Sex Dependent Dysregulation of Hepatic Glucose Production in Lean Type 2 Diabetic Rats.

Chellakkan S Blesson,Chandra Yallampalli,Shaji Chacko,Meena Balakrishnan,Pretty Rose Mathew,Amy Schutt,Daren Tanchico,Juan C Marini

doi:10.3389/fendo.2019.00538

Abstract

We have characterized a lean type 2 diabetic rat model by gestational low protein programming. We aimed to identify if the regulation of hepatic glucose production (HGP) via gluconeogenesis and glycogenolysis is affected and if there are any sex differences. Fasting (6–7 months old) type 2 diabetic rats received 2H2O followed by a primed constant rate infusion of [6,6-2H2] glucose. Blood samples were drawn during steady states after 4 h of fasting and following a euglycemic hyperinsulinemic clamp. HGP and the fraction of glucose derived from gluconeogenesis under fasting and euglycemic states were measured from steady state glucose enrichments after the infusion of [6,6-2H2]glucose and 2H2O tracers. Glycogenolysis was determined by calculating the difference between total HGP and gluconeogenesis rates. Hepatic gene expression of enzymes involved in HGP were quantified using qPCR. HGP rates was similar during fasting in both groups and sexes. However, under simulated fed condition, HGP rate was suppressed in controls but not in type 2 diabetic rats. They also showed inefficient HGP suppression in a simulated fed state. Differential analysis showed that suppression of both gluconeogenesis and glycogenolysis under simulated fed state was affected in these low protein programmed type 2 diabetic rats. These effects were greater in females when compared to males. Further, key genes involved in these processes like G6Pase, Pepck, pyruvate carboxylase, and glycogen phosphorylase in liver were dysregulated. Our data shows impaired suppression of HGP via gluconeogenesis and glycogenolysis in type 2 diabetic rats with greater effects on females.

Highlights

Liver plays a vital role in maintaining glucose homeostasis by regulating glucose production via gluconeogenesis (GNG) and glycogenolysis (GYG) [1]
Data from the euglycemic hyperinsulinemic clamp demonstrated that type 2 diabetes (T2D) males are markedly insulin resistant compared to controls, as the glucose infusion rate during euglycemia was nearly 2.5-fold lower in T2D males when compared to their controls (Figures 2A,B)
Most investigations have focused on the obese population; there is a distinct sub-population of T2D patients who are lean with normal BMI [33]

Summary

Introduction

Liver plays a vital role in maintaining glucose homeostasis by regulating glucose production via gluconeogenesis (GNG) and glycogenolysis (GYG) [1]. Insulin and glucose levels play vital roles in regulating hepatic glucose production (HGP) by both GNG and GYG [2,3,4,5]. Diabetic patients have increased rates of GNG and impaired suppression of GYG contributing to excessive glucose production leading to elevated blood glucose levels [9]. There are sporadic reports on the role of glucose production in gestational low LP programmed T2D rat models. T2D rats expressed low LXRα and high 11β-HSD1 and G6Pase [15], and upregulated fetal and maternal hepatic G6Pase and PEPCK activities [16], supporting a role for increased GNG. Another study suggested sex differences in the expressions of PEPCK and 11β-HSD1 in fetal liver when LP was given during the pre-implantation period [17]

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