GLUCAGON READ...

[muscle_4you]

Glucagon

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Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels.

Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (enteroglucagon).

Physiologic Effects of Glucagon
The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:


Glucagon stimulates breakdown of glycogen stored in the liver. When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose.
Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job.
Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells.

Control of Glucagon Secretion
Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose.

Two other conditions are known to trigger glucagon secretion:

Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal: In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.
Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose.
In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin.

Disease States
Diseases associated with excessively high or low secretion of glucagon are rare. Cancers of alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion. These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin lesions.

Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is considerable evidence that aberrant secretion of glucagon contributes to the metabolic derangements seen in this important disease. For example, many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is normally suppressed by elevated levels of blood glucose.

NTR

[Newman]

Hmmmm...

Interesting info.

I wonder if & how Glucagon could be used to help make sugary post WO whey shakes & slin shots safer & more healthful?

[biochemist]

Glucagon is a very interesting hormone and its story is yet to be fully told. The fact that glucagon itself has poor handling properties and its initial characterizations made it seem like a "pro-diabetic magnet" has slowed research on it. However that is all changing and relatively quickly. It appears that glucagon perhaps has more of an ability to stimulate lipolysis (safely) over the long-term than previously recognized. In fact, it might not be so "pro-diabetic" after all. These folks from IU and Merck are at the head of the game:

Nat Chem Biol. 2009 Jul 13.
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.
Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, Holland J, Hembree J, Abplanalp W, Grant E, Ruehl J, Wilson H, Kirchner H, Lockie SH, Hofmann S, Woods SC, Nogueiras R, Pfluger PT, Perez-Tilve D, Dimarchi R, Tschöp MH.

Department of Chemistry, Indiana University, Bloomington, Indiana, USA.

We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.

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Diabetes. 2009 Jul 14.
GLP-1/GCGR dual agonism reverses obesity in mice.
Pocai A, Carrington PE, Adams JR, Michael W, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capito' E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, Sinharoy R.

Merck Research Laboratories, Rahway, NJ 07065, USA.

Objective- Oxyntomodulin (OXM) is a GLP-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from that obtained with a GLP1R-selective agonist. Research design and methods- We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in DIO mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r(-/-) and Gcgr(-/-) mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG. Results- Peptide DualAG exhibits superior weight loss, lipid lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The anti-obesity effects of DualAG require activation of both GLP1R and GCGR. Conclusions- Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.

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Now for some more physiological short reads if anyone is interested.

Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E695-707.
Pancreatic beta-cell overexpression of the glucagon receptor gene results in enhanced beta-cell function and mass.
Gelling RW, Vuguin PM, Du XQ, Cui L, Rømer J, Pederson RA, Leiser M, Sørensen H, Holst JJ, Fledelius C, Johansen PB, Fleischer N, McIntosh CH, Nishimura E, Charron MJ.

Department of Biochemistry, Pediatric Endocrinology, Children's Hospital at Montefiore, Albert Einstein College of Medicine (hell yea Einstein & medicine!), Bronx, New York, Bronx, NY 10461, USA.

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic beta-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. beta-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic beta-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, beta-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

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(full text is free for this on pubmed):

J Clin Invest. 2009 Aug;119(8):2412-22.
Hepatic energy state is regulated by glucagon receptor signaling in mice.
Berglund ED, Lee-Young RS, Lustig DG, Lynes SE, Donahue EP, Camacho RC, Meredith ME, Magnuson MA, Charron MJ, Wasserman DH.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor- null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism.

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And another older paper, with regards to glucagon acting during exercise to increase available energy:

Can J Physiol Pharmacol. 1997 Jan;75(1):26-35.
Glucose metabolism during exercise in man: the role of insulin and glucagon in the regulation of hepatic glucose production and gluconeogenesis.
Lavoie C, Ducros F, Bourque J, Langelier H, Chiasson JL.

Research Group on Diabetes and Metabolic Regulation, Clinical Research Institute of Montréal, Canada.

This study was designed to further characterize the role of insulin and glucagon in the regulation of glucose production and gluconeogenesis during a 2-h mild intensity exercise (40% VO2max) in 14 h fasted healthy male subjects. Endogenous insulin and glucagon secretions were suppressed by the infusion of somatostatin. The pancreatic hormones were replaced singly or in combination to match the hormonal concentrations observed during exercise in control subjects. Glucose turnover was determined by a tracer method using the stable isotope D-[2,3,4,6,6-2H]glucose. Gluconeogenesis was estimated by the simultaneous infusion of L-[1,2,3-13C]alanine to follow the conversion of alanine to glucose. Hepatic glucose production significantly increased from a resting rate of 12.1 +/- 0.2 to 27.6 +/- 1.4 mumol.kg-1.min-1 during exercise (p < 0.05). In the absence of glucagon, this increase in hepatic glucose production during exercise was totally abolished (p < 0.05). When insulin was made deficient, in the presence of glucagon, there was an overshoot in the increase in hepatic glucose production during exercise to 36.4 +/- 1.6 mumol.kg-1.min-1 (p < 0.05). The normal increase in hepatic glucose output during exercise was reproduced when both insulin and glucagon were replaced. Exercise increased gluconeogenesis by 47% above the resting level (p < 0.05). When glucagon was made deficient, in the absence or presence of insulin, this increase in gluconeogenesis was totally suppressed (p < 0.05). Furthermore, glucagon replacement during exercise in the absence of insulin resulted in a further increase in gluconeogenesis to 93% above resting value (p < 0.05). From these observations, it is concluded that during prolonged mild intensity exercise in healthy subjects, the rise in glucagon is essential for the increase in hepatic glucose production and the increase in gluconeogenesis. It is also suggested that the lower level of insulin during exercise still exerts a restraining effect on glucagon-stimulated glucose production and gluconeogenesis, thus preventing hyperglycemia.

[biochemist]

Originally Posted by Newman

I wonder if & how Glucagon could be used to help make sugary post WO whey shakes & slin shots safer & more healthful?

Well for the protein shakes probably not much. There is actually a lot of research coming out recently looking at how whey protein stimulates differential secretion of endocrine hormones versus other foods. A lot has focused on GLP-1 because GLP-1 has been receiving a lot of attention as an "anti-diabetic holy grail" of pharmacology (probably not so much now with the coagonist work coming out, which should trump pure GLP-1 agonists) and GLP-1 is a known stimulator of satiety through multiple mechanisms. But is has been shown that whey protein drinks stimulate more GLP-1 release per amount ingested than any other food I have seen it compared to to date.

Also when you drink whey protein your body upregulates glucagon secretion. I am not sure to what degree glucagon and GLP-1 release are associated with production & cleavage of the preproglucagon mini gene. You might always release all the gene products simultaenously:

Br J Nutr. 2008 Jul;100(1):61-9.
Glucagon and insulin responses after ingestion of different amounts of intact and hydrolysed proteins.
Claessens M, Saris WH, van Baak MA.

Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, Maastricht 6200, MD, The Netherlands.

Ingestion of dietary protein is known to induce both insulin and glucagon secretion. These responses may be affected by the dose and the form (intact or hydrolysed) in which protein is ingested. The aim of the study was to investigate the effect of different amounts of intact protein and protein hydrolysate of a vegetable (soya) and animal (whey) protein on insulin and glucagon responses and to study the effect of increasing protein loads for both intact protein and protein hydrolysate in man. The study employed a repeated-measures design with Latin-square randomisation and single-blind trials. Twelve healthy non-obese males ingested three doses (0.3, 0.4 and 0.6 g/kg body weight) of intact soya protein (SPI) and soya protein hydrolysate (SPH). Another group of twelve healthy male subjects ingested three doses (0.3, 0.4 and 0.6 g/kg body weight) of intact whey protein (WPI) and whey protein hydrolysate (WPH). Blood was sampled before (t = 0) and 15, 30, 60, 90 and 120 min after protein ingestion for insulin, glucagon and glucose determination. SPI induced a higher total area under the curve for insulin and glucagon than SPH while no difference between WPI and WPH was found. Insulin and glucagon responses increased with increasing protein load for SPI, SPH, WPI and WPH, but the effect was more pronounced for glucagon. A higher dose of protein or its hydrolysate will result in a lower insulin:glucagon ratio, an important parameter for the control of postprandial substrate metabolism. In conclusion, insulin and glucagon responses were protein and hydrolysate specific.

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As far as using it to protect against insulin-induced hypoglycemia, as I eluted to earlier glucagon itself has very poor handling properties. You could obtain some and use it for this sure, but you would have to inject a strong acidic solution every time (its aggregates would clog your syringe if you try to dissolve/inject it at neutral pH ;-P) and it would burn. Alternatively you could just wait for someone to come out with a better glucagon preparation (there are people working on this and some new publications if you want to search for them) or a more soluble glucagon analog (there are lots of people working on this as well, especially with all the co-agonist noise coming out). Or just keep drinking whey protein and let your body do it. =)

[biochemist]

Originally Posted by muscle_4you

Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is considerable evidence that aberrant secretion of glucagon contributes to the metabolic derangements seen in this important disease. For example, many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is normally suppressed by elevated levels of blood glucose.

I guess one last bit while I'm on a roll. The aberrant glucagon release seen in T1D is a result of loss of the pancreatic B-cell. It turns out that the alpha and beta cells in your pancreas (I say your because I am T1D and have no betas!) are connected in specific cross-talk mechanisms that regulate their activity. It has recently been shown that insulin receptors on the alpha cells are capable of supressing glucagon secretion, when the insulin receptors are activated, ie, after the beta cell releases it (of course the alpha cells are right near by so they obviously get hit).

So when you are type 1 and you have no insulin, you also have lost a primary method you use to shut off glucagon. This has long been therapeutically ignored as something type 1s should be trying to combat, but the fact is no suitable therapies even exist to try changing things. As we create more new analogs like the co-agonist stuff though, this is sure to change as more and more hypothesis can be tested and better therapies revealed.

It is also interesting to note that in type 2 diabetes glucagon secretion is increased. Hence people have been trying to develop glucagon receptor antagonists to stop this since the 80s. But the question is, is that truly the best way to target the disease? In coming back to the type 1 case, where total loss of the beta cells is the cause of the glucagon problem, we have to look towards the disease state of the type 2 diabetic to understand what they really need. That is, the type 2 diabetic loses beta cell function and mass and if a therapy can restore this, then the "glucagon problems" (ie, postprandial hyperglycemia) can be fixed. Sorry I didn't post sources for most of this info if anyone wants to see some I can post some good ones.

Anyways the bottom line to the weight lifting / bodybuilding community is this: glucagon can cause significant weight loss and apparently with a bias towards burning fat versus muscle. It can also reduce hunger, especially when paired with the activity of GLP-1. It may also even increase available energy due to hepatic gluconeogenesis.

Take from that what you will...