Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 9; pp. 2569 - 2579
• Main Authors: Esterson, Yonah B., Carey, Michelle, Boucai, Laura, Goyal, Akankasha, Raghavan, Pooja, Zhang, Kehao, Mehta, Deeksha, Feng, Daorong, Wu, Licheng, Kehlenbrink, Sylvia, Koppaka, Sudha, Kishore, Preeti, Hawkins, Meredith
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2016
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Cross-Over Studies; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diazoxide - pharmacology; Diazoxide - therapeutic use; Female; Glucose; Glucose - metabolism; Glucose Clamp Technique; Humans; Hyperglycemia; Male; Metabolism; Middle Aged; Pancreas - drug effects; Pancreas - metabolism; Rats; Rats, Zucker; Rodents
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db15-1465

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.