Normalization of Plasma Glucose Concentration by Insulin Therapy Improves Insulin-Stimulated Glycogen Synthesis in Type 2 Diabetes

Pratipanawatr, Thongchai; Cusi, Kenneth; Ngo, Peter; Pratipanawatr, Wilailak; Mandarino, Lawrence J.; DeFronzo, Ralph A.

doi:10.2337/diabetes.51.2.462

Cited by 47 publications

(23 citation statements)

References 83 publications

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“…In our diabetic population there was no activation of GS by insulin infusion in physiological concentrations (40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 ), which is consistent with observations in a recent study of poorly controlled obese diabetic subjects (48). Because this defect was not caused by defects in the signaling steps generally believed to be involved in insulin activation of GS, what mechanisms are involved?…”

Section: Discussionsupporting

confidence: 91%

Increased Phosphorylation of Skeletal Muscle Glycogen Synthase at NH2-Terminal Sites During Physiological Hyperinsulinemia in Type 2 Diabetes

Højlund

Stæhr²,

Hansen³

et al. 2003

Diabetes

119

125

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In type 2 diabetes, insulin activation of muscle glycogen synthase (GS) is impaired. This defect plays a major role for the development of insulin resistance and hyperglycemia. In animal muscle, insulin activates GS by reducing phosphorylation at both NH 2 -and COOH-terminal sites, but the mechanism involved in human muscle and the defect in type 2 diabetes remain unclear. We studied the effect of insulin at physiological concentrations on glucose metabolism, insulin signaling and phosphorylation of GS in skeletal muscle from type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Analysis using phospho-specific antibodies revealed that insulin decreases phosphorylation of sites 3a ؉ 3b in human muscle, and this was accompanied by activation of Akt and inhibition of glycogen synthase kinase-3␣. In type 2 diabetic subjects these effects of insulin were fully intact. Despite that, insulin-mediated glucose disposal and storage were reduced and activation of GS was virtually absent in type 2 diabetic subjects. Insulin did not decrease phosphorylation of sites 2 ؉ 2a in healthy human muscle, whereas in diabetic muscle insulin infusion in fact caused a marked increase in the phosphorylation of sites 2 ؉ 2a. This phosphorylation abnormality likely caused the impaired GS activation and glucose storage, thereby contributing to skeletal muscle insulin resistance, and may therefore play a pathophysiological role in type 2 diabetes.

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Section: Discussionsupporting

confidence: 91%

Increased Phosphorylation of Skeletal Muscle Glycogen Synthase at NH2-Terminal Sites During Physiological Hyperinsulinemia in Type 2 Diabetes

Højlund

Stæhr²,

Hansen³

et al. 2003

Diabetes

119

125

View full text Add to dashboard Cite

show abstract

“…Despite a reduced activity in muscle of type 2 diabetes, glycogen synthase expression is normal, suggesting altered regulation. Normalization of plasma glucose concentration in type 2 diabetic patients by diet or insulin therapy improves insulinstimulated glycogen synthesis, suggesting that these abnormalities may be secondary to hyperglycemia per se (253,254). In an interesting study of monozygotic twin pairs discordant for type 2 diabetes, insulin stimulation of glycogen synthase expression was only impaired in muscle of the affected twin (255).…”

Section: Role Of Impaired Glycogen Synthesis and Breakdown In Human Tmentioning

confidence: 99%

The Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes

et al. 2004

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Type 2 diabetes is a complex disorder with diminished insulin secretion and insulin action contributing to the hyperglycemia and wide range of metabolic defects that underlie the disease. The contribution of glucose metabolic pathways per se in the pathogenesis of the disease remains unclear. The cellular fate of glucose begins with glucose transport and phosphorylation. Subsequent pathways of glucose utilization include aerobic and anaerobic glycolysis, glycogen formation, and conversion to other intermediates in the hexose phosphate or hexosamine biosynthesis pathways. Abnormalities in each pathway may occur in diabetic subjects; however, it is unclear whether perturbations in these may lead to diabetes or are a consequence of the multiple metabolic abnormalities found in the disease. This review is focused on the cellular fate of glucose and relevance to human type 2 diabetes. (Endocrine Reviews 25: 2004)

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“…We and others have demonstrated that short-term insulin intensive therapy (IT) is effective to reduce hyperglycemic-induced insulin resistance (17,18). As insulin resistance would be reduced whereas circulating insulin level is not decreased or even increased during IT, we hypothesized that IT would be an optimal regimen to determine whether it is the reduction of insulin resistance or circulating insulin per se that is responsible for serum SHBG elevation.…”

Section: Introductionmentioning

confidence: 99%

Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients

Tong

Hua

Zhong

et al. 2014

European Journal of Endocrinology

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Objective: Many studies have shown that low sex hormone-binding globulin (SHBG) is associated with insulin resistance, but only few studies have examined how serum SHBG is regulated by insulin in humans. This interventional study aimed to investigate the effect of insulin therapy (IT) on serum SHBG levels in newly diagnosed type 2 diabetic patients. Methods: A total of 80 newly diagnosed type 2 diabetic subjects were enrolled and randomly grouped into a 2-week intensive IT with/without metformin. Serum SHBG, total testosterone, glucose, liver enzymes, lipids, insulin, and C-peptide levels were measured before and after IT. Results: Before IT, serum SHBG levels were negatively correlated with BMI, waist circumference (WC), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (g-GT), triglyceride (TG), fasting insulin, and C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR), and positively with HDL-C (all P for trend !0.05), after adjustment for age and sex. IT increased serum SHBG levels from 26.5G14.5 to 33.2G15.0 nmol/l (P!0.001), increased by 25.2% (95% CI, 20.3 to 30.9%, P!0.001). In a multiple linear regression model adjusting for age, sex, BMI, and WC, the decreases in DALT (standardized regression coefficient bZK0.374, PZ0.012) and DTG (bZK0.380, PZ0.020) were independent contributors to the increase in DSHBG. Conclusions: IT increases serum SHBG likely through improving insulin resistance and liver function.

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Normalization of Plasma Glucose Concentration by Insulin Therapy Improves Insulin-Stimulated Glycogen Synthesis in Type 2 Diabetes

Cited by 47 publications

References 83 publications

Increased Phosphorylation of Skeletal Muscle Glycogen Synthase at NH2-Terminal Sites During Physiological Hyperinsulinemia in Type 2 Diabetes

Increased Phosphorylation of Skeletal Muscle Glycogen Synthase at NH2-Terminal Sites During Physiological Hyperinsulinemia in Type 2 Diabetes

The Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes

Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients

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