Endogenous glucose production and glucose effectiveness in type 2 diabetic subjects derived from stable-labeled minimal model approach.

Abstract

Insulin sensitivity, glucose effectiveness, and endogenous glucose production (EGP) during stable-labeled, frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) were evaluated by a single-and two-compartment minimal model combined with nonparametric deconvolution in eleven nonobese Japanese type 2 diabetic patients. Four patients were treated with sulfonylureas, and the remaining seven with diet therapy alone. None had diabetic retinopathy and microalbuminuria. Their fasting glucose level was 117+/-7 mg/dl (mean +/- SE), and HbA1c was 6.6+/-0.3%. Age-, sex-, and BMI-matched subjects with normal glucose tolerance served as control subjects. Plasma insulin response to the stimuli and insulin sensitivity indexes (S(I), S(I)*, and S(I)2* were derived from a minimal model and single- and two-compartment-labeled minimal models) were impaired in the type 2 diabetic patients. The combined ability of glucose, per se, to increase its own uptake and suppress EGP (glucose effectiveness [SG]), which was derived from kinetic analysis of plasma glucose by a minimal model, was significantly lower in the type 2 diabetic patients (0.0132+/-0.0015 vs. 0.0203+/-0.0022; P<0.05). However, the ability of glucose, per se, to stimulate glucose uptake, assessed as S(G)* and S(G)2* from the kinetic analysis of labeled glucose by single- and two-compartment minimal model, was not impaired in those patients. EGP of the type 2 diabetic patients as a whole was suppressed to the level similar to that of the control subjects despite a higher plasma glucose level throughout FSIGT. When EGP in the diabetic subjects was analyzed, considering their recent glycemic control, the initial suppression was blunted in the patients with higher HbA1c levels. In conclusion, glucose mass action to stimulate glucose uptake remains near-normal in the lean Japanese type 2 diabetic patients of this study, whereas ability of glucose to suppress EGP is impaired in the patients with recent hyperglycemia. This blunted suppression of EGP might be one of the conspirators for decreased S(G) in subjects with type 2 diabetes.

Complex Haplotypes of the PGC-1α Gene Are Associated With Carbohydrate Metabolism and Type 2 Diabetes

“…PGC-1␣ has been shown to participate in insulin-regulated hepatic gluconeogenesis by coactivating HNF-4␣ and FOXO1 (2-4). Moreover, hepatic gluconeogenesis contributes to glucose effectiveness ascertained in human studies (35,36). Conversely, PGC-1␣ enhances oxidative phosphorylation and glucose uptake in skeletal muscle (5,10,12).…”

Effect of Moderate Exercise Training on Peripheral Glucose Effectiveness, Insulin Sensitivity, and Endogenous Glucose Production in Healthy Humans Estimated by a Two-Compartment-Labeled Minimal Model

“…The serum free fatty acid levels were assayed using the standard method (12). Deuterated glucose was analyzed as a penta-acetate derivative using the method by Wolfe (13) as previously described (14). The measurement error associated with the labeled glucose measurement was assumed to be independent, white, and Gaussian, with zero mean and coefficient of variation of 3.0%.…”

“…The data were analyzed using the SAAMII software package (SAAM Institute, Seattle, WA). EGP was estimated by nonparametric deconvolution as previously described (6,14). Computer program for nonparametric deconvolution to estimate EGP was written in Pascal (Borland International, Scotts Valley, CA) on a Macintosh IIcx (Apple Computer, Cupertino, CA).…”

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

“…Increased endogenous glucose production (EGP) appears to be the main source of fasting hyperglycaemia in type 2 diabetes mellitus [1,2] and seems to be proportional to the degree of metabolic dysregulation [3,4]. In non-diabetic individuals, rising glucose levels per se result in rapid and potent suppression of EGP, a phenomenon termed 'glucose effectiveness'.…”