ABSTRACT
We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.
Subject(s)
Drug Evaluation, Preclinical , Drugs, Investigational/adverse effects , Energy Metabolism/drug effects , Hypoglycemic Agents/adverse effects , Insulin, Regular, Human/analogs & derivatives , Liver/drug effects , Absorption, Physiological/drug effects , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Dogs , Dose-Response Relationship, Drug , Drugs, Investigational/administration & dosage , Drugs, Investigational/pharmacokinetics , Gluconeogenesis/drug effects , Glucose Clamp Technique , Glycosylation , Humans , Hyperglycemia/metabolism , Hyperglycemia/prevention & control , Hypoglycemia/chemically induced , Hypoglycemia/metabolism , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/blood , Hypoglycemic Agents/pharmacokinetics , Infusions, Intravenous , Insulin, Regular, Human/administration & dosage , Insulin, Regular, Human/adverse effects , Insulin, Regular, Human/pharmacokinetics , Liver/metabolism , Male , Metabolic Clearance Rate , Random Allocation , Somatostatin/administration & dosage , Somatostatin/adverse effectsABSTRACT
MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Homeostasis/drug effects , Leptin/administration & dosage , Liver/innervation , Vagus Nerve/drug effects , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Drug Evaluation, Preclinical , Infusions, Intraventricular , Leptin/pharmacology , Liver/drug effects , Liver/metabolism , Liver/physiopathology , Male , Mice , Mice, Knockout , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Thinness/metabolism , Thinness/pathology , Vagus Nerve/metabolism , Vagus Nerve/physiologyABSTRACT
The liver plays a pivotal role in the regulation of glucose metabolism because it is the key organ that maintains glucose levels during fasting. An emerging body of literature has demonstrated the important role of the hypothalamus in controlling hepatic glucose production (HGP). The hypothalamus senses circulating nutrients and hormones, conveying the energy status to the central nervous system, which, in turn, controls HGP in part by way of the autonomic nervous system. Overfeeding results in the failure of the hypothalamus to sense circulating nutrients and hormones, and in a loss of the central control of HGP.