The Insulin / Glucagon Ratio and Why Diabetics and People W/ Severe Insulin Resistance Must be Careful With Protein

The Insulin / Glucagon Ratio and Why Diabetics and People W/ Severe Insulin Resistance Must be Careful With Protein

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You're insulin resistant and trying to lose weight with high protein intakes? Then you got to read this article carefully...

High protein diets can help you lose weight while maintaining muscle mass. This should make them the ideal choice of diabetic patients, many of whom are suffering from weight issues that are often not corollary, but rather causatively involved in the development of type II diabetes.

Unfortunately, studies in type I diabetics and preliminary evidence from type II diabetics and other insulin resistant individuals suggests that - if the disease has progressed significantly - eating too much protein can be a problem, as well, one that may worsen the ill effects of diabetes.

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The reason for the potentially detrimental effects of high protein intakes on glycemia is well-known, but rarely acknowledge: gluconeogensis. As early as in the 1970s, researchers observed that the administration of a high-protein diets to rats, can significantly elevate plasma glucose and insulin concentrations and reduce the sensitivity of fat cells to insulin (Blazquez. 1970).

Figure 1: Post-prandial insulin and glucose levels in rats after several weeks of high protein feeding (Blazquez. 1970).

Over the decades after the publication of the Blazquez study, evidence for both the beneficial (Tremblay. 2007) and potential ill effects (Unger. 1971; Eisenstein. 1974) of high protein diets on diabetes and insulin resistance has been accumulating (Linn. 2000).

Sign. increases in urea prod. are another consequence of protein-based gluconeogenesis (Gannon. 2001).

As usual you will find conflicting evidence: In 2001, for example, Gannon et al. found only a modest increase in serum glucose levels in type II diabetics in response to the ingestion of 50g of protein - in spite of the fact that ~20-23g of it were converted to glucose in the liver.

What is important to note, however, is the fact that the protein source in the Gannon study was lean beef - one of the slowest sources of protein you can have and thus not exactly the #1 candidate for being subjects to immediate and thus glucose raising gluconeogenesis.

In that, it has been know for almost as long that the degree of offset of the ratio of glucagon to insulin in type I and II diabetics may decide, whether the ingestion of high(er) protein diets will help or hinder glucose management. In the pertinent, seminal review, Unger observes that "the insulin:glucagon ratio (I/G) varies inversely with need for endogenous glucose production, being lowest in total starvation and highest during loading with exogenous carbohydrate" (Unger. 1971). It is thus not surprising that studies have observed that

• the infusion of the glucose precursor, alanine, in the fasting state causes a fall in I/G, a “catabolic response,” but increases I/G during a glucose infusion, an ”anabolic response, which spares alanine from the fate of being abused for gluconeogenesis, 
• similar effects have been observed after a protein load; normally after an overnight fast I/G rises in response to a beef meal, an anabolic response, while in the carbohydrate-deprived subject, the I/G does not rise, remaining at a catabolic level (cf. Chevalier. 2006)

Now, back in the day these observations were mainly used to support the concept of a "protein sparing action" of glucose. Today, the effect on gluconeogenesis, i.e. the production of glucose from proteins / amino acids in the liver, has moved to the center of attention of a number of scientists. Calbet and MacLean, for example, investigated how the plasma glucagon and insulin responses of humans would depend on the rate of appearance of amino acids after ingestion of very fast vs. fast protein sources.

Figure 2: Glucose and glucagon levels in the blood of healthy volunteers after ingesting either 25g glucose or protein solutions containing whey protein hydrolysate (WPH), pea peptide hydrolysate (PPH) or milk protein (MS | Calbet. 2002).

Their results (see Figure 2) indicate the obvious: Even in healthy individuals and even upon co-administering protein sparing and 25 g of anti-gluconeogenic glucose, the fastest protein sources (whey protein, WPI; pea peptide hydrolysate; PPH) produce the highest increase in glucagon, gluconeogenesis and thus serum glucose levels in the first 20 minutes after the ingestion of the 25 g of glucose plus ~30g of the different proteins.

Let's just be clear here: I am not saying that high protein diets cannot help with diabetes. I am just saying that bolus intakes of protein can be problematic for type I diabetics and people with severe insulin resistance and progressive type II diabetes.

What may not be a major problem for healthy individuals, though, can be a deal-breaker for diabetics, in whom studies into the inter-organ flux of substrates after a protein-rich meal (slow digesting beef 3g/kg body weight) show that the normally non-significant effect on glycemia (<5% in healthy subjects) was exuberant in the diabetic subjects in whom you will see a greater rise in blood glucose, and a three-to-fourfold increment in splanchnic glucose output at 30-90 min that was triggered by a doubling of arterial glucagon, which was not compensated for by an concomitant increase in insulin as it occurred in the healthy test subjects (Wahren. 1976).

Figure 3: Rel. changes in blood glucose after ingestion of 3g/kg lean meat in healthy and diabetic subjects (Wahren. 1976).

Whether an increase in protein intake will have beneficial or ill effects on your ability to control your glucose levels will thus clearly depend on the degree of hepatic insulin resistance / pancreatic dysfunction you expose.

• If you are severely diabetic and/or insulin resistance, i.e. you either don't produce enough or no insulin in response to the ingestion of protein or your body does not react to the insulin, as it would be the case in type I diabetes and progressive type II diabetes, your glycemia may be impaired by high protein meals.
• If you are only slightly insulin resistant, you will probably benefit from the insulinogenic effects of protein and the ability to replace carbohydrates in your meals with protein. You may nevertheless want to test your individual glucose response to fast-digesting proteins like whey or amino acid supplements, which may still result in an uncontrolled gluconeogenic response.
• If you are healthy and insulin sensitive, you won't have to worry about the gluconeogenic effects of high protein intakes - regardless of whether we are talking about fast or slow protein sources, because the former will spike insulin enough to blunt any pro-gluconeogenic effects of the concomitant increase in glucagon to keep the rates of gluconeogenesis and thus your glucose levels in check.

So, just as you've read it here at the SuppVersity before, what's good and what's bad for your cannot be generalized - even when it comes to something as popular as increasing your protein intake.

What do you have to remember? High protein intakes, especially in form of large bolus intakes of 30g or more protein per session can trigger unwanted glucose excursions. These problems with glucose management occur almost exclusively in diabetics, in whom the protein-induced increase in insulin and / or the effects of this increase in insulin is / are blunted.

Figure 1: GIP and GLP-1 response to whey and white bread (left, top & bottom); insulin release (%) per islet relative to glucose after incubation with different amino acids, amino acid mixtures and mixture + GIP (Salehi. 2012) | more

Due to the unavoidable protein induced increase in glucagon, diabetics and people with severe insulin resistance will fall into a catabolic state in which the lions share of the protein they ingest will be subject to gluconeogenesis, i.e. the production of glucose from proteins / their amino acids in the liver. The consequence of the skyrocketing rates of gluco-neogenesis is an increase in blood glucose that will only exacerbate the existing damaging effects of elevated glucose levels in diabetics and people with severe insulin resistance. Since the of gluco-neogenesis depends on the rate of appearance of amino acids in the blood, fast-digesting proteins like whey are more prone to trigger this effect than slow-digesting proteins like meat.

If you don't belong to the previously referred to group of people suffering from type I or severe type II diabetes and/or severe insulin resistance, though, you don't have to worry that high(er) protein diets could mess with your ability to manage your glucose levels | Comment on Facebook!

References:

• Blazquez, E., and C. Lopez Quijada. "The effect of a high-protein diet on plasma glucose concentration, insulin sensitivity and plasma insulin in rats." Journal of Endocrinology 46.4 (1970): 445-451.
• Calbet, Jose AL, and Dave A. MacLean. "Plasma glucagon and insulin responses depend on the rate of appearance of amino acids after ingestion of different protein solutions in humans." The Journal of nutrition 132.8 (2002): 2174-2182.
• Chevalier, Stéphanie, et al. "The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism." Diabetes 55.3 (2006): 675-681.
• Eisenstein, Albert B., Inge Strack, and Alton Steiner. "Glucagon stimulation of hepatic gluconeogenesis in rats fed a high-protein, carbohydrate-free diet." Metabolism 23.1 (1974): 15-23.
• Gannon, M. C., et al. "Effect of Protein Ingestion on the Glucose Appearance Rate in People with Type 2 Diabetes 1." The Journal of Clinical Endocrinology & Metabolism 86.3 (2001): 1040-1047.
• Linn, T., et al. "Effect of long-term dietary protein intake on glucose metabolism in humans." Diabetologia 43.10 (2000): 1257-1265.
• Tremblay, Frédéric, et al. "Role of dietary proteins and amino acids in the pathogenesis of insulin resistance." Annu. Rev. Nutr. 27 (2007): 293-310.
• Unger, Roger H. "Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses." Diabetes 20.12 (1971): 834-838.
• Wahren, J., P. H. I. P. Felig, and L. A. R. S. Hagenfeldt. "Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus." Journal of Clinical Investigation 57.4 (1976): 987.

GABA Supplementation Improves Glucose Management - Even in Healthy Subjects | Significant Reduction in Glycated Albumin Levels After Only 7 Days on 3x2g GABA per Day

GABA Supplementation Improves Glucose Management - Even in Healthy Subjects | Significant Reduction in Glycated Albumin Levels After Only 7 Days on 3x2g GABA per Day

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No acute changes in blood glucose, but extreme changes in insulin levels. How can this trigger a reduction in glycated albumin - How's that possible? 

You've read about gamma aminobutyric acid (GABA) at the SuppVersity before. While most people think of it mainly as a calming agent, though, SuppVersity readers know that it has the remarkable ability to heal the insulin producing β-cell in rodents by stimulating their replication, protecting them against apoptosis, and attenuating insulitis (Soltani. 2011; Tian. 2013; Prud'homme. 2014; Purwana. 2014). And while these favorable effects were first observed in mice, researchers are quite sure that they are valid in humans, too- that's also because said effects have been confirmed only recently by Tian et al. (2014) and Purwana et al. (2014) in vitro as well as in xenotransplanted human islets.

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If you know that, the observations researchers from the Fudan University in Shanghai report in their latest study probably won't come as a surprise. In their investigation into the  pharmacokinetics and pharmacodynamics of GABA in healthy volunteers, the researchers found that the chronic provision of 2g of GABA three times per day triggers a highly significant decrease in glycated albumin (GA) levels, the intermediate measure of blood glucose control (in-between acute blood glucose measurements and HbA1c | Roohk. 2008), within only 7 days.

Figure 1: Acute glucose (top) and insulin (bottom) response after single and repeated administration of 2g of GABA (left). Chronic effects of repeated dose-administration of GABA on glycated albumin (right | Li. 2015).

If you scrutinize the data in Figure 1, though, there are a few questions we still need to find answers to. Obviously, the acute administration of GABA (Figure 1, left) lead to significant increases in insulin - both, under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01).

Glucose, insulin and glucagon: Let's briefly recap how the three are related. To lower your glucose levels, your body produces insulin which will then tell your cells suck the glucose from the bloodstream. If the glucose levels are getting lower and lower, your body produces glucagon which will then trigger a cascade of events to increase your blood glucose levels. This can be done by mobilizing stored glycogen (mostly from the liver) or producing new glucose via gluconeogensis - a process that relies heavily on amino acids, first and foremost alanine and glutamine.

Usually, this 1.4-fold or 1.6-fold increase in insulin should trigger a significant (at least transient) decrease in blood glucose. Since the latter wasn't the case in either the fasted or the fed tests the scientists conducted on the twelve subjects, who participated in the open-labeled, three-period trial, it appears more than counter-intuitive that the chronic administration of GABA which does not accumulate in the body and was found to be almost completely absorbed in 60 minutes and to have a half-life of 5h still lead to an GA decrease of approximately 11-12%.

Now this obviously confirms that GABA, due to its ability to increase islet hormonal secretion, has potential therapeutic benefits for diabetes, what the study does not tell us, though, is whether the lack of immediate effects on blood glucose levels can, as the scientists suspect, "in part be attributed to GABA-induced counter regulatory mechanisms, especially elevated glucagon" (Li. 2015) which rose so that the insulin-to-glucagon ratio remained unchanged. Yet while the latter could explain why the subjects did not become hypoglycemic in the face of increased insulin levels, the lack of certainty with respect to the underlying mechanisms makes the study results difficult to interpret.

As a loyal SuppVersity reader you will know that I talked about the potential need to re-balance glucose levels and its paradoxically agitating effects in a 2013 episode of SHR, already.

So what's the verdict, then? Whether and for whom GABA can be useful tool to improve his or her blood glucose management is virtually impossible to tell based on the study at hand. In spite of the fact that the scientists observed only minor adverse events such as transient dizziness and a sore throat, a further reduction of glycated albumin levels is not necessary an advantage that's worth having elevated insulin and glucagon levels. The latter would after all promote the use of proteins or rather amino acids as substrate for gluconeogenesis, the process of which the scientists believe that it is responsible for the non-existent instantaneous glucose response in the study at hand, while the former, i.e. the increase in insulin levels, is well-known for its negative effects on fatty acid oxidation.

Overall, "the verdict" is thus that we need additional research in both, healthy and diabetic individuals to be able to tell for whom the benefits of chronic high(er) dose (3x2g per day) GABA supplementation outweigh potential side effects. If you asked me for an educated guess, though, I would say (pre-)diabetics benefit while the average individual sees either no relevant benefits or detrimental effects due to the repeated need to re-stabilize the blood sugar levels... a phenomenon of which I have by the way previously said and written that it may explain the paradoxically agitating effects the ingestion of GABA has on some individuals - most likely those with already low(ish) blood glucose levels | Comment on Facebook!

References:

• Li, Junfeng, et al. "Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics." Frontiers in Pharmacology 6 (2015): 260.
• Prud’homme, Gérald J., et al. "GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone." Transplantation 96.7 (2013): 616-623.
• Prud’homme, Gérald J., et al. "GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity." Biochemical and biophysical research communications 452.3 (2014): 649-654.
• Purwana, Indri, et al. "GABA promotes human β-cell proliferation and modulates glucose homeostasis." Diabetes 63.12 (2014): 4197-4205.
• Roohk, H. Vernon, and Asad R. Zaidi. "A review of glycated albumin as an intermediate glycation index for controlling diabetes." Journal of diabetes science and technology 2.6 (2008): 1114-1121.
• Soltani, Nepton, et al. "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes." Proceedings of the National Academy of Sciences 108.28 (2011): 11692-11697.
• Tian, Jide, et al. "γ-Aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model." The Journal of Immunology 173.8 (2004): 5298-5304.
• Tian, Jide, et al. "Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis." Autoimmunity 44.6 (2011): 465-470.
• Tian, Jide, et al. "γ-Aminobutyric acid regulates both the survival and replication of human β-cells." diabetes 62.11 (2013): 3760-3765.
• Tian, Jide, et al. "Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting β-Cell Replication in Newly Diabetic NOD Mice." Diabetes 63.9 (2014): 3128-3134.