MD Conference Express EASD 2012 - (Page 6)

n F E A T U R E Understanding Incretin Hormone Action and the Treatment of Diabetes Written by Maria Vinall In the 44th Claude Bernard Lecture on diabetes, Daniel J. Drucker, MD, University of Toronto, Toronto, Ontario, Canada, discussed his research findings concerning incretin hormone action and the treatment of diabetes. The lecture covered the pharmacological/physiological mechanisms of the glucagon-like peptides GLP-1 and GLP-2, and their relevance to the treatment of human disease. The importance of GLP-1 system basal control of glucose homeostasis was first evidenced in animal studies in which GLP-1 receptor (GLP-1R) knockout (–/–) mice exhibited increases in fasting blood glucose and decreases in circulating insulin following oral and intraperitoneal glucose challenges [Scrocchi LA et al. Nat Med 1996]. Since then, numerous studies have shown that the GLP-1/GLP-1R system, although classically focused on the β-cell, is also critically important for the physiology of many other systems (eg, energy expenditure, central nervous system stress response, and the immune system). Given that glucagon is a critical hormone in the pathophysiology of diabetes and the control of glucose homeostasis, can hyperglucagonemia of type 2 diabetes mellitus (T2DM) be attenuated successfully and used as a treatment for diabetes? One concern is whether blocking the glucagon receptor (Gcgr) is the right approach. GLP-1 and GLP-2 play key roles in cell proliferation and survival, and it is possible that the Gcgr may have a similar function that would make blocking it a poor choice for T2DM therapy. Gcgr–/– mice have shown that the Gcgr is required for control of lipid metabolism during the adaptive metabolic response to fasting. Glucagon inhibits hepatic lipid production and acutely increases hepatic lipid secretion. Fasting Gcgr–/– mice are unable to control plasma lipids and experience an increase in triglyceride secretion from the liver. These mice are also resistant to diet-induced obesity and fat deposition in peripheral organs; however, they do not resist lipid deposition in the liver, somewhat negating any therapeutic potential [Longuet C et al. Cell Metab 2008]. Gcgr–/– mice also show enhanced susceptibility to hepatosteatosis on a methionine choline-deficient diet. Restoration of hepatic Gcgr expression attenuates the development of hepatocellular injury, which extends the essential actions of the Gcgr beyond the metabolic control of glucose homeostasis to encompass the regulation of hepatocyte survival [Sinclair EM et al. Gastroenterology 2008]. Independent of the lipid pathway, Gcgr plays a critical role in the balance between survival and cell death by way of lipid oxidation control. During fasting, increases in many of the genes in the liver important for liver oxidation are seen, but Gcgr–/– mice are unable to activate similar hepatic gene expression systems (Figure 1) [Longuet C et al. Cell Metab 2008]. Thus, glucagon actions in the liver are essential for both hepatocyte survival and lipid accumulation. Gcgr also plays an important role in the pancreas in that Gcgr–/– mice have increased pancreatic weight, enhanced β-cell function, and massive islet and α-cell hyperplasia. Reductions in Gcgr signaling direct the pancreas to enhance islet α-cell proliferation, which develops independently of GLP-1R in Gcgr–/– mice [Ali S et al. J Clin Invest 2011]. The liver sends the signal to β-cells to proliferate; in control experiments genetic disruption of liver Gcgr sends a signal promoting proliferation of transplanted wild-type (WT) α-cells Peer-Reviewed Highlights of 6 November 2012 www.mdconferencexpress.com  http://www.mdconferencexpress.com

Table of Contents for the Digital Edition of MD Conference Express EASD 2012

MD Conference Express EASD 2012
Contents
Understanding Incretin Hormone Action and the Treatment of Diabetes
New ADA/EASD Guidelines Focus on Patient-Centered Care
ORIGIN Trial: Insulin Glargine and n-3 Fatty Acids Fail to Reduce CV Events in Diabetic Patients
Exenatide Once Weekly Sustained Improvement in Glycemic Control with Weight Loss Through 4 Years
DiaPep277® Shows Promise as a Therapeutic Strategy for T1DM
Linagliptin Proves Safe and Effective as Add-on Therapy to Basal Insulin
12-Week Treatment with LY2409021 Significantly Lowers HbA1C and Is Well Tolerated in Patients with T2DM
Insulin Degludec Is Superior to Sitagliptin in Improving Glycemic Control in Uncontrolled Patients with Type 2 Diabetes on Oral Agents
Dapagliflozin Does Not Impact Renal Function in Patients with T2DM
Population-Based Screening for T2DM:The ADDITION-Cambridge Trial
The Challenges of Pharmaceutical Management of Painful Diabetic Peripheral Neuropathy
Enterovirus Infection
Novel Oral Agents
GLP-1
Genetics
Renal Denervation
Hypertension and Renal Function Are Risk Factors for CAD in T1DM

MD Conference Express EASD 2012

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