A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

Abstract

Increased glucose production is associated with fasting hyperglycaemia in type 2 diabetes but whether or not it causes glucose intolerance is unclear. This study sought to determine whether a primary defect in gluconeogenesis (GNG) resulting in elevated glucose production is sufficient to induce glucose intolerance in the absence of insulin resistance and impaired insulin secretion. Progression of glucose intolerance was assessed in phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats, a genetic model with a primary increase in GNG. Young (4-5 weeks of age) and adult (12-14 weeks of age) PEPCK transgenic and Piebald Virol Glaxo (PVG/c) control rats were studied. GNG, insulin sensitivity, insulin secretion and glucose tolerance were assessed by intraperitoneal and intravascular substrate tolerance tests and hyperinsulinaemic/euglycaemic clamps. Despite elevated GNG and increased glucose appearance, PEPCK transgenic rats displayed normal glucose tolerance due to adequate glucose disposal and robust glucose-mediated insulin secretion. Glucose intolerance only became apparent in the PEPCK transgenic rats following the development of insulin resistance (both hepatic and peripheral) and defective glucose-mediated insulin secretion. Taken together, a single genetic defect in GNG leading to increased glucose production does not adversely affect glucose tolerance. Insulin resistance and impaired glucose-mediated insulin secretion are required to precipitate glucose intolerance in a setting of chronic glucose oversupply.

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

“…Mice were tracked for a further 2 weeks on their respective diets. During the 6th week of feeding, voluntary physical activity (individually housed running wheels, which have been shown to correlate well with infrared photoelectric measurements of spontaneous motor activity (Thorburn et al 2000)), resting energy expenditure (REE) and respiratory quotient (RQ; indirect calorimetry; 10 min interval sampling over 75 min during the resting period (daytime)) were measured (Fam et al 2007, Mangiafico et al 2011, Wong et al 2011, Visinoni et al 2012. At the conclusion, mice were anaesthetised in the non-fasted state (0900 h) (Ahren & Scheurink 1998, Fam et al 2007 with an i.p.…”

Systemic VEGF-A Neutralization Ameliorates Diet-Induced Metabolic Dysfunction

“…Hyperinsulinemic-euglycemic clamps were performed in 5-h-fasted mice as previously described (30). In the current study, an initial priming dose of insulin was followed by constant infusion at a rate of 10 mU/kg/min.…”

Normal muscle glucose uptake in mice deficient in muscle GLUT4

“…All animal work was conducted according to relevant national and international guidelines and approved by the Austin Health Animal Ethics Committee (AEC #A2007/02764). For all glucose metabolism investigations, mice were tested in an anaesthetised state as previously published (Kaczmarczyk et al 2003, Lamont et al 2003, Steinberg et al 2006, Visinoni et al 2008, Mangiafico et al 2011, Wong et al 2011.…”

“…The relative quantification method was used to assess the expression level of the target genes. This analysis uses the 2^(KDDC t ) method, which is based on relative quantification of the KO mice to the control mice as previously published (Kebede et al 2008, Visinoni et al 2008, 2012, Mangiafico et al 2011, Wong et al 2011.…”