Contribution Of Plasma Glucose Research Articles

246-OR: Contribution of Plasma Glucose and Hormones to the Acute Compensatory Rise in Endogenous Glucose Production (EGP) during Glucosuria in T2D Patients

Aim: To examine the role of plasma glucose (GLU), insulin (INS) and glucagon (GG) changes in EGP stimulation during glucosuria (UGE) following SGLT2i administration. Methods: Using tracer (3-3H-glucose), 30 T2D patients (Age=55±1y, BMI=32.2±0.7kg/m2, FPG=140±6mg/dl, A1c=7.3±0.1%) received three 300-min procedures at 2-weeks intervals: (I) control clamp (CON) with no glucose/hormone infusions; (II) pancreatic clamp (PAN) with somatostatin (0.75mg/h), basal replacement of insulin (0.1mU/kg.min) and glucagon (0.3ng/kg.min); (III) isoglycemic clamp (ISO) with variable dextrose infusion to maintain GLU equal to baseline. Prior to start of each clamp subjects received placebo (PCB, n=10) or dapagliflozin 10mg (DAPA, n=20). Results: After DAPA (CON), INS decreased (-7±1µU/ml) while GG increased (+10±1pg/ml) (both p<0.05 vs. PCB). Despite UGE of 0.48mg/kg.min, GLU decline was modest (-31±1) due to a “paradoxical” rise in EGP after DAPA. During PAN with DAPA and PCB, INS and GG were unchanged from baseline, and EGP stimulation in DAPA compared to PCB still increased, yet GLU decline was modest (-28.4±3.0). During ISO, EGP decreased markedly with DAPA as well as PCB despite similar plasma GG and INS concentrations. Conclusion: DAPA-induced glucosuria stimulation of EGP cannot be entirely explained by the rise in plasma glucagon or decline in plasma insulin. Disclosure M. Alatrach: None. C. Agyin: None. N. Laichuthai: None. J.M. Adams: None. M. Abdul-Ghani: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.

Estimates of hepatic glyceroneogenesis in type 2 diabetes mellitus in humans

Glyceroneogenesis, that is, formation of triglyceride-glycerol from pyruvate, is a critical component of triglyceride fatty acid cycling in vivo. The quantitative contribution of glyceroneogenesis to triglyceride-glycerol and its hormonal regulation have not been examined in humans. We have quantified the contribution of pyruvate to very low-density lipoprotein (VLDL) triglycerides in subjects with type 2 diabetes mellitus using the deuterium labeling of body water technique. Subjects with type 2 diabetes mellitus were studied before and after a 6-month behavioral intervention therapy, during fasting and during a hyperinsulinemic normoglycemic clamp. Response to glucagon infusion was examined in 5 healthy subjects after an overnight fast. Glyceroneogenesis contributed ∼54% to VLDL triglyceride-glycerol in type 2 diabetes mellitus as compared with ∼12% contribution of plasma glucose. There was no effect of insulin plus glucose during hyperinsulinemic clamp on glyceroneogenesis even after clinical interventions, when insulin sensitivity had improved. In healthy subjects, the contribution of triosephosphates to plasma VLDL triglycerides was ∼45%. Glyceroneogenesis, in contrast to glycolysis, is the predominant source of triglyceride-glycerol carbon for VLDL triglycerides in subjects with type 2 diabetes mellitus. The contribution of glyceroneogenesis to triglyceride-glycerol is not affected by short (4 hours) infusion of insulin in type 2 diabetes mellitus.

The role of hyperglycemia in FAT/CD36 expression and function

FAT/CD36 is a long-chain fatty acid transporter and scavenger receptor for oxidized LDL. Defects in FAT/CD36 have been linked to the hypertriglyceridemia and insulin resistance. Expression of FAT/CD36 was reported increase in type 1 diabetes; however, it remains unclear whether serum glucose or insulin plays an important role in this regulation. To elucidate the individual contribution of plasma glucose and insulin in the regulation of FAT/CD36 mRNA expression, we induced type 1 diabetes in male Sprague-Dawley rats using streptozotocin (STZ) and compared traditional insulin treatment with administration of the orally absorbed chemical agent vanadate, which reduces blood glucose levels via mechanisms that bypass insulin receptor action. STZ-exposed animals showed significant decreases in body weight (285.5 +/- 2.8 vs. 233.1 +/- 3.5 g, P < 0.001) and serum insulin levels (9.7 +/- 0.7 vs. 2.8 +/- 0.6 microU/ml, P < 0.05), accompanied by significant increases in blood glucose (71 +/- 3 vs. 433 +/- 11 mg/dl, P < 0.001), water intake (38.9 +/- 0.9 vs. 205.9 +/- 3.3 ml/day, P < 0.001) and food intake (22.0 +/- 0.4 vs. 36.9 +/- 1.0 g/day, P < 0.001). Diabetic animals demonstrated significant increases in FAT/CD36 mRNA levels in duodenum (2.2-fold), jejunum (1.8-fold), ileum (1.5-fold), adipose tissue (1.7-fold), and heart (2.5-fold) (P < 0.05). Insulin treatment reversed body weight loss and corrected hyperglycemia at diabetic rats as expected. Insulin treatment also corrected increased FAT/CD36 mRNA expression at diabetic rats. Vanadate significantly reduced serum glucose levels without increasing serum insulin or affecting body weight but reversed increased FAT/CD36 mRNA expression in diabetic rats. These data suggest that plasma glucose levels play more important role in the regulation of FAT/CD36 expression than concurrent changes in plasma insulin.