Diabetes and Liver Metabolism

GLP-1 byproduct, antisense drug, and resveratrol help to improve diabetic control…. 

Ip et al, studied the degradation product, GLP-1 (28-36) amide, of GLP-1. GLP-1 (28-36) amide is shown to dispose glucose and decrease the development of diabetes and hepatic steatosis. Researchers examined mice for 13 weeks after they were subjected to high fat diets (60% fat) followed by intraperitoneal administration of GLP-1 (28-36) amide. Glucose production, gene expression, and hepatic signaling were examined in the mice. The authors concluded that there were no significant changes in body weight post GLP-1 (28-36) administration. GLP-1 (28-36) slightly increased glucose disposal, and may reduce hepatic glucose production in vivo.

Morgan et al evaluated the safety and tolerability of an antisense drug known to reduce hepatic glucagon receptor expression for T2DM patients who are severely diabetic and uncontrolled. Subjects were given up to 300mg/week of the investigational drug and evaluated over 4 weeks. The drug was well tolerated and there were no significant changes in vital signs, triglycerides, total cholesterol, LDL, blood pressure, hepatic or renal function, and no hypoglycemia was observed. The drug increased total GLP-1 levels in treated subjects.           

Resveratrol is reported to activate surtuins, a protein that has histone deacetylase activity. Resveratrol also protects against insulin resistance and type 2 diabetes by increasing insulin sensitivity in muscle and adipose tissue. Rats were treated for 30 days with saline, insulin NPH, or insulin plus resveratrol given intraperitoneally. Plasma glucose concentration was additionally decreased post resveratrol treatment; however, there was weight gain noted with the combination treatment. Conclusively, insulin plus resveratrol increases hepatic insulin sensitivity, by reducing glucose output, and improves glycemic control, but it does not alter the expression of glucose transporters in renal tubules and therefore does not alter nephropathy development.

• GLP-1 (28-36) increases glucose disposal, and may reduce hepatic glucose production.
• Antisense drug increases GLP-1 levels with no change in cholesterol or BP.
• Resveratrol improves glycemic control.

EASD Barcelona, September 27 2013

1. W Ip, W Shao, YT Chiang, and T Jin^. GLP-1-derived nonapeptide GLP-1(28-36)amide represses hepatic gluconeogenesis and improves pyruvate tolerance in high fat diet fed mice.
2. E Morgan,C Bethune,L Watts,S Xia,M McDonnell, R Geary, S Bhanot. Reduction of hepatic glucagon receptor expression with an antisense drug (ISIS-GCGR_RX) increases total GLP-1 levels without affecting cholesterol or BP in normal subjects.
3. H.S. Freitas, E.P. Machado, A. David-Silva, M.M. Okamoto, U.F. Machado. Effect of resveratrol in hepatic and renal expression of the glucose transporters GLUT2 and SGLT2 in diabetic rats.