Obesity and Type 2 Diabetes Impair Insulin-Induced Suppression of Glycogenolysis as Well as Gluconeogenesis

Abstract

To determine whether the hepatic insulin resistance of obesity and type 2 diabetes is due to impaired insulininduced suppression of glycogenolysis as well as gluconeogenesis, 10 lean nondiabetic, 10 obese nondiabetic, and 11 obese type 2 diabetic subjects were studied after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Gluconeogenesis and glycogenolysis were measured using the deuterated water method. Before the clamp, when glucose and insulin concentrations differed among the three groups, gluconeogenesis was higher in the diabetic than in the obese nondiabetic subjects (P < 0.05) and glycogenolysis was higher in the diabetic than in the lean nondiabetic subjects (P < 0.05). During the clamp, when glucose and insulin concentrations were matched and glucagon concentrations were suppressed, both glycogenolysis and gluconeogenesis were higher (P < 0.01) in the diabetic versus the obese and lean nondiabetic subjects. Furthermore, glycogenolysis and gluconeogenesis were higher (P < 0.01) in the obese than in the lean nondiabetic subjects. Plasma free fatty acid concentrations correlated (P < 0.001) with glucose production and gluconeogenesis both before and during the clamp and with glycogenolysis during the clamp (P < 0.01). We concluded that defects in the regulation of glycogenolysis as well as gluconeogenesis cause hepatic insulin resistance in obese nondiabetic and type 2 diabetic humans. Diabetes 54: [1942][1943][1944][1945][1946][1947][1948] 2005 T ype 2 diabetes is characterized by both fasting and postprandial hyperglycemia. Numerous studies have established that glucose production in people with type 2 diabetes is either elevated or not appropriate for the prevailing glucose and insulin concentrations (1-8). The cause(s) of these inappropriately elevated rates of glucose production remains an area of active investigation. A series of studies have shown that gluconeogenesis, whether measured with magnetic resonance spectroscopy (7) or the deuterated water method, is increased in people with type 2 diabetes (2,9 -13). On the other hand, rates of glycogenolysis have been reported to not differ in diabetic and nondiabetic individuals (2,9,10,12). However, because both hyperglycemia and hyperinsulinemia are potent inhibitors of glycogenolysis (14 -17), equal rates of glycogenolysis, despite higher glucose and insulin concentrations in diabetic subjects, imply abnormal regulation of the glycogenolytic as well as the gluconeogenic pathway.We recently confirmed this supposition (11) by demonstrating that the contribution of glycogenolysis to endogenous glucose production (henceforth referred to as glycogenolysis) was fully suppressed in nondiabetic subjects when insulin concentrations were clamped at levels slightly above basal and glucose concentrations were raised to levels typically observed in people with type 2 diabetes (i.e., ϳ11 mmol/l). In contrast, glycogenolysis persisted in people with mild (e.g., fasting glucose ϳ8 mmol/l) or severe (e.g., fasting glucose ϳ12 mmol/l) diabetes who...

Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats

“…As in type 2 diabetic patients, endogenous glucose production was found to be significantly increased in fasting 10-week-old male ZDF rats in the current studies, with rates elevated more than twofold relative to those described in normal rats in a similar nutritional state (29). The contribution of gluconeogenesis to overall endogenous glucose production was high but not dissimilar to that in human patients, where the contribution of gluconeogenesis has been reported to be ϳ68 and 88% after a 15-and 23-h fast, respectively (6,35). Acute MB06322 treatment inhibited gluconeogenesis by ϳ70%.…”

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…Particularly when insulin levels are low or during insulin resistance, hyperglucagonemia results in increased hepatic glucose production (Basu et al, 2005;Larsson & Ahrén, 2000). Therefore, inhibition of the glucagon signal has been suggested as a target for the treatment of type 2 diabetes (Sloop et al, 2005).…”

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

“…Regulation of hepatic gluconeogenesis is another important process in regulation of blood glucose levels, and pathological changes in glucose production of liver are a central characteristic in type 2 diabetes (44,45). It is known that increased hepatic gluconeogenesis is induced by overexpression of PEPCK, a key gluconeogenic enzyme, and the catalytic subunit glucose-6-phosphatase, which is regulated by transcriptional and nontranscriptional mechanisms (46,47).…”