For nearly 2 decades now, GLP-1 has been heavily investigated as the most promising therapy target in type 2 diabetes patients....
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GLP-1 analogs on beta-cells: Glucose dependent insulin secretion
For nearly 2 decades now, GLP-1 has been heavily investigated as the most promising therapy target in type 2 diabetes patients. GLP stands for "glucagon like peptide" and the receptors for GLP-1 are expressed mainly in pancreatic beta-cells, where its activation can lead to multiple acute and long term effects. The most well-known effect of GLP-1 analogs is glucose dependent insulin production, leading to fewer episodes of hyperglycemia. When GLP-1 directly stimulates the beta-cell, the acute effect is insulin secretion. Glucose stimulated ionic and nonionic signaling pathways, also known as K+ dependent and independent pathways regulate insulin secretion. By blocking K+ channels, GLP-1 depolarizes the cell and causes calcium influx, and thus causes exocytosis of insulin from the beta-cell. GLP-1 also stimulates insulin gene transcription and islet cell growth. All of these functions lead to beta-cell proliferation and increased beta-cell capacity. However, these latter effects are currently only observed in animal studies. It is hoped that over the long-term, effects of GLP-1 analogs will preserve beta-cell function and increase beta-cell mass, a much-desired effect in type 2 diabetes patients.8
GLP-1 analogs on alpha-cells and liver: Glucagon production
GLP-1 analogs also exert some of their most important effects on the pancreatic alpha-cells and liver. GLP-1 inhibits pancreatic alpha-cells, thus inhibiting glucagon secretion, although the exact mechanism by which it acts on alpha-cells is not fully understood.2 Researchers have been able to show through many studies that GLP-1 indirectly works in the liver by inhibiting glucagon secretion by pancreatic alpha-cells, thereby inhibiting gluconeogenesis and glycogenolysis, thus decreasing hepatic glucose production. Researchers have also shown that GLP-1 receptors are present in the liver, although at much lower concentrations than in the pancreas. Many researchers postulate that GLP-1 also works directly on the GLP-1 receptors in the liver to decrease glucose production, complementing the effects of decreased glucagon levels.1
GLP-1 analogs in gut: Regulate gut hormones
There is also a growing body of evidence suggesting wide-spread beneficial effects of GLP-1 outside of the pancreas and liver. Endogenous GLP-1 production occurs in the L-cells of the distal ileum and colon in response to meals. Research has shown this is a vagal feed-forward response, not triggered directly by stimulation to the GI tract.1 GLP-1 secretion leads to multiple actions in the gut, including slowing gastric emptying time, reduced intestinal motility, and reduced gastric acid secretion. GLP-1 induces the "ileal brake" phenomenon by inhibition of gastric emptying and intestinal transit time. GLP-1 decreases gastric smooth muscle motility and inhibits postprandial acid secretions. It also inhibits intestinal smooth muscle motility. Reduced gastric and intestinal motility causes slower absorption of nutrients from GI tract resulting in a gradual increase of glucose levels in general circulation. Due to these effects lower postprandial insulin response is required. Coupled with GLP-1's ability to improve insulin sensitivity to skeletal muscles and adipose tissue, ultimately a significantly lower insulin response is required.8
GLP-1 analogs: Glucose disposal in an insulin independent manner
It is well known that GLP-1 reduces post-prandial hyperglycemia in type 2 diabetes patients by stimulating pancreatic beta-cells to secrete insulin. GLP-1 is less appreciated for controlling glucose through mechanisms independent of its effect on insulin and glucagon. Researchers have been able to show that GLP-1 diminishes post-meal glucose excursions in type-1 diabetes patients and GLP-1 increases glucose disposal in an insulin independent manner.3 The effect of GLP-1 on glucose utilization by muscle and adipose cells has been a source of much debate.3 There is some evidence that GLP-1 affects glucose utilization by directly stimulating glycogen synthesis in both rat skeletal muscle4 and rat adipose tissue5, at the same time causing an increase in glycogen synthase-alpha.4 Similar effects on glycogen synthase-alpha in hepatocytes of both normal and diabetic rats have been demonstrated.6 There have however been other studies that failed to replicate these results.7 Ayala et al. recently showed GLP-1 stimulates insulin independent glucose disposal in rats using an insulin clamp. Although the exact mechanism was not elucidated, the results were attributed to GLP-1 by comparing wild-type rats to those lacking the gene for the GLP-1 receptor. Clearly, the growing body of evidence supports GLP-1's actions in skeletal muscle and adipose tissue as important contributors to effective glucose management, although the exact mechanism is not yet known.
GLP-1 analogs' effect on CNS: Satiety and weight loss
The final beneficial effect of GLP-1, which is becoming quite a fad in doctors' weight loss clinics, is its effect on satiety. Maintaining a healthy body weight and diet has been shown to slow the progression from pre-diabetes to type-2 diabetes and is also important in preventing complications in diabetes patients. It is not easy to alter our diets completely, but making small changes in the types of food we eat along with the size and frequency of our meals can make a big difference in maintaining a healthy weight. GLP-1 analogs have been shown to help diabetes patients lose weight by inducing satiety and reducing caloric intake. A 1998 study compared either saline or GLP-1 infused in non-diabetic men 15 minutes before a meal. When surveyed after the meal, men in the GLP-1 group showed a significant increase in feelings of satiety and fullness at 1 hour and 4 hours post-meal.1 Studies have also shown significant long-term weight loss in patients using GLP-1 analogs.9 For many years there was dispute about whether GLP-1 acts peripherally or in the CNS to induce satiety. Researchers have been able to show, however, that GLP-1 binds receptors in multiple nuclei within the hypothalamus. These findings suggest GLP-1 acts directly on the hypothalamic feeding centers.2 As with most of the beneficial effects of GLP-1 in type-2 diabetic patients, the exact mechanism by which it induces satiety is not known and more research is underway.
In conclusion, GLP-1 analogs appear to have wide-spread benefits that address almost all DeFronzo's "Octet of Mechanisms" involved in the pathogenesis of diabetes, with the exception of the kidney. However, researchers have shown that GLP-1 receptors are present in the kidneys and there is emerging research that may eventually include the kidney into the proven sites of action. Given their broad range of effects and comparatively few side-effects, GLP-1 analogs continue to be the most promising target for diabetes therapy in the past 2 decades.
References:
Näslund E, Gutniak M, Skogar S, Rössner S, Hellström PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998 Sep;68(3):525-30
Holst JJ Gut hormones are pharmaceuticals: from enteroglucagon to GLP-1 and GLP-2. Regul Pept 93:45-51 2000
Perfetti R, Merkel P. Glucagon like Peptide-1: a major regulator of pancreatic beta cell function. Eur J Endocrinol 143: 717-725, 2000
Villanueva-Penacarillo ML, Alcantara AI, Clemente F, Delgado E, Valverde I. Potent glycogenic effect of GLP-1(7-36) amide in rat skeletal muscle. Diabetologia 1994 37 1163-1166
Perea A, Vinambres C, Clemente F, Villanueva-Penacarrillo ML & Valverde I. GLP-1 (7-36) amide: effects on glucose transport and metabolism in rat adipose tissue. Hormone and Metabolic Research 1997 29 417-421.
Lopez-Delgado M, Morales M, Villanueva-Penacarrillo M, Malaisse W & Valverde I. Effects of glucagon-like peptide 1 on the kinetics of glycogen synthase a in hepatocytes from normal and diabetic rats. Endocrinology 1998 139 2811-2817.
Furnsinn C, Ebner K & Waldhausl W. Failure of GLP-1 (7-36) amide to affect glycogenesis in rat skeletal muscle. Diabetologia 1995 38 864-867.
Patrick E. et. Al. The Multiple Actions of GLP-1 on the process of glucose-stimulated insulin secretions. DIABETES, VOL 51, SUPP 3, DEC 2002. University of Toronto.
Dushay J, Gao C, Gopalakrishnan GS, Crawley M, Mitten EK, Wilker E, Mullington J, Maratos-Flier E. Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes. Diabetes Care. 2012 Jan;35(1):4-11. Epub 2011 Oct 31.
Chris Conetta, Mihir Patel, LECOM Mercer University, 2/22/2012
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