MD Conference Express EASD 2012 - (Page 7)
D2012
nderstanding Incretin Hormone Action and the Treatment of Diabetes
Figure 1. Ggcr Signaling Is Essential for Control of Hepatic Lipid Oxidation.
6 5 4 3 2 1 0
WT KO WT KO WT KO WT KO WT KO WT KO WT KO WT KO
re1 Ggcr Signaling Is Essential for Control of Hepatic Lipid Oxidation.
Fold changes expression during fasting
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5h Fasting 16h Fasting
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KO=Gcgr–/–vmice *** ***
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***
***
Facl 2
Derc2
CPT1a
CPT2
Acadm
Ehadh
Hadha
Hadhb Control Glucagon
Fold changes expression after treatment
2.5 2.0 1.5 1.0 0.5 0
Glucagon administration activates genes controlling lipid oxidation in WT mice * * ** * ** * *
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Facl2
Derc2
CPT1a
CPT2
Acadm
Ehadh
Hadha
Hadhb
* p<0.05; ** p < 0.01; *** p<0.001. KO=knockout; WT=wild-type. Reprinted from Longuet C et al. The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting. Cell Metab Nov 5, 2008;8(5):359-371, with permission from Elsevier.
under the kidney capsule. But α-cell hyperplasia and proliferation can still occur very rapidly if WT islets are placed under the kidney capsule in mice with liver-selective inactivation of Gcgr. Thus, organized nerves, α-cells within the islets, or even islet cells organized within their normal location are not needed for this signal to be communicated [Longuet C et al. Diabetes. In press]. The importance of liver Gcgr to the α-cell axis has also been shown in humans. In a recent clinical study the Gcgr antagonist MK-0893 produced robust reductions in HbA1C levels in patients with T2DM [Engel SS et al. ADA 2011 Abstract 309-OR] but was associated with elevations in transaminase and lipids. The attenuation of Gcgr signaling produces substantial improvement of glucose homeostasis in mice and humans. This signaling is essential for hepatocyte survival, lipid metabolism, and controlling the rate of α-cell proliferation—likely through a circulating factor.
However, the therapeutic window for reduction of glucagon action to manifest beneficial effects for glucose control while avoiding enhancement of hepatic lipid storage, dyslipidemia, hepatocyte injury, and α-cell proliferation in diabetic subjects is unclear. Two classes of medication that enhance incretin action (the GLP-1R agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) are used to treat T2DM. Prof. Drucker discussed the cardiovascular biology of these medications, including their direct and indirect effects on cardiomyocytes, blood vessels, adipocytes, blood pressure control, and postprandial lipoprotein secretion. When the mesenteric arteries of WT and Glp1r–/– mice were treated with GLP-1, GLP-1 (9-36), and exendin-4 (a GLP-1 agonist), GLP-1 and GLP-1 (9-36) exerted direct vasodilatory effects but exendin-4 did not. When the degradation of native GLP-1 is blocked by the addition of
Peer-Reviewed Highlights of the 48th Annual Meeting of the European Association for the Study of Diabetes
7
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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