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OBJECTIVE--To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action. RESEARCH DESIGN AND METHODS--Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) [...]

To determine the mechanism(s) by which insulin inhibits endogenous glucose production (EGP) in nondiabetic humans, insulin was infused at rates of 0.25, 0.375, or 0.5 mU * [kg.sup.-1] * [min.sup.-1] and glucose was clamped at ~5.5 mmol/l. EGP, gluconeogenesis, and uridine-diphosphoglucose (UDP)-glucose flux were measured using [3-³H]glucose, deuterated water, and the acetaminophen glucuronide methods, respectively. An increase in insulin from ~75 to ~100 to ~150 pmol/l (~12.5 to ~17 to ~25 µU/ml) resulted in progressive (ANOVA; P < 0.02) suppression of EGP (13.1 ± 1.3 vs. 11.7 ± 1.03 vs. 6.4 ± 2.15 µmol * [kg.sup.-1] * [min.sup.-1]) that was entirely due to a progressive decrease (ANOVA; P < 0.05) in the contribution of glycogenolysis to EGP (4.7 ± 1.7 vs. 3.4 ± 1.2 vs. -2.1 ± 1.3 µmol * [kg.sup.-1] * [min.sup.-1]). In contrast, both the contribution of gluconeogenesis to EGP (8.4 ± 1.0 vs. 8.3 ± 1.1 vs. 8.5 ± 1.3 µmol * [kg.sup.-1] * [min.sup.-1]) and UDP-glucose flux (5.0 ± 0.4 vs. 5.0 ± 0.3 vs. 4.0 ± 0.5 µmol * [kg.sup.-1] * [min.sup.-1]) remained unchanged. The contribution of the direct (extracellular) pathway to UDP-glucose flux was minimal and constant during all insulin infusions. We conclude that higher insulin concentrations are required to suppress the contribution of gluconeogenesis of EGP than are required to suppress the contribution of glycogenolysis to EGP in healthy nondiabetic humans. Since suppression of glycogenolysis occurred without a decrease in UDP-glucose flux, this implies that insulin inhibits EGP, at least in part, by directing glucose-6-phosphate into glycogen rather than through the glucose-6-phosphatase pathway., Insulin is the primary regulator of endogenous glucose production (EGP). Insulin can inhibit hepatic glucose release via a variety of mechanisms. Insulin can decrease net hepatic release of glucose by [...]

The present study sought to determine whether elevated plasma free fatty acids (FFAs) 'alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at ~8.3 mmol/l and insulin was increased to ~300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 ± 2.6 vs. 65.0 ± 7.9 µ mol * [kg.sup.-1] * [min.sup.-1]). Whole-body glucose disappearance (37.0 ± 2.2 vs. 70.9 ± 8.7 µmol * [kg.sup.-1] * [min.sup.-1]; P < 0.001) and leg glucose uptake (24.3 ± 4.2 vs. 59.6 ± 10.0 µmol * kg fat-free mass of the [leg.sup.-1] * [min.sup.-1]; P < 0.02) were also lower, whereas splanchnic glucose production (8.2 ± 0.8 vs. 4.3 ± 0.7 µ mol * [kg.sup.-11 * [min.sup.-1]; P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting wholebody glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production., Elevated plasma free fatty acid (FFA) concentrations are common in both obesity and type 2 diabetes (1-4). Currently, there is substantial evidence that FFAs may contribute to insulin resistance in [...]

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To [...]

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether [...]

In vitro studies indicate that glucagon-like peptide-1(7-36)-amide (GLP-1) can enhance hepatic glucose uptake. To determine whether GLP-1 increases splanchnic glucose uptake in humans, we studied seven subjects with type 1 [...]

The proportion of glucose initially extracted by the splanchnic bed following ingestion of carbohydrate is controversial with estimates ranging from 0 to 45%. To determine whether this is due to [...]

To determine whether Type 2 diabetes mellitus alters systemic and regional (splanchnic and leg) free fatty acid (FFA) ([[sup.3]H] palmitate) metabolism, 14 nondiabetic (ND) and 14 Type 2 diabetic (D) [...]

Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To [...]

Evidence for a Defect in Hepatic Glucokinase Activity Insulin-induced stimulation of muscle glucose uptake (MGU) is impaired in people with type 2 diabetes. To determine whether insulin-induced stimulation of splanchnic [...]

To determine whether type 2 diabetes mellitus alters the ability of insulin and glucose to regulate splanchnic and extrasplanchnic glucose metabolism, 14 nondiabetic (ND) and 16 type 2 diabetic (D) [...]

The ability of glucose to stimulate its own uptake and suppress its own release is impaired in type 2 diabetes. To determine whether glucose effectiveness is improved by short-term euglycemia, [...]

Glucagon like-peptide-1-(7,36)-amide (GLP-1) suppresses glucagon release and increases the early phase of insulin secretion. However, it is currently controversial as to whether GLP-1 alters insulin action and/or glucose effectiveness. To [...]

People with type 2 diabetes have defects in both [Alpha] and [Beta] cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but [...]

The rate of appearance of meal-derived glucose is determined by a variety of factors. Ingested complex carbohydrates require enzymatic digestion into monosaccharides before absorption. Although this step per se is [...]