Mechanisms and time course of impaired skeletal muscle glucose transport activity in streptozocin diabetic rats.

Napoli, Raffaele; Hirshman, Michael F.; Horton, Edward S.

doi:10.1172/jci118053

Cited by 48 publications

(44 citation statements)

References 74 publications

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“…In rats with streptozotocin-induced diabetes, hyperglycaemia per se affects insulin-stimulated glucose transport by altering glucose transporter translocation in skeletal muscle (44). The impairment of glucose uptake in adipocytes does not seem to involve GLUT1 since it was unaffected by high glucose in diabetic rats (45,46).…”

Section: Discussionmentioning

confidence: 97%

High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes

et al. 2003

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Objective: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins. Design and methods: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10 4 mU/ml of insulin or without insulin. After washing, 125 I-insulin binding, basal and acutely insulin-stimulated D-[ 14 C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed. Results: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by , 40%, and shifted the doseresponse curve for insulin's acute effect on glucose uptake 2-to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by ,30 -50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by ,20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100 -400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose -response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by , 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration. Conclusions: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.

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Section: Discussionmentioning

confidence: 97%

High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes

et al. 2003

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“…In this model of diabetes, similar to what happens in human diabetes, insulin therapy does not restore insulinmediated skeletal muscle glucose uptake (32) and insulin-stimulated glucose transport and transporter translocation to normal (33). However, when phlorizin is used instead of insulin to reduce plasma glucose, insulin-mediated skeletal muscle glucose uptake is normalized (32), and glucose transport and transporter translocation are improved (28). Thus, three hypotheses can be proposed to explain the inability of insulin therapy to restore glucose uptake, transport, and transporter translocation in human diabetes, as well as in the rat model of diabetes: ( a ) although insulin treatment reduces glucose level, the increase in plasma insulin induced by the chronic insulin therapy might exert per se a negative effect on insulin-stimulated muscle glucose uptake (34)(35)(36); ( b ) subcutaneous insulin therapy in rats cannot produce a completely normal glucose profile: variable high and low glucose values adversely influence glucose uptake by muscle; and/or ( c ) the insulin therapy was not adequate in terms of route of administration (37), because insulin was not administered in the portal system, as occurs physiologically, but subcutaneously into the peripheral circulation.…”

Section: Introductionmentioning

confidence: 56%

“…For this purpose, we studied streptozocin diabetic rats treated with islet transplantation under the kidney capsule. An additional aim of this study was to verify the hypothesis that hypoinsulinemia, and not hyperglycemia, was the factor responsible for the decrease in transporter intrinsic activity reported in streptozocin diabetic rats studied in the basal nonfasted state (28). Therefore, we examined the skeletal muscle glucose transport system in animals in the fasting state.…”

Section: Introductionmentioning

confidence: 94%

“…Although insulin-stimulated muscle glucose uptake (8)(9)(10)(11)(12)) and transport (13) are impaired in human diabetes, GLUT4 content is not reduced, either in the whole muscle (14)(15)(16)(17)(18) or in the plasma membrane (19). Therefore, the reduction of glucose transport that occurs in diabetic patients might be due to abnormalities in the cellular localization of glucose transporters or to a decrease in transporter intrinsic activity (20)(21)(22)(23)(24)(25)(26)(27), as we have recently suggested (28), rather than to a reduction in muscle GLUT4 content. However, no data on transporter intrinsic activity in human diabetes are available.…”

Section: Introductionmentioning

confidence: 94%

“…Streptozocin diabetic rats are characterized by reduction of muscle glucose uptake (32) and transport (5,28) due to decreased GLUT4 content and insulin-induced transporter translocation (5,28), and to impairment of transporter intrinsic activity (28). In this model of diabetes, similar to what happens in human diabetes, insulin therapy does not restore insulinmediated skeletal muscle glucose uptake (32) and insulin-stimulated glucose transport and transporter translocation to normal (33).…”

Section: Introductionmentioning

confidence: 99%

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Islet transplantation under the kidney capsule fully corrects the impaired skeletal muscle glucose transport system of streptozocin diabetic rats.

Napoli¹,

Davalli²,

Hirshman

et al. 1996

J. Clin. Invest.

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Chronic insulin therapy improves but does not restore impaired insulin-mediated muscle glucose uptake in human diabetes or muscle glucose uptake, transport, and transporter translocation in streptozocin diabetic rats. To determine whether this inability is due to inadequate insulin replacement, we studied fasted streptozocin-induced diabetic Lewis rats either untreated or after islet transplantation under the kidney capsule. Plasma glucose was increased in untreated diabetics and normalized by the islet transplantation (110 Ϯ 5, 452 Ϯ 9, and 102 Ϯ 3 mg/dl in controls, untreated diabetics, and transplanted diabetics, respectively). Plasma membrane and intracellular microsomal membrane vesicles were prepared from hindlimb skeletal muscle of basal and maximally insulin-stimulated rats. Islet transplantation normalized plasma membrane carrier-mediated glucose transport V max , plasma membrane glucose transporter content, and insulin-induced transporter translocation. There were no differences in transporter intrinsic activity ( V max / R o ) among the three groups. Microsomal membrane GLUT4 content was reduced by 30% in untreated diabetic rats and normal in transplanted diabetics, whereas the insulininduced changes in microsomal membrane GLUT4 content were quantitatively similar in the three groups. There were no differences in plasma membrane GLUT1 among the groups and between basal and insulin stimulated states. Microsomal membrane GLUT1 content was increased 60% in untreated diabetics and normalized by the transplantation. In conclusion, an adequate insulin delivery in the peripheral circulation, obtained by islet transplantation, fully restores the muscle glucose transport system to normal in streptozocin diabetic rats. ( J. Clin. Invest. 1996. 97:1389-1397.)

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Correction of glycaemia and GLUT1 level by mildronate in rat streptozotocin diabetes mellitus model

Sokolovska

Isajevs

Sugoka

et al. 2011

Cell Biochem. Funct.

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Anti-ischaemic drug mildronate suppresses fatty acid metabolism and increases glucose utilization in myocardium. It was proposed that it could produce a favourable effect on metabolic parameters and glucose transport in diabetic animals. Rats with streptozotocin diabetes mellitus were treated with mildronate (100 mg/kg daily, per os, 6 weeks). Therapeutic effect of mildronate was monitored by measuring animal weight, concentrations of blood glucose, insulin, blood triglycerides, free fatty acids, blood ketone bodies and cholesterol, glycated haemoglobin per cent (HbA1c%) and glucose tolerance. GLUT1 mRNA and protein expression in kidneys, heart, liver and muscles were studied by means of real time RT-PCR and immunohistochemistry correspondingly. In the streptozotocin + mildronate group, mildronate treatment caused a significant decrease in mean blood glucose, cholesterol, free fatty acid and HbA1c concentrations and improved glucose tolerance. Induction of streptozotocin diabetes mellitus provoked increase of both GLUT1 gene and protein expression in kidneys, heart and muscle, mildronate treatment produced normalization of the GLUT1 expression levels. In the liver a similar effect was observed for GLUT1 protein expression, while GLUT1 gene expression was increased by mildronate. Mildronate produces therapeutic effect in streptozotocin diabetes model. Mildronate normalizes the GLUT1 expression up-regulated by streptozotocin diabetes mellitus in kidneys, heart, muscle and liver. Copyright © 2011 John Wiley & Sons, Ltd.

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Mechanisms and time course of impaired skeletal muscle glucose transport activity in streptozocin diabetic rats.

Cited by 48 publications

References 74 publications

High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes

High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes

Islet transplantation under the kidney capsule fully corrects the impaired skeletal muscle glucose transport system of streptozocin diabetic rats.

Correction of glycaemia and GLUT1 level by mildronate in rat streptozotocin diabetes mellitus model

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