabsorption of glucose and sodium chloride via SGLT1 and SGLT2 (Fig. 2).

    Figure 2
    Figure 2

    Effects of diabetes and SGLT2 inhibition on nephron hemodynamics. A: Increased reabsorption of glucose by SGLT2 in the proximal convoluted tubule decreases delivery of solutes to the macula densa. The resulting decrease in ATP release from the basolateral membrane of tubular epithelial cells reduces production of adenosine and produces a vasodilatation of the afferent arteriole. B: SGLT2 inhibitors restore solute delivery to the macula densa with resulting adenosine activation and reversal of vasodilation of the afferent arteriole.

    Tubuloglomerular feedback is an adaptive mechanism through which reabsorption of sodium and chloride in the macula densa promotes adenosine release (Fig. 2). Adenosine, in turn, acts in paracrine manner to constrict the afferent arteriole. In diabetes, as a result of increased reabsorption of sodium and chloride in the proximal tubule, delivery to the macula densa is decreased, leading to lower solute reabsorption and a consequent decrease in adenosine production. By promoting relative afferent arteriolar vasodilation, this mechanism contributes to glomerular hyperperfusion, hypertension, and hyperfiltration in diabetes (54).

    By blocking reabsorption of sodium chloride in the proximal tubule, SGLT2 inhibition restores solute delivery to the macula densa and thereby restores normal tubuloglomerular feedback (Fig. 2). A net effect is reversal of afferent vasodilation and normalization of glomerular hemodynamics (55). This effect has been observed with the nonspecific SGLT2 inhibitor phlorizin in a T1D model in rats and, more recently, with the selective SGLT2 inhibitor empagliflozin in a mouse T1D model (56,57). In humans with T1D and glomerular hyperfiltration, treatment with empagliflozin decreased directly measured GFR (inulin clearance) by 33 mL/min/1.73 m2 (mean ± SD 172 ± 23 mL/min/1.73 m2 to 139 ± 25 mL/min/1.73 m2) in conjunction with decreased plasma flow to the kidney, lower plasma nitric oxide levels, and increased kidney vascular resistance. This effect was only observed in patients with diabetes with glomerular hyperfiltration (58).

    SGLT2 inhibition may have additional anti-inflammatory and antifibrotic actions that protect the kidney. In primary proximal tubular cells, SGLT2 inhibition suppressed the generation of a hyperglycemia-mediated increase in reactive oxygen species (47,59). Experimental rat and mouse models of diabetes have shown attenuation of glomerulosclerosis and tubulointerstitial fibrosis with SGLT2 inhibition (6062). Decreased urinary excretion of markers of kidney tubular injury (e.g., kidney injury molecule 1) and inflammatory markers (e.g., interleukin-6) have been observed in humans with T2D treated with dapagliflozin (47).

    Effects of SGLT2 Inhibition on Risk Factors for DKD

    Glycemic control is known to decrease risk of DKD onset, particularly if implemented early in the course of diabetes (14,15). In patients with diabetes and preserved kidney function, SGLT2 inhibition reduces HbA1c by approximately 1% (63). Due to the intrinsic mechanism of action, the glycemic-lowering effects of SGLT2 inhibitors are blunted in patients with low eGFR (36,39,43,44,48,63,64). For instance, the adjusted mean treatment difference in HbA1c was −0.7% (P < 0.001) in patients with eGFR >60 and ≤90 mL/min/1.73 m2 who received empagliflozin when compared with placebo, and in those with eGFR >30 and ≤60 mL/min/1.73 m2, the adjusted mean difference was −0.4% (P < 0.001) (43). Pooled analysis of phase III empagliflozin clinical trials confirmed this finding with evidence of placebo-corrected reductions in HbA1c decreasing with declining eGFR (64). Treatment with dapagliflozin reduced HbA1c between 0.3% and 0.4% in patients with eGFR >45 and ≤60 mL/min/1.73 m2. No HbA1c reduction was observed in patients with eGFR ≤40 mL/min/1.73 m2 (44). As such, the antihyperglycemic effects of SGLT2 inhibition seem less likely to confer kidney protection in the setting of moderate-to-severe CKD.

    As body fat loss per se may decrease albuminuria and glomerular hyperfiltration, weight reduction effect of SGLT2 inhibition may indirectly protect the diabetic kidney (44,55). In patients with normal kidney function, SGLT2 inhibition leads to a loss of 60–80 g of glucose (240–320 calories) per day via glycosuria, with expected weight loss of 2–3 lb (0.9–1.4 kg) per month (65). However, weight loss plateaus after about 6 months of treatment, after achieving a total weight loss of 5–7 lb (2.3–3.2 kg) (63). After more than 2 years of dapagliflozin treatment in patients with T2D and a mean weight of 225 lb (102 kg), experienced weight loss was 11 lb (5 kg) with a concomitant decrease in waist circumference (66,67). Notably, a recent pooled analysis of phase III empagliflozin trials and secondary analysis of the CANVAS Program found that the weight loss effects were maintained in patients with eGFR as low as 30 mL/min/1.73 m2 (39, 64).

    Antihypertensive effects are observed with empagliflozin, dapagliflozin, and canagliflozin. Each of them lower systolic blood pressure by approximately 5 mmHg and diastolic blood pressure by approximately 2 mmHg (63,6870). The systolic blood pressure reduction appears greatest within 3–4 months of initiation of treatment with empagliflozin and dapagliflozin (34,66). In contrast to blood glucose lowering, the magnitude of blood pressure reduction is maintained, or perhaps increased, in patients with low eGFR (39). For example, in patients with T2D, the mean placebo-corrected changes in systolic blood pressure among those treated with empagliflozin were −3 mmHg with eGFR ≥90 mL/min/1.73 m2, −4 mmHg with eGFR 60–89 mL/min/1.73 m2, −6 mmHg with eGFR 30–59 mL/min/1.73 m2, and −7 mmHg with eGFR <30 mL/min/1.73 m2 (64). The mechanisms underlying blood pressure reduction are likely multiple and may include natriuresis, weight loss, and improved endothelial function and vascular compliance (7176).

    The natriuretic effect may be enhanced in diabetes due to greater proximal tubular sodium reabsorption related to increased expression of SGLT2 and SGLT1 (77, 78). Another postulated mechanism for the natriuretic effect of SGLT2 inhibition is “cross talk” with other solute transporters, including the Na+/H+ exchanger 3 (NHE3). NHE3 is responsible for much of the sodium reabsorption from the glomerular filtrate (79). In rats, SGLT2 and NHE3 colocalize in the membrane of proximal tubular cells (80). SGLT2 inhibition with phlorizin inhibits sodium bicarbonate reabsorption by NHE3, though the specific mechanism of this effect remains unclear (81).

    Clinical Use of SGLT2 Inhibitors

    Since the U.S. Food and Drug Administration (FDA) approval of canagliflozin for the treatment of T2D in 2013, the SGLT2 inhibitor class has quickly gained usage. Major guidelines and consensus statements, such as the American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) algorithm for the comprehensive management of people with T2D, recommend SGLT2 inhibition because of the combined effects on glycemia, weight, and blood pressure in people with preserved eGFR (8284). Based largely on results of the EMPA-REG OUTCOME and CANVAS clinical trials, the consensus report from the ADA and European Association for the study of Diabetes (EASD) recommends use of SGLT2 inhibitors as an add-on antihyperglycemic therapy of choice in patients who have CVD or CKD (84). Dosing recommendations (eGFR >30 mL/min/1.73 m2 for dapagliflozin, canagliflozin, and ertugliflozin and >45 mL/min/1.73 m2 for empagliflozin), which are based on the limited antihyperglycemic efficacy of SGLT2 inhibition in patients with lower eGFR, are not changed.

    Though both empagliflozin and canagliflozin have now been approved by the FDA for the indication of reducing the risk of cardiovascular events and cardiovascular death in adults with T2D and established CVD, to date, SGLT2 inhibitors have not been recommended for the express purpose of improving CKD outcomes (85,86). The current recommendations to limit use of SGLT2 inhibitors by eGFR criteria may change once results of CREDENCE and other ongoing clinical trials with primary CKD outcomes are reported (Table 2) (41,42,87).

    Table 2

    Summary of dosing recommendations for FDA-approved SGLT2 inhibitors

    Conclusions

    SGLT2 inhibitors show great promise for prevention and treatment of DKD. Trials with empagliflozin have demonstrated, for the first time, a reduction in all-cause and cardiovascular mortality in patients with T2D and CKD. The mortality risk in this population has heretofore been unacceptably high and largely unmitigated; thus, the importance of improving survival while maintaining kidney function in patients with DKD is of urgent and utmost importance. Research is needed to inform the use of SGLT2 inhibitors in the setting of T1D and perhaps for indications outside of diabetes, such as CKD without diabetes. Progress on these fronts is already under way. For example, the dual SGLT1/2 inhibitor sotagliflozin is currently under study for use in patients with T1D (88,89). Empagliflozin will soon be studied for primary CKD outcomes and cardiovascular deaths among those with established diabetic and nondiabetic CKD. Elucidation of the biological mechanisms underlying the effects of SGLT2 inhibition is necessary to advance understanding and more fully optimize clinical applications of these agents for the treatment of diabetes, CKD, and CVD.

    • Received August 13, 2018.
    • Accepted November 7, 2018.

    References

    1. Alchon SA. A Pest in the Land: New World Epidemics in a Global Perspective. Diálogos series, 1st ed. Albuquerque, University of New Mexico Press, 2003

    2. JARDIANCE (empagliflozin) tablets, for oral use [package insert], Ingelheim, Germany, Boehringer Ingelheim International GmbH, 2018

    3. INVOKANA (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ, Janssen Pharmaceuticals, Inc., 2018



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    Losing Weight with Type 2 Diabetes or Prediabetes

    By electricdiet / January 29, 2020


    In general, I avoid talking about losing weight when it comes to managing Type 2 diabetes and prediabetes. Weight is such a personal thing. Instead of stressing about those judgmental numbers on the scale, I encourage people to focus on eating foods with the biggest nutritional bang for the buck (in reasonable quantities).

    Losing Weight with Type 2 and Prediabetes

    Recently, however, I’ve spoken with a lot of people who are trying to better manage their weight. One person received a prediabetes diagnosis and wants to do whatever she can to stave off Type 2. One gained weight after starting insulin therapy and wants to stop the upward trend. Another needs to drop 15 pounds in a short period of time in order to schedule knee surgery. They all asked for help.

    When I was diagnosed with Type 2 back in 1999, I was about 45 pounds heavier than I am now. Like many of you, I’ve had ups and downs over the years with my weight but in general, I’ve kept the weight off. Here’s more about my weight loss journey if you’re interested. Here’s the food philosophy I follow most of the time.

    How to Lose Weight and Keep it Off

    Unfortunately, just like there’s no one magic diabetes diet, there isn’t one way to lose weight and keep it off that works for everyone. Instead, let me give you a few guidelines that may help you decide where to start.

    • You’re making a lifestyle change. You are not dieting. Pick a way of eating that will work for you long-term.
    • Eat foods that contain a lot of fiber and nutrients. Beans, leafy greens, berries, cruciferous vegetables (broccoli, cauliflower, cabbage, etc.), whole grains, nuts, and seeds fall into this category. Eating carbs (while controlling portion size) is perfectly fine, but make sure the ones you choose are actually fueling your body and not just providing empty calories.
    • Don’t focus on the number. Just like your blood glucose (BG), your weight is simply a number to help guide you in making decisions. If you’re trending up, you need to analyze what’s happening and make a change.
    • Exercise to keep weight off. People who participated on the TV show The Biggest Loser were studied for six years to see how many of them maintained their weight loss. Bottom line: Exercise is key.
    • Manage the stress in your life. I’ve found that the 5-Minute Journal (affiliate link) helps me focus on positive things happening in my life. Yoga, meditation, walking, bubble baths, or reading a good book while sipping a cup of tea can also help manage stress. Find your happy (quiet) place and go there at least once a day.
    • Get enough sleep. A small study on Japanese adults with type 2 diabetes showed that the optimal amount of sleep per night was 6.5 to 7.4 hours. More or less negatively impacted blood glucose levels. Aim for 7 hours each night.
    • Do the best you can and don’t beat yourself up. You’re human. It’s a journey. If you eat something that doesn’t align with your goals one day, do better the next.

    Losing Weight with Type 2 - stress management

    Resources for Losing Weight with Type 2 Diabetes or Prediabetes

    If you have recently been diagnosed with prediabetes, I highly recommend reading Jill Weisenberger’s book Prediabetes: A Complete Guide (affiliate link). In it, she walks you through the process of doing a “lifestyle reset” which includes tips for managing your weight.

    Organizations like Weight Watchers and apps like MyFitnessPal and Daily Dozen (iPhone or Android) can help you set goals and track your progress.

    If you need help with portion control, you can also download a copy of Livliga’s Get Started Guide. (For those who don’t know, Livliga makes gorgeous portion-controlled dinnerware and that’s an affiliate link because I love their products so much.)

    You can also grab a copy of my book The Pocket Carbohydrate Counter Guide for Diabetes, which is full of nutritional strategies for managing your blood sugar and your weight.

    Takeaway

    If you are actively trying to lose weight in order to better manage your type 2 diabetes or prediabetes, think of it as a lifestyle change rather than a diet. Find an eating plan that works for you, move every day, manage the stress in your life, get enough rest, and reach out for support when you need it.

    The post Losing Weight with Type 2 Diabetes or Prediabetes appeared first on Diabetic Foodie.



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    Marzetti Avocado Ranch Taco Salad – My Bizzy Kitchen

    By electricdiet / January 27, 2020


    Hi guys!  I’ve missed you!  But promise, things are working behind the scenes to give you the best blog experience.  Guess what?  You’ll actually be able to find my recipes!  I hope to have it up and running with the new look in the next week or so.  Thank you for being patient!

    I have still been busy in my kitchen though.  Some things will never change 😀

    I recently found Marzetti Simply Dressed Salad Dressings in the refrigerated section and I have a new favorite salad dressing.  Most of my salads are zero points, so it’s totally worth the 2-3 points for 2 tablespoons of their dressings.  

    Print

    Marzetti Avocado Ranch Taco Salad

    A quick and easy taco salad using pantry staples and Marzetti Simply Dressed Salad Dressing.  


    Scale

    Ingredients

    • 4 ounces chicken breast
    • 1 tablespoon taco seasoning
    • avocado oil spray
    • 2 cups romaine lettuce, chopped
    • 1/2 cup canned corn, drained
    • 1/2 cup canned black beans, drained
    • 1/4 cup chopped radish
    • 1/3 cup sliced grape tomatoes
    • 2 tablespoons Marzett Avocado Ranch Dressing

    Instructions

    Heat a non-stick skillet over medium heat with avocado spray.

    Season the chicken with the taco seasoning, and cook for 6-8 minutes, flipping half way through, until it reads 165 degrees.

    While the chicken rests, plate the salad – romaine, corn, black beans, radish and cherry tomato.

    Slice the chicken after it’s rested 10 minutes, and top on salad.  Drizzle with Marzetti Avocado Ranch Dressing.  That’s it!

    Notes

    Most salads no matter which plan you are on are zero points.

    On team purple and team blue on WW, this salad is only 3 points – you only have to count the dressing.

    On team green, it’s will be 6 points – you just have to count the chicken. 😀

    This salad is so good and can easily be on your weekly lunch or dinner rotation, because you can meal prep the chicken ahead of time as well as the veggies.

    You can find this dressing in the produce section – they have lots of flavors to choose from and range from 2-3 points for 2 tablespoons.  Totally worth it because this dressing is delicious and will actually make you crave salad – pinky swear!

    I hope you had a great weekend!  I am still going strong with my #dryjanuary – even with having people over on Saturday!  We had a “vision 2020 party” and I’ll post my vision board tomorrow.

    Happy Monday!  Make it a great day!



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    Everything You Need to Know About Walmart Insulin

    By electricdiet / January 25, 2020


    The cost of insulin is a serious problem for many people who live with insulin-dependent diabetes in the United States. 

    That’s why some people turn to Walmart’s ReliOn Insulin and other over-the-counter insulins.

    In this article, we’ll discuss what kinds of insulin are available from Walmart’s “ReliOn” brand, what they cost, how they work, and if they are a good option for you.

    Bottle of Walmart's ReliOn insulin

    Walmart’s ReliOn Insulin

    The over-the-counter insulin from Walmart that costs about $25 per vial is limited to two types of insulin:

    • Regular (insulin R)
    • NPH (insulin N)

    You can also get a premixed combination of NPH and Regular called 70-30. 

    Both of these insulins are what’s called “synthetic human insulin”. It’s different from newer insulins that are called insulin analogs. 

    Both require a very rigid eating schedule. In the “old days” of type 1 diabetes management, a patient taking Regular and NPH insulin would have to eat a very specific number of carbohydrates ever 2 to 3 hours.

    If you don’t adhere to a consistent eating schedule and carbohydrate quantity, you will experience recurring severe low blood sugars. 

    For example, as a child with type 1 diabetes in the 90s, I followed a regimen like this:

    • 8 a.m.: 45 grams of carbohydrate
    • 10:30 a.m.: 15 grams of carbohydrate
    • 12 p.m.: 60 grams of carbohydrate 
    • 3 p.m.:15 grams of carbohydrate 
    • 6 p.m.: 60 grams of carbohydrate 
    • 8:30 p.m.: 15 grams of carbohydrate

    Your life is ruled by the clock when you’re taking these types of insulin compared to the flexibility and freedom that comes with today’s insulin options.

    For patients who switch to these insulins without guidance from a healthcare professional, they may be unaware that these insulins do not work in the body like the newer insulin they were likely taking before. This can lead to severe blood sugar fluctuations and be potentially fatal. 

    Let’s take a closer look at Regular and NPH insulin.

    Regular insulin 

    Regular insulin is also referred to as “short-acting” insulin and is taken several times per day.

     It used to be the only option for managing your blood sugar around meals, but compared to today’s “rapid” and “fast” acting insulins, Regular insulin is very slow-working because it stays in your system for a long time, up to 8 hours, and peaks nearly 4 hours after injecting it.

    If you don’t eat every 2 to 3 hours while taking multiple daily doses of Regular insulin, you will experience multiple low blood sugars.

    More modern insulin is active in your bloodstream within 15 minutes and out of your bloodstream within 4 hours. This means you don’t have to worry about dropping low or feeding that insulin dose after 2 to 3 hours of taking it. 

    In hospitals, patients will find that when receiving insulin via IV, short-acting insulin is still commonly used based on traditional “sliding scale” insulin dosing protocols.

    NPH insulin 

    NPH insulin is also referred to as “intermediate-acting” insulin. It used to be the only “background” insulin option, but much like Regular insulin, it pales in comparison to today’s other background options.

    NPH only stays in your system for anywhere from 10 to 16 hours and has to be taken twice per day in order to cover your 24-hour background insulin needs. 

    It also takes several hours to become active in your bloodstream, and it peaks at approximately 4 to 6 hours after taking it. Today’s long-acting insulin options — Basalgar, Lantus, Levemir, Tresiba, Toujeo — have generally no peak at all.

    The peak in NPH contributes to the rigid eating schedule a person must follow if they’re using these older insulins to manage their blood sugars.

    Do you need a prescription?

    In short, no, you do not need a prescription to buy Walmart’s Regular or NPH insulin. However, you won’t find it sitting on the counter next to the Tylenol either. 

    You’ll have to go to a Walmart store and ask a pharmacist for a vial in order to purchase it.

    While it’s considered an “over-the-counter” medication now, it’s still managed very carefully by the pharmacy because it needs to be refrigerated and it’s still a high-value medication despite being only $25 per vial.

    Is Walmark insulin a good option for you?

    Considering that today’s most modern insulin options cost at least $300 per vial, the affordability of Walmart’s insulin is appealing. Unfortunately, the rigid schedule and limitations of these insulins truly make them a “last resort” option.

    They are especially challenging for younger children who have unpredictable eating habits and an inevitably lesser understanding of how important it is to eat a specific amount of food at a specific time of day.

    These insulins will help you stay alive if you truly cannot afford more modern insulin. If they are the only type of insulin you have access to, then yes, it is a good option for you.

    If you can get more modern insulin through your health insurance or one of the many financial assistance programs that exist today, you’d be better off going that route.

    Sure, it’s nice that these older insulins are easily accessible but they are not the solution for a long, healthy, full life for a person with diabetes. They are the last resort.  

    Suggested next posts:

    If you found this guide to Walmart insulin useful, please sign up for our newsletter (and get a free chapter from the Fit With Diabetes eBook) using the form below. We send out a weekly newsletter with the latest posts and recipes from Diabetes Strong.



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    Easy Chicken and Dumplings Recipe with Bisquick – Two Shortcuts + Healthy

    By electricdiet / January 23, 2020


    Easy Chicken and Dumplings Recipe With Favorite Two Shortcuts!

    Tastes like grandma cooked it! This go-to easy Chicken and Dumplings recipe is the ultimate comfort food. Healthy chicken and dumplings recipe is from the Rapid Rotisserie Chicken Chapter in KITCHEN 101. Make this wonderful, scrumptious creamy Bisquick chicken and dumplings recipe in minutes instead of hours. You can find many homemade chicken and dumplings recipes but this simple Chicken and Dumplings Bisquick Recipe with Rotisserie chicken is such a quick chicken and dumplings recipe!

    Classic Favorite Gets Makeover for Healthy Chicken and Dumplings

    This classic is always a family favorite, but now try this simple version.  Kids love chicken and gravy so they clean their plates.  Actually, this recipe makes a quick last minute dinner effortlessly with all my shortcuts. KITCHEN 101, Holly’s easiest cookbook, is perfect for busy cooks or new cooks who want to cook healthy and eat healthy!

    Easy Chicken and Dumplings Recipe from Rapid Rotisserie Chicken Chapter in KITCHEN 101

    Easy Chicken and Dumplings
    With rotisserie chicken, canned broth and drop Bisquick dumplings, my healthy Chicken and Dumplings recipe becomes an effortless one-dish meal! After making my Chicken and Dumplings Bisquick recipe, you will find yourself making this quick delicious dinner meal all the time. Featured On Reader’s Digest Article: 11 Healthy Makeovers of Your Favorite Family Recipes

      Servings8 (1 cup) servings

      Ingredients

      • 1


        onionchopped

      • 1 1/2cups


        baby carrots

      • 1/2teaspoon


        minced garlic

      • 1/4cup


        all-purpose flour

      • 6cups


        fat-free chicken brothdivided

      • 1/2teaspoon


        dried thyme leaves

      • 2cups


        chopped skinless rotisserie chicken breast

      • 2cups


        biscuit baking mix

      • 2/3cup


        skim milk

      Instructions
      1. In large nonstick pot coated with nonstick cooking spray, sauté onion, carrots, and garlic over medium heat until tender.


      2. In small cup, stir flour and 1/3 cup  broth, mixing until smooth. Gradually add flour mixture and remaining broth to pot; bring to boil. Add thyme and chicken.


      3. In bowl, stir together biscuit baking mix and milk. Drop the mixture by spoonfuls into boiling broth.


      4. Return to boil, reduce heat, and cook, covered, carefully stirring occasionally, 15-20 minutes or until dumplings are done. Season to taste. If soup is too thick, add more broth.

      Recipe Notes

      Per Serving: Calories 218, Calories from Fat 23%, Fat 6g, Saturated Fat 1g, Cholesterol 32mg, Sodium 1207mg, Carbohydrates 28g, Dietary Fiber 2g, Total Sugars 4g, Protein 15g, Dietary Exchanges: 1 1/2 starch, 1 vegetable, 1 1/2 lean meat

      Terrific Tip: Another short-cut for dumplings: cut flaky biscuits into fourths and drop into boiling broth or you can even use flour tortillas cut into fourths. You can slice carrots — but I find baby carrots a time-saver.

      chicken and dumplings Bisquick

      Healthy Chicken And Dumplings Recipe Featured On Reader’s Digest Article: 11 Healthy Makeovers of Your Favorite Family Recipes

      This recipe featured in this Reader’s Digest article for healthy makeovers.  Who doesn’t like this comfort food recipe? If you grew up in the south, this might be your favorite comfort food recipe! Bisquick Chicken and Dumplings recipe makes the dumplings process so simple and remember, this is also a great Rotisserie chicken recipe!

      Best of all, this is a healthy chicken and dumplings recipe from KITCHEN 101 cookbook. Doesn’t get much better than that! After making Holly’s Chicken and Dumplings Bisquick recipe, you’ll make this quick delicious dinner meal all the time. Featured On Reader’s Digest Article: 11 Healthy Makeovers of Your Favorite Family Recipes.

      Bisquick Chicken and Dumplings Recipe Is Healthy Chicken and Dumplings Recipe

      Who  has time to cook?  To the rescue- Holly’s Chicken and Dumplings Bisquick recipe for one of her top healthy easy recipes. There’s a Rotisserie Chicken Chapter in KITCHEN 101.  Look for containers of Rotisserie chicken packaged in the deli section. Another step saver option for this delicious healthy chicken and dumplings recipe.

      KITCHEN 101 is a time saver cookbook and includes your favorite comfort food healthier! Rotisserie chicken is the secret in Quick Chicken Lasagna and turns lasagna into a quick recipe. This cookbook simplifies cooking and perfect for the busy person or new cook.

       Kitchen Scissors Are Kitchen Necessity for Bisquick Chicken and Dumplings

      Why are kitchen scissors a kitchen necessity? Kitchen scissors are a top must have gadget because they help you cook faster and more efficiently.

      Kitchen scissors are the EASIEST way to trim and cut chicken into pieces. Whether you’re using raw, cooked or rotisserie chicken, these scissors really speed up the chopping!

      There’s so many uses from cutting pizza to all meats. You’ll grab these scissors all the time and these inexpensive scissors work great. 

      easy chicken and dumplings

      Make Bisquick Chicken And Dumplings Recipe Diabetic Chicken One-Dish Meal

      Turn this simple recipe into an easy diabetic recipe and use reduced sodium broth for diabetic chicken and dumplings recipe!  No guilt eating because it is a healthy chicken and dumplings recipe. If you used to make a recipe that takes a lot longer, why cook that way anymore?!  KITCHEN 101 simplifies even Chicken and Dumplings with 10 ingredients and shortcuts.  Best of all this is a simple healthy chicken and dumplings recipe!

      More Easy Recipes in This 15 Fast & Fabulous Back To School Dinners E-book Only $1.99!

      back to school recipes

      For more family favorite go-to easy, healthy homemade dinners during the back-to-school rush, check out my Back-To-School Downloadable Ebook. With family friendly recipes including shopping lists, serving suggestions, plus tips and hints – make the hustle and bustle extra easy to get that dinner on the table fast!

      Download it now for only $1.99 and you will have all you need to easily feed your family a delicious, healthy homemade meal in minutes!

      Do You Know About Silicon Pot Holders?

      4PCS Multipurpose Silicone Pot Holder Non Slip Heat Resistant4PCS Multipurpose Silicone Pot Holder Non Slip Heat Resistant

      Once you use these silicon pot holders, they will be your one and only kitchen pot holders for several reasons. They are easy to use and best of all, they never get dirty. Cloth pot holders end up so filthy so these colorful clean heat resistant pot holders are inexpensive and the best!  Also, love the fact they double as a handy trivet!

      Check out Holly’s favorite Silicon Gadget List you will love these options.

       

       

      If You Liked Easy Chicken and Dumplings Bisquick Recipe

      There are lots of recipes on the healthy food blog that start with Rotisserie chicken.  You’ll love Holly’s simple Pulled Chicken! There is also the best chicken salad recipe. You’ll get addicted to this time saver because it also adds so much flavor to whatever you are making. Remember to always remove the skin to make healthy chicken recipes.  Like in chicken and dumplings Bisquick recipe, Bisquick is a time saver.  I also have some great easy Bisquick recipes like Simple Baked Chicken.

      Easy Cookbooks To Start Cooking Healthy Easy Recipes

      Just like this healthy chicken and dumplings recipe, you’ll find all your favorite recipes in Holly’s cookbooks.  You don’t have to change what you eat but just how you prepare the recipe.  

      The post Easy Chicken and Dumplings Recipe with Bisquick – Two Shortcuts + Healthy appeared first on The Healthy Cooking Blog.



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      The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism

      By electricdiet / January 21, 2020


      Introduction

      For maintenance of normal physiological function, a living organism needs to obtain nutrients from the environment and convert it into energy through its metabolic system. Meanwhile, the organism has to protect itself from attacks of potential pathogenic invaders. Evolutionarily, it is not surprising that the functions of the immune and metabolic systems are closely linked and coordinated. It is well known that an effective immune response is highly energy dependent in order to activate innate immunity and promote adaptive immunity in response to various environmental insults. Under conditions of energy insufficiency such as famine, prolonged and intensive physical activities, and overloaded neuronal and cardiovascular functions, the immune responses in an organism may be sacrificed, leading to increased infections and other immune-related defects (1). On the other hand, overnutrition may lead to overactivated immunity, resulting in inflammation and related metabolic diseases such as insulin resistance and type 2 diabetes (2). To maintain homeostasis, an organism thus codevelops the immune and metabolic systems to adapt to environmental changes. Although metabolic cells and tissue-resident immune cells exert distinct functions, numerous studies have already demonstrated that these cells undergo intensive and dynamic cross talks to coordinate their action in preserving homeostasis. Emerging evidence accumulated over the past several years also reveals the presence of distinct immune signatures and signaling pathways in key metabolic cells and vice versa, further signifying an integral link between immune activity and metabolic function.

      Activation of the cGAS-cGAMP-STING Pathway in Immunity

      Over the past several years, a key DNA immune response pathway, the cGAMP synthase (cGAS [also known as Mb21d1])–cGAMP–stimulator of interferon genes (STING [also called TMEM173, MITA, MPYS, and ERIS]) pathway, has been discovered in immune cells. The cGAS-cGAMP-STING pathway was originally identified as a signaling cascade that is activated by double-stranded DNA (dsDNA) during pathogen infections. cGAS senses viral and bacterial dsDNA aberrantly localized in the cytosol independent of its sequence context (35), and binding dsDNA promotes cGAS oligomerization and activation (3,6,7). In addition to playing a critical role in antiviral immune response, cGAS has also been shown to be involved in some other important biological processes such as macular degeneration (8), cellular senescence (911), myocardial infarction–related inflammation (12), and macrophage transformation (13). Activated cGAS catalyzes the formation of 2′3′-cGAMP, a cyclic dinucleotide (CDN) composed of adenosine and guanosine linked via two phosphodiester linkages. Apart from cGAMP, STING is also activated by CDNs such as cyclic di-AMP or cyclic di-GMP from bacteria (14).CDNs and 2′3′-cGAMP bind to the endoplasmic reticulum (ER)-localized STING, which promotes STING dimerization and translocation from the ER to perinuclear punctuate structures (14,15). During the trafficking process, STING recruits and activates TANK binding kinase 1 (TBK1), stimulating phosphorylation and nuclear translocation of the transcription factor interferon regulatory factor 3 (IRF3), and to a lesser extent nuclear factor-κB (NF-κB), which can also be activated by IκB kinase (IKK) (16,17), leading to the production of type 1 interferons (IFNs) and many other inflammatory cytokines (18) (Fig. 1). By binding to the IFN-α/β receptor on the cell membrane of target cells, IFNs promote the expression of proteins involved in inhibiting viral replication and thus enhances the protective defenses of the immune system (7,19). In addition to initiation of IFN signaling in cells in which it is produced by cGAS, there is some evidence showing that 2′3′-cGAMP is able to promote downstream signaling in neighboring cells via distinct mechanisms such as gap junction–, membrane fusion–, or viral particle–mediated transfer (2022), thus mediating the cross talk between immune cells and their targeting cells. Intriguingly, activation of the cGAS-cGAMP-STING pathway could also be detected in nonimmune cells such as mouse embryonic fibroblasts and adipocytes (23,24), suggesting that activation of this pathway may have broader roles in addition to immune defense functions.

      Figure 1
      Figure 1

      Activation and regulation of the cGAS-cGAMP-STING pathway in cells. The cGAS is activated by viral and bacterial DNA as well as mtDNA and phagocytosed DNA aberrantly localized in the cytosol. Activated cGAS uses ATP and GTP as substrates to catalyze the formation of the second messenger, cGAMP, which binds to STING localized on the ER membrane. The binding of cGAMP to STING promotes STING translocation to the Golgi apparatus. During the translocation, STING recruits and activates TBK1, which in turn catalyzes the phosphorylation and nuclear translocation of IRF3, and to a lesser extent NF-κB, which can also be activated by IKK, leading to increased synthesis of IFN and other inflammatory genes.

      Activation of the cGAS-cGAMP-STING Pathway by Self-DNA

      In a healthy cell, host DNA normally resides in the nucleus or mitochondria. However, under certain pathophysiologic conditions such as DNA instability and/or mitochondrial stress, genomic DNA and/or mtDNA may be released into the cytoplasm, where it serves as a danger-associated molecular pattern to trigger immune responses. West et al. (23) found that, via heterozygosity of the mitochondrial transcription factor A (TFAM), disruption of mtDNA stability promoted mtDNA release into the cytosol, where it activated the cGAS-cGAMP-STING pathway and increased IFN gene expression. mtDNA-mediated activation of the cGAS-cGAMP-STING pathway is also observed by Bax/Bak-induced permeabilization of mitochondrial outer membrane (25,26). Besides mtDNA, recent studies show that the cGAS-cGAMP-STING pathway could also be activated by genomic DNA such as ruptured micronuclei and double-strand broken DNA of the primary nucleus caused by genomic instability and/or DNA damage (19,2729). In addition to genomic DNA and mtDNA, phagocytic DNA inadequately digested in the lysosomes has been shown to activate the cGAS-cGAMP-STING pathway (7,19,30,31) (Fig. 1). These results demonstrate that self-DNA is an important source of sterile inflammatory response induction that has been widely studied in many of the autoimmune disease and cancers. These findings raise an interesting question as to whether self-DNA–induced sterile inflammation is associated with metabolic disorders.

      Activation of the cGAS-cGAMP-STING Pathway in Obesity-Induced Inflammation and Metabolic Diseases

      Obesity is associated with various metabolic diseases such as type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and many types of cancer. Numerous studies have shown that chronic sterile inflammation in adipose tissue plays a key role in mediating obesity-induced insulin resistance and its associated metabolic diseases (32,33). However, the precise mechanisms by which obesity causes inflammation remain to be fully elucidated.

      During the past several years, evidence has accumulated to suggest an important role of the cGAS-cGAMP-STING pathway in regulating inflammation and energy homeostasis. The expression levels and/or activities of components in this signaling cascade, including cGAS, STING, and TBK1, are significantly upregulated under obesity conditions in mice (24,34,35). Activation of the cGAS-cGAMP-STING pathway in mouse adipose tissue could be triggered by high-fat diet (HFD)–induced mtDNA release, leading to an increase in chronic sterile inflammatory response (24). HFD-induced obesity and activation of the cGAS-cGAMP-STING pathway are prevented by adipose tissue–specific overexpression of disulfide bond A oxidoreductase-like protein (DsbA-L), a chaperone-like and mitochondrial localized protein whose expression in adipose tissue is greatly suppressed by obesity (36). Alternatively, knockout of DsbA-L in adipose tissue impaired mitochondrial function, increased mtDNA release, and activated the cGAS-cGAMP-STING pathway, leading to increased inflammation and exacerbated obesity-induced insulin resistance (24) (Fig. 2). These findings reveal that activation of the cGAS-cGAMP-STING pathway may mediate obesity-induced inflammation and metabolic dysfunction, beyond its well-characterized roles in innate immune surveillance. Consistent with this view, global knockout of the cGAS-cGAMP-STING downstream target TBK1 (37) or IRF3 (38), or pharmacological inhibition of IκB kinase ε (IKKε) and TBK1 by amlexanox, reduced body weight, enhanced insulin sensitivity, and improved glucose tolerance in obese mice and in a subset of patients with type 2 diabetes (34,39). However, it should be noted that while fat-specific knockout of TBK1 increased energy expenditure and attenuated HFD-induced obesity, it also exaggerated adipose tissue inflammation and insulin resistance, suggesting that TBK1 may have a feedback role in regulating obesity-induced inflammation (35) (Fig. 2). Indeed, activation of TBK1 has been found to reduce NF-κB activity and inflammation by promoting phosphorylation-dependent degradation of NF-κB–inducing kinase (NIK), an upstream kinase of IKKs (35). TBK1 has also been shown to attenuate cGAS-cGAMP-STING–mediated response by promoting STING ubiquitination and degradation (40) (Fig. 2). These findings explain the bidirectional roles of TBK1 in regulating inflammation (35). Nevertheless, it remains to be determined what role cGAS-cGAMP-STING signaling, which activates TBK1, may play in inflammation, insulin resistance, and energy expenditure in metabolic cells.

      Figure 2
      Figure 2

      Activation of the cGAS-cGAMP-STING pathway mediates obesity-induced inflammation and metabolic disorders. Obesity reduces the expression levels of disulfide bond A oxidoreductase-like protein (DsbA-L) in adipose tissue, leading to mitochondrial stress and subsequent mtDNA release into the cytosol. Aberrant localization of mtDNA in the cytosol activates the cGAS-cGAMP-STING pathway, leading to enhanced inflammatory gene expression and insulin resistance. Phosphorylated and activated TBK1 exerts a feedback inhibitory role by promoting STING ubiquitination and degradation or stimulating phosphorylation-dependent degradation of NF-κB–inducing kinase (NIK), thus attenuating cGAS-cGAMP-STING–mediated inflammatory response.

      The Potential Role of the cGAS-cGAMP-STING Pathway in NAFLD

      In addition to mediating obesity-induced insulin resistance in adipose tissue, activation of the cGAS-cGAMP-STING pathway has also been implicated in other metabolic diseases including NAFLD. NAFLD is characterized by hepatic steatosis, which contributes to the development of nonalcoholic steatohepatitis (NASH), a potentially progressive liver disease that may lead to cirrhosis and hepatocellular carcinoma. There is some evidence suggesting that the innate immune response contributes to NAFLD and NASH (4144). However, the underlying mechanisms by which the innate immune response promotes NALFD remain elusive. Luo et al. (42) and Yu et al. (45) recently independently found that activation of the liver cGAS-cGAMP-STING signaling pathway may mediate overnutrition-induced NAFLD and/or NASH. Indeed, STING levels were higher in liver tissues from NAFLD human patients compared with those without NAFLD. In addition, the mRNA levels of cGAS and STING are elevated in NASH mouse livers (42,46). Furthermore, the phosphorylation states of TBK1 and IRF3, two downstream targets of the cGAS-cGAMP-STING pathway, were significantly higher in livers of mice fed an HFD, which is coupled with NAFLD (42). Consistent with these findings, cGAS-cGAMP-STING–dependent activation of TBK1 in hepatocytes promotes the formation of insoluble p62/sequestosome 1 (SQSTM1) aggregates, a critical marker of NASH (47). On the other hand, STING deficiency attenuates steatosis, fibrosis, and inflammation in livers of mice fed with either methionine- and choline-deficient diet or HFD (42,45). Interestingly, both systemic or myeloid cell–specific knockout of STING increased resistance to HFD-induced or methionine- and choline-deficient diet–induced hepatic steatosis, inflammation, and/or fibrosis in mice (42,45). In addition, transplantation of bone marrow cells from control mice to STING knockout mice restored HFD-induced severity of steatosis and inflammation (42), suggesting that the improved metabolic phenotypes in the STING knockout mice were due to STING deficiency in liver-resident macrophages rather than in hepatocytes. These results are consistent with the finding that STING is not present in human and murine hepatocytes but is expressed at high abundance in hepatic nonparenchymal cells (48). Indeed, there is some evidence showing that hepatocytes do not express STING (45,49) and that by facilitating hypoxia-induced autophagy in hepatocytes, cGAS protects the liver from ischemia-reperfusion injury via a STING-independent mechanism. The lack of STING in human hepatocytes also explains why hepatitis virus has adapted to specifically replicate in hepatocytes (48). It is well known that selective pressures in evolution promote the development of an effective immune surveillance system to ensure survival in the face of pathogen invasion. While at early stages infection initiates various biochemical processes such as glucose release from stored glycogen, glycogenolysis, and gluconeogenesis, the glucose synthesis ability of the infected body may be greatly impaired at later stages of overwhelming infection, leading to hypoglycemia (50). Because hypoglycemia is detrimental to an organism, in the frame of evolution there is no host survival advantage for chronic pathogen infection. Therefore, a successful immune response is often short-lived, resulting in the termination of the pathogen-induced response quickly to ensure an organism’s survival. However, the lack of STING in hepatocytes results in type 1 IFN deficiency in response to hepatitis virus infection, which facilitates hepatitis viruses to escape from immune detection and causes not only acute but also chronic inflammation in the liver, leading to consequent hepatitis, cirrhosis, and hepatocellular carcinoma (48), which is often accompanied with metabolic dysfunction such as insulin resistance (51,52). Activation of the cGAS-STING pathway by overexpression of STING specifically in hepatocytes significantly suppressed the replication of hepatitis virus in vivo (48,53). Nevertheless, there are some reports showing that STING is present in hepatocytes and that knocking down either STING or IRF3 in hepatocytes alleviated lipid accumulation, hepatic inflammation, and apoptosis (5456). These findings raise a possibility that some of the NAFLD phenotypes observed in the whole-body STING knockout mice may result from STING deficiency in the hepatocytes of the mice. Further studies are needed to clarify this discrepancy.

      The Cross Talk Between the cGAS-cGAMP-STING and the mTORC1 Signaling Pathways

      The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient sensor that integrates energy, hormonal, metabolic, and nutritional inputs to regulate cellular metabolism, growth, and survival. Activation of the mTORC1 signaling pathway promotes anabolic processes such as protein, nucleotide, fatty acid, and lipid biosynthesis while inhibiting catabolic processes such as lipolysis and autophagy (57). Hasan et al. (58) recently found that chronic activation of the cGAS-cGAMP-STING signaling pathway is associated with reduced mTORC1 signaling in metabolically relevant tissues such as liver, fat, and skeletal muscle of the three-prime repair exonuclease 1 knockout (Trex1−/−) mice, concurrently with increased inflammation and altered metabolic phenotypes such as reduced adiposity and increased energy expenditure. Interestingly, STING deficiency in the Trex1−/− mice rescued both inflammatory and metabolic phenotypes, but IRF3 deficiency only rescued inflammation, suggesting that a component downstream of STING but upstream of IRF3 in the cGAS-cGAMP-STING pathway may play a role in regulating metabolism. Consistent with this view, they found that TBK1, the downstream target of STING, directly inhibited mTORC1 signaling by interacting with the mTORC1 complex (58) (Fig. 3). This result is in agreement with the findings of others that TBK1 inhibits mTORC1 activity in prostate cancer cells (59,60) and in an experimental autoimmune encephalomyelitis model (60). Nevertheless, one study reported that TBK1 may activate, rather than inhibit, mTORC1 through site-specific phosphorylation of mTOR at Ser2159 in response to epidermal growth factor but not insulin treatment (61). On the other hand, there is some evidence showing that mTOR may inhibit the cGAS-cGAMP-STING antiviral pathway. Meade et al. (62) recently identified a cytoplasmically replicating poxviruses–encoded protein, F17, that binds and sequesters Raptor and Rictor. The binding of F17 to Raptor promotes mTORC1-mediated suppression of STING activity and IRF3 translocation to the nucleus. The binding of F17 to Rictor, on the other hand, facilitates mTORC2-mediated cGAS degradation. By disrupting the mTORC1-mTORC2 cross talk, F17 inhibits cGAS-cGAMP-STING signaling and thus retains the benefits of mTOR-mediated stimulation of viral protein synthesis. Likewise, the mTOR downstream effector ribosomal protein S6 kinase 1 (S6K1) has been found to interact with STING in a cGAS-cGAMP–dependent manner, and the interaction promotes TBK1-mediated phosphorylation of STING and recruitment of IRF3 for antiviral immune responses (63). Of note, the interaction of S6K1 with STING is mediated by the kinase domain but not the kinase function of S6K1, suggesting a mTORC1-independent regulation of S6K1 on STING signaling (Fig. 3). Taken together, all these findings indicate a complex cross talk between the cGAS-cGAMP-STING and the mTORC1 signaling pathways. Further investigations will be needed to clarify these controversies and to elucidate the molecular details as well as the metabolic consequences of the cross talk between the cGAS-cGAMP-STING and the mTORC1 signaling pathways.

      Figure 3
      Figure 3

      The interplay between the cGAS-cGAMP-STING pathway with mTORC1 signaling. Knockout of three-prime repair exonuclease 1 (Trex1), which degrades DNA in the cytosol, leads to the activation of the cGAS-cGAMP-STING pathway and suppression of the mTORC1 activity in mice. The cGAS-cGAMP-STING pathway may inhibit mTORC1 activity through a TBK1-dependent mechanism. Conversely, the cGAS-cGAMP-STING pathway may be inhibited by mTORC1-dependent suppression of STING activity and IRF3 translocation or by mTORC2-mediated cGAS degradation. Of note, the kinase domain but not the kinase function of ribosomal protein S6 kinase 1 (S6K1) is essential for S6K to interact with STING, which facilitates TBK1-mediated phosphorylation of STING and recruitment of IRF3 for antiviral immune responses.

      The cGAS-cGAMP-STING Pathway and Autophagy/Mitophagy

      In addition to cross talking to mTORC1, the cGAS-cGAMP-STING pathway has also been found to interact with the autophagy machinery in innate immune responses (Fig. 4). Autophagy exerts its quality control function by sequestering damaged organelles and protein aggregates and invading intracellular pathogens in the cytoplasm for lysosomal-mediated degradation (64). This programmed survival pathway also acts as a recycling system to maintain essential protein biosynthesis during stress conditions, such as nutrient insufficiency, growth factor depletion, and pathogen invasion (65). Thus, autophagy is important for the maintenance of the metabolic homeostasis of a cell, and its dysregulation might contribute to the development of metabolic disorders (6668).

      Figure 4
      Figure 4

      The cross talk between the cGAS-cGAMP-STING pathway and autophagy/mitophagy. Autophagy is initiated with the activation of ULK1 complex. ULK1-induced activation of beclin-1 complex favors the nucleation of autophagosome precursors and promotes autophagy. Mitophagy is a selective form of autophagy. Activation of the cGAS-cGAMP-STING pathway may stimulate autophagy via a cGAS/beclin-1 interaction–dependent mechanism. The cGAS-cGAMP-STING pathway also promotes autophagy/mitophagy by TBK1-dependent phosphorylation and activation of receptors OPTN and p62 (SQSTM). Alternatively, activation of the cGAS-cGAMP-STING pathway promotes an autophagy-dependent negative feedback regulation by 1) the interaction of cGAS with beclin-1, which in turn inhibits cGAS activity; 2) cGAMP-induced activation of ULK1, which promotes STING degradation by phosphorylation at Ser366; and 3) TBK1-p62/SQSTM1–dependent ubiquitination and degradation of STING. PINK/Parkin-induced mitophagy also restrains cGAS-cGAMP-STING signaling and innate immunity by mitophagy-mediated mtDNA clearance.

      Autophagy is initiated with the activation of the ULK1 complex, which is inhibited by mTORC1 and promoted by nutrient deprivation and AMPK activation (6769) (Fig. 4). Autophagy is also regulated by a multiprotein complex comprising beclin-1, a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6), vacuolar protein sorting 34 (VPS34), and autophagy/beclin-1 regulator 1 (AMBRA1), which favors the nucleation of autophagosome precursors (67,70). Activation of the cGAS-cGAMP-STING pathway has been found to prompt ubiquitin-mediated autophagy that delivers bacteria to autophagosomes for degradation (71). Similarly, cGAS protects hepatocytes from ischemia-reperfusion injury–induced apoptosis in vivo and in vitro through an induction of autophagy in mouse hepatocytes (49). How cGAS stimulates autophagy in hepatocytes is currently unknown but appears to be mediated by a STING-independent mechanism (49). Interestingly, cGAS has been found to competitively bind beclin-1 to dissociate the negative autophagy factor rubicon from the beclin-1–phosphatidylinositol 3-kinase class III (PI3KC3) autophagy complex, leading to PI3KC3 activation and subsequent autophagy induction (72,73). This finding provides a possible explanation for the finding that cGAS promotes autophagy via a STING-independent mechanism. It is interesting to note that in addition to stimulating autophagy, the interaction between cGAS and beclin-1 negatively regulates cGAS enzyme activity in immune cells such as RAW264.7 and L929 cells, thus promoting cytosolic DNA degradation and preventing overactivation of the cGAS-cGAMP-STING pathway–mediated IFN responses and persistent immune stimulation (72). Activation of the cGAS-cGAMP-STING pathway also promotes an autophagy-dependent negative feedback regulation of STING, which is mediated by cGAMP-induced dephosphorylation of AMPK and activation of ULK1 that phosphorylates and promotes autophagosome-dependent degradation of STING (74) or by TBK1-p62/SQSTM1–dependent ubiquitination and degradation of STING (40), providing a mechanism to prevent the persistent transcription of innate immune genes (Fig. 4). However, a very recent study showed that upon binding cGAMP, STING translocated from the endoplasmic reticulum to the endoplasmic reticulum-Golgi intermediate compartment, which served as a membrane source for LC3 lipidation, leading to autophagosome formation and autophagy (75). This study reveals that the STING-induced activation of autophagy is mediated by a mechanism that is dependent on the Trp-Asp (W-D) repeat domain phosphoinositide-interacting protein (WIPI2) and autophagy-related gene 5 (ATG5), but independent of TBK1, ULK, or VPS34-beclin kinase complexes. Interestingly, p62/SQSTM1 has been shown to interact with mTOR and Raptor, which is critical for mTOR recruitment to lysosomes and for amino acid signaling–induced activation of S6K1 and 4EBP1 (76). However, it remains unknown whether the cGAS-cGAMP-STING signaling–induced and TBK1-mediated phosphorylation of p62/SQSTM1 plays a role in regulating mTORC1 signaling and function.

      Mitophagy is a selective form of autophagy that mitigates inflammation by removing damaged mitochondria from cells (77). Mitochondrial damage induces mitophagy by promoting the accumulation of the ubiquitin kinase PINK1 on the outer membrane of the damaged mitochondria, which in turn phosphorylates Parkin at Ser65, leading to the activation of this E3 ubiquitin ligase and subsequent degradation of ubiquitinated substrates (78). A recent study showed that Parkin and PINK deficiency promoted mtDNA release and activation of the cGAS-cGAMP-STING pathway in mouse heart tissue, leading to a strong inflammatory phenotype (77). These results support a role of PINK/Parkin-mediated mitophagy in restraining cGAS-cGAMP-STING signaling and innate immunity. By quantitative proteomics analysis, Richter et al. (79) recently found that the cGAS-cGAMP-STING downstream target TBK1 phosphorylated several mitophagy receptors such as optineurin (OPTN) and p62 (SQSTM) at their autophagy-relevant sites, which creates a signal loop amplifying mitophagy (Fig. 4). However, while these findings reveal a link between the cGAS-cGAMP-STING pathway and autophagy/mitophagy, the detailed biochemical mechanism underlying the link remains largely elusive, especially in metabolic tissues. Seeking answers to these questions would be an attractive subject for further investigation.

      The cGAS-cGAMP-STING Signaling and Apoptosis

      Apoptosis is a programmed cell death process that provides a mechanism to maintain organismal homeostasis (80). Apoptosis is regulated by prodeath proteins such as Bak and Bax and prosurvival proteins such as BCL-2 and BCL-XL. Bak/Bax activation promotes mitochondrial outer-membrane permeabilization and the release of apoptotic proteins such as cytochrome c to the cytosol, leading to further activation of the downstream pathway of intrinsic apoptosis through initiator and executioner caspases cascade (81) (Fig. 5). Activation of caspases, which is a hallmark of apoptosis, has been found to not only promote cell death but also prevent dying cells from triggering a host immune response (82). However, while apoptosis has long been known as an immunologically silent form of cell death, the molecular basis underlying the suppression of immune responses remains unknown. Several recent studies suggest that caspase-mediated inhibition of the cGAS-cGAMP-STING signaling pathway may contribute to the silencing of immune process in apoptotic cells. In agreement with this, TBK1 phosphorylation and IFNα-stimulated gene expression are increased in caspase-9 knockout or caspase-3/-7 double knockout mice and cells (25). Constitutive activation of the type I IFN response was also observed in caspase-9–deficient mouse embryonic fibroblasts (26). In addition, inhibition of caspases led to increased phosphorylation of TBK1 and IRF3 in Bax/Bak-sufficient cells but not in Bax/Bak knockout cells. Furthermore, the caspase deficiency–induced IFNβ response was prevented by knocking out cGAS or STING (25). These findings suggest that apoptosis may suppress immune responses by inhibiting the cGAS-cGAMP-STING pathway. However, the precise biochemical mechanism(s) by which caspases negatively regulate the cGAS-cGAMP-STING pathway remains unclear but could result from multiple redundant processes such as attenuated gene expression, cleavage and inactivation of a component or components of the type I IFN production pathway, and caspase-mediated degradation of mtDNA, thereby disrupting its interaction with cGAS, thus preventing the activation of the cGAS-cGAMP-STING signaling pathway and its downstream IFN action (26). Consistent with this, Wang et al. (83) found that cGAS could be cleaved by several inflammatory caspases including caspase-1, which can be activated by mtDNA release–induced formation of inflammasome, or by caspase-4, -5, and -11. Alternatively, activation of the cGAS-cGAMP-STING pathway may promote apoptosis via both transcriptional and nontranscriptional mechanisms (84,85). It has been shown that STING activation in T cells induces apoptosis through an IRF3- and p53-mediated transcriptional proapoptotic program (86). A proapoptotic but transcription-independent role of STING is observed in hepatocytes that is mediated by the association of IRF3 with the proapoptotic molecule Bax/Bak, which contributes to alcoholic liver disease (55). The proapoptotic role of STING was also found in other cells such as B cells and endothelial cells (87,88). Collectively, these findings demonstrate a complicated cross talk between cGAS-cGAMP-STING signaling and apoptosis. Given the importance of apoptosis in regulating metabolic homeostasis, it would be of great interest to determine the functional roles of the cross talk between cGAS-cGAMP-STING signaling and apoptosis in metabolic tissues.

      Figure 5
      Figure 5

      The association of cGAS-cGAMP-STING signaling with apoptosis. The activation of prodeath proteins such as Bax/Bak promotes mitochondrial outer-membrane permeabilization and the release of cytochrome c to the cytosol, leading to activation of intrinsic apoptosis through initiator and executioner caspases cascade. Defects in apoptosis by knocking out caspase-9 or caspase-3/-7 lead to constitutive activation of the cGAS-cGAMP-STING pathway; however, the precise mechanisms by which caspase-induced apoptosis inhibits innate immune remain unknown. Inflammatory caspases including caspase-1, which can be activated by mtDNA release–induced formation of inflammasome, or caspase-4, -5, and -11 cleave cGAS, thus preventing the activation of immune response. Alternatively, activation of the cGAS-cGAMP-STING pathway promotes apoptosis via both transcriptional and nontranscriptional programs in a TBK1-IRF3–dependent manner.

      Concluding Remarks

      Inflammation is now clearly recognized as a major risk factor for obesity-induced metabolic disorders. Suppressing inflammatory pathways, therefore, holds promise for developing effective therapeutic treatment of obesity-related diseases. However, identification of pharmacological targets to suppress inflammation is usually a challenge, requiring better understanding of the mechanisms underlying obesity-induced inflammation. The identification of the cGAS-cGAMP-STING pathway as a key player in mediating obesity-induced chronic low-grade inflammation has pointed out an exciting new direction to elucidate the mechanism underlying obesity-induced metabolic diseases and to develop potential therapeutic strategies to improve metabolic homeostasis. However, a number of important questions remain to be answered.

      First, while the pivotal roles of the cGAS-cGAMP-STING pathway in immune defense against various microbial pathogens have been extensively studied (35), its function in nonimmune cells remains largely unexplored. The findings that the cGAS-cGAMP-STING pathway components such as cGAS, STING, and TBK1 are highly expressed in adipocytes and that the expression levels of these molecules are stimulated under obesity conditions (24) raise a possibility that activation of this pathway may play an important role in metabolic diseases. However, it should be acknowledged that HFD feeding activates the cGAS-cGAMP-STING pathway not only in adipocytes but also in macrophages (24,42), the predominant proinflammatory immune cell type in obese adipose tissue (89), suggesting that activation of the cGAS-cGAMP-STING pathway in adipose tissue–resident macrophages may make a significant contribution to the deteriorated metabolic phenotypes of the obese mice. Further studies will be warranted to dissect the relative contribution of the cGAS-cGAMP-STING pathway in metabolic relevant cells, such as such hepatocytes and adipocytes, and tissue-resident immune cells and the potential cross talk between these cells triggered by cGAS-cGAMP-STING pathway activation.

      It is interesting to note that the function of cGAS and STING is regulated by mTOR complexes and vice versa (63,74) (Fig. 3), suggesting that activation of the cGAS-cGAMP-STING pathway may be modulated by environmental inputs such as cellular nutrient status and/or growth factors’ stimulation. However, the underlying mechanism by which DNA-induced activation of the cGAS-cGAMP-STING pathway is moderated by environmental changes remains unexplored. In addition, given that mTORC1 plays a pivotal role in regulating cell metabolism and energy homeostasis, it is possible that activation of the cGAS-cGAMP-STING pathway may mediate some of the multifaceted roles of mTORC1 signaling pathway. Interestingly, activation of TBK1 has been shown to inhibit mTORC1 activity (58), suggesting a potential negative regulation of mTORC1 signaling by activation of the cGAS-cGAMP-STING pathway. Further studies will be needed to elucidate the precise mechanism underlying the cross talk between these two signaling pathways and the physiological roles of the interaction. In addition to the mTORC1 signaling pathway, available evidence suggests that the cGAS-cGAMP-STING pathway also cross talks to both autophagy and apoptosis (Figs. 4 and 5). Autophagy and apoptosis regulate the turnover of cellular organelles and cells within organisms, and their interaction is highly context dependent and in most of cases mutually inhibitory (90). The identification of the cGAS-cGAMP-STING pathway linking to both autophagy and apoptosis suggests an important new layer of regulation of these distinct mechanisms for the control of cell homeostasis. However, an integrated understanding of the interplay between the cGAS-cGAMP-STING and these cellular pathways remains largely unclear. It is also unknown when and which inputs to the network are dominant and how this depends on the physiological or pathophysiological context. Answers to these questions will likely require both deeper biochemical and physiological studies of the interaction both in vitro and with tissue-specific transgenic and/or knockout mouse models that enable more specific perturbation and monitoring of these pathways in vivo.

      Lastly, it remains to be established whether and how targeting the cGAS-cGAMP-STING pathway is a suitable strategy to treat metabolic diseases. Given that the cGAS-cGAMP-STING pathway is activated by mitochondrial stress under obesity conditions, it is tempting to speculate that at least a part of the effects of increased inflammation may be due to activation of the cGAS-cGAMP-STING pathway. In fact, much progress has been made on the development of small-molecule inhibitors targeting components in the cGAS-cGAMP-STING pathway over the past several years. As of now, several cGAS inhibitors have been reported. By in silico screening of drug libraries using mouse cGAS/DNA target (PDB 4LEZ), An et al. (91) recently identified hydroxychloroquine, quinacrine, and 9-amino-6-chloro-2-methoxyacridine as potential cGAS inhibitors. These molecules do not bind to the active site of cGAS but are instead found to localize to the minor groove of DNA between the cGAS/DNA interface (91). RU.521 and RU.365, however, are found to inhibit cGAS by binding at the cGAS active site (92). Wang et al. (93) showed that suramin, a drug used clinically for the treatment of African sleeping sickness (94), binds to the DNA binding site of cGAS and inhibits cGAS activity by disrupting dsDNA/cGAS binding. In addition to targeting cGAS, several small-molecule inhibitors of STING have also been reported. By a cell-based chemical screen, Haag et al. (95) recently identified two nitrofuran derivatives—C-178 and C-176—that strongly reduced STING-mediated, but not RIG-I– or TBK1-mediated, IFNβ reporter activity. Excitingly, they found that these derivatives reduce STING-mediated inflammatory cytokine production in both human and mouse cells and attenuate pathological features of autoinflammatory disease in mice (95). Very recently, Dai et al. (96) reported that aspirin, a nonsteroidal anti-inflammatory drug, can directly bind and enforce the acetylation of cGAS, leading to a robust inhibition of cGAS enzymatic activity and self-DNA–induced immune response in both Aicardi-Goutières syndrome patient cells and a mouse model of Aicardi-Goutières syndrome. These results provide proof of concept that targeting the cGAS-cGAMP-STING pathway may be efficacious in the treatment of inflammatory diseases, which opens new avenues for developing novel therapies for inflammation-related metabolic diseases. Future work on the molecular details of the regulation and network of the cGAS-cGAMP-STING pathway and its tissue-specific function should enable the rational targeting of this signaling to unravel the full therapeutic potential of this extraordinary pathway in metabolism and relevant biological functions.



      Sell Unused Diabetic Strips Today!

      Banh Mi Chicken Burger Lettuce Wraps

      By electricdiet / January 19, 2020


      I love banh mi sandwiches primarily due to all of their pickled vegetable goodness. (I’m a huge vinegar fan, as you know.) Unfortunately, most of them have way too little meat and vegetables for all of the bread they include. These Banh Mi Chicken Burger Lettuce Wraps give you all of the flavors, but no bun at all.

      Banh Mi Chicken Burger Lettuce Wraps

      In Vietnamese, bánh mi technically means bread, but it also refers to a sandwich made with meat (usually pork), pickled carrots and daikon radish, cucumber, cilantro, and spicy mayonnaise. It’s typically eaten as street food but can also serve as a meal.

      How to make Banh Mi Chicken Burger Lettuce Wraps

      Here I’ve substituted ground chicken for the pork and mixed in a little bit of ginger, garlic, soy sauce, and lime with the meat before grilling. The carrots, cucumbers, and Daikon radish (or onion) get a quick soak in brine to pickle them. The burgers, veggies, plus spicy mayo and jalapeños (if you dare) come together in a low carb lettuce wrap. No bread required.

      Like chicken burgers and lettuce wraps?

      If you like the chicken burger concept, check out my recipe for Buffalo Chicken Burgers. If you’re a fan of lettuce wraps, try Hoisin Chicken Lettuce Wraps. You can cook the chicken in an Instant Pot® or buy a rotisserie chicken for a super-quick meal.

      Banh Mi Chicken Burger Lettuce Wraps

      Enjoy the pickled flavors of a Banh Mi sandwich minus the bread

      Author: Adapted from kikkomanusa.com

      Prep Time: 10 minutes

      Cook Time: 10 minutes

      Freezer Time: 10 mins

      Total Time: 30 minutes

      Course:

      Main Course

      Cuisine:

      Asian

      Keyword:

      banh mi, banh mi chicken burger, chicken banh mi, chicken burger, low-carb banh mi

      Servings: 4

      Banh Mi Chicken Burger Lettuce Wrap

      Ingredients

      FOR THE PICKLED VEGETABLES

      • 1/3
        cup
        rice vinegar
      • 1
        tablespoon
        sugar
      • 1
        teaspoon
        kosher salt
      • 1/2
        English cucumber
        cut into matchsticks
      • 2
        medium carrots
        cut into matchsticks
      • 1/2
        Daikon radish
        cut into matchsticks (optional)

      FOR THE BURGERS

      • 1
        pound
        ground chicken or turkey
      • 1
        scallion
        thinly sliced (about 2 tablespoons)
      • 1
        teaspoon
        freshly grated ginger
      • 1/2
        teaspoon
        minced garlic
      • 1
        tablespoon
        soy sauce or tamari
      • juice from 1/2 lime
      • 1
        tablespoon
        light brown sugar

      FOR SERVING

      • lettuce leaves
      • sriracha mayonnaise
        optional
      • thinly sliced jalapeños
        optional

      Instructions

      MAKE THE PICKLED VEGETABLES

      1. In a medium bowl, stir together the vinegar, sugar, and salt. Add the cucumber, carrot, and radish sticks. Let it sit at room temperature for at least 10 minutes (while you make the burgers).

      2. When ready to serve, drain the vegetables.

      MAKE THE BURGERS

      1. In a medium bowl, combine the ground chicken, scallions, ginger, garlic, soy sauce, lime juice, and brown sugar. Shape into 4 patties and place on a cookie sheet or plate that will fit in your freezer. Freeze for 10 minutes.

      2. Grill burgers for about 5 minutes per side or until they are cooked to an internal temperature of 165°F. If you don’t have a grill, you can use the broiler.

      SERVE

      1. Spread some sriracha mayonnaise, if using, on 4 large lettuce leaves. Top each with a burger.

      2. Add the drained pickled vegetables and the jalapeños, if using.

      Recipe Notes

      If you can’t find daikon radish, you can use another type of radish or some thinly sliced onion.

      Nutrition information does not include optional ingredients.

      Nutrition facts per serving (1 burger)

      Calories: 242kcal

      Fat: 11g

      Saturated fat: 3g

      Cholesterol: 85mg

      Sodium: 561mg

      Potassium: 63mg

      Carbohydrates: 11g

      Fiber: 2g

      Sugar: 11g

      Protein: 23g

      Vitamin A: 57%

      Vitamin C: 12%

      Calcium: 7%

      Iron: 12%



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      Marzetti Avocado Ranch Taco Salad

      By electricdiet / January 17, 2020


      Hi guys!  I’ve missed you!  But promise, things are working behind the scenes to give you the best blog experience.  Guess what?  You’ll actually be able to find my recipes!  I hope to have it up and running with the new look in the next week or so.  Thank you for being patient!

      I have still been busy in my kitchen though.  Some things will never change 😀

      I recently found Marzetti Simply Dressed Salad Dressings in the refrigerated section and I have a new favorite salad dressing.  Most of my salads are zero points, so it’s totally worth the 2-3 points for 2 tablespoons of their dressings.  

      Print

      Marzetti Avocado Ranch Taco Salad

      A quick and easy taco salad using pantry staples and Marzetti Simply Dressed Salad Dressing.  


      Scale

      Ingredients

      • 4 ounces chicken breast
      • 1 tablespoon taco seasoning
      • avocado oil spray
      • 2 cups romaine lettuce, chopped
      • 1/2 cup canned corn, drained
      • 1/2 cup canned black beans, drained
      • 1/4 cup chopped radish
      • 1/3 cup sliced grape tomatoes
      • 2 tablespoons Marzett Avocado Ranch Dressing

      Instructions

      Heat a non-stick skillet over medium heat with avocado spray.

      Season the chicken with the taco seasoning, and cook for 6-8 minutes, flipping half way through, until it reads 165 degrees.

      While the chicken rests, plate the salad – romaine, corn, black beans, radish and cherry tomato.

      Slice the chicken after it’s rested 10 minutes, and top on salad.  Drizzle with Marzetti Avocado Ranch Dressing.  That’s it!

      Notes

      Most salads no matter which plan you are on are zero points.

      On team purple and team blue on WW, this salad is only 3 points – you only have to count the dressing.

      On team green, it’s will be 6 points – you just have to count the chicken. 😀

      This salad is so good and can easily be on your weekly lunch or dinner rotation, because you can meal prep the chicken ahead of time as well as the veggies.

      You can find this dressing in the produce section – they have lots of flavors to choose from and range from 2-3 points for 2 tablespoons.  Totally worth it because this dressing is delicious and will actually make you crave salad – pinky swear!

      I hope you had a great weekend!  I am still going strong with my #dryjanuary – even with having people over on Saturday!  We had a “vision 2020 party” and I’ll post my vision board tomorrow.

      Happy Monday!  Make it a great day!





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