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

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 2 H 2 O followed by a primed constant rate infusion of [6,6- 2 H 2 ] 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- 2 H 2 ]glucose and 2 H 2 O 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.

Low Protein Programming Causes Increased Mitochondrial Fusion and Decreased Oxygen Consumption in the Hepatocytes of Female Rats

“…Data from other laboratories show that a gestational LP diet caused changes in hepatic gene expression by various mechanisms linked to glucose metabolism [ 10 , 11 , 12 , 13 ]. Similarly, our previous study in LP-programmed females showed impaired hepatic glucose metabolism [ 2 , 14 , 15 , 16 , 17 ]. However, the molecular mechanism leading to defects in hepatic glucose metabolism and its relationship to mitochondrial abnormalities in the liver is not well studied.…”

“…Such developmental reprogramming of the offspring often leads to various metabolic diseases later in life, including insulin resistance and type 2 diabetes (T2D). It is known that maternal dietary protein is important for fetal liver development, and an in utero low-protein diet (LP) causes insulin resistance and impaired liver function in offspring [ 2 ]. As one of the major hubs of metabolism, the liver regulates glucose metabolism in response to the changing nutrient availability [ 3 ].…”

Prenatal Low-Protein Diet Affects Mitochondrial Structure and Function in the Skeletal Muscle of Adult Female Offspring

“…They developed progressively worsening glucose intolerance and insulin resistance with advancing age without any increase in body weight, body mass index, or fat content when compared with controls [ 25 , 28 ]. We also showed that gestational LP diet caused T2D in adult offspring with different signaling mechanisms in males and females [ 25 , 26 , 27 , 29 , 30 ]. Our studies in females showed that impaired glucose homeostasis is caused due to a defect in the insulin signaling cascade, which regulates glycogen synthesis [ 26 ].…”

“…Our studies in females showed that impaired glucose homeostasis is caused due to a defect in the insulin signaling cascade, which regulates glycogen synthesis [ 26 ]. Further, we also showed that LP programming affects hepatic glucose production via both gluconeogenesis and glycogenolysis in a sex-dependent manner with greater dysregulation in females when compared to males [ 29 ]. The present study aims to investigate the role of mitochondrial health in the skeletal muscle in LP-programmed T2D female offspring.…”

Brain-Body Control of Glucose Homeostasis—Insights From Model Organisms

“…Not only is vascular catheterization less technically challenging in the rat compared to the mouse, but mice require infusion of donor blood to replace erythrocytes and sustain hematocrit during clamping procedures, which results in larger colony number and more complex experimental design (137). Independently of rodent model choice, however, blood glucose assessments must take into consideration; strain (40,139), age (140,141), sex (142)(143)(144), fasting length (137,145) and husbandry (146)(147)(148) as all of these parameters differentially impact glucose homeostasis and the translatability of each model to human physiology (discussed in detail in 7,9). Nonmammalian species, while having critical distinctions in their mechanisms of glucose homeostasis, particularly with respect to the brain, offer unique opportunities afforded by their genetic tractability, lower cost, and fecundity.…”