Rate-limiting steps for insulin-mediated glucose uptake into perfused rat hindlimb

Kubo, Katsumaro; Foley, James E.

doi:10.1152/ajpendo.1986.250.1.e100

Cited by 84 publications

(67 citation statements)

References 15 publications

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“…The finding that the defect in glucose phosphorylation exceeds that of inward glucose transport is consistent with previous studies from our laboratory that have demonstrated a severe defect in insulin-stimulated muscle hexokinase II activity, mRNA levels, and protein content (37,40,48,63,64). This observation is also consistent with prior studies demonstrating that, under insulin-stimulated conditions, post-glucose transport defects can be rate limiting for intracellular glucose metabolism (10,29,38,42,44,47,49,69). However, it should be emphasized that, even if the defect in hexokinase II were corrected, a severe defect in glucose transport most likely would remain (11) and become rate limiting.…”

Section: Discussionsupporting

confidence: 92%

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Pendergrass¹,

Bertoldo

Bonadonna

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Our objectives were to quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2DM) subjects, and in normal glucose-tolerant, insulin-resistant offspring of two T2DM parents. Subjects received a euglycemic insulin (40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 ) clamp with brachial artery/deep forearm vein catheterization. After 120 min of hyperinsulinemia, a bolus of3 H]glucose (tripletracer technique) was given into brachial artery and deep vein samples obtained every 12-30 s for 15 min. Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40 -50% in obese nondiabetic, lean T2DM, and obese T2DM subjects (all P Ͻ 0.01); in offspring, the reduction in FGU and M was ϳ30% (P Ͻ 0.05). Inward glucose transport and glucose phosphorylation were decreased by ϳ40 -50% (P Ͻ 0.01) in obese nondiabetic and T2DM groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean T2DM, obese T2DM, and offspring compared with lean controls. We conclude that 1) obese nondiabetic, lean T2DM, and offspring manifest moderate-tosevere muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus T2DM; and 2) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and T2DM groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport. insulin resistance; muscle; glucose phosphorylation; type 2 diabetes; obesity INSULIN RESISTANCE IN MUSCLE, the primary tissue responsible for glucose disposal (18), is a characteristic feature of type 2 diabetes mellitus (T2DM) (19,20,31) and obesity (4,5,19,20,31,33). In T2DM, impaired insulin action is an inherited trait (41, 65), whereas in obesity insulin resistance is acquired (58) secondarily to disturbances in free fatty acid (FFA) metabolism (27, 53), altered fat topography (13), and deranged secretion of adipocytokines (3). Skeletal muscle insulin resistance in T2DM and obesity affects both the glycogen synthetic and glucose oxidative pathways (22), suggesting a proximal defect in insulin action. Recent studies have demonstrated multiple disturbances in insulin signaling in T2DM subjects (15,35,36). However, there has been considerable debate about the contributions of impaired glucose transport vs. reduced glucose phosphorylation to the defect in insulin action in T2DM (6, 7, 12, 36, 56, 66 -68).Only one previous study (7) has examined the contributions of impaired muscle glucose transport vs. reduced glucose phosphorylation to the defect in insulin action in lean T2DM subjects. Inward transmembrane glucose transport was markedly impaired in lean T2DM subjects under conditions of euglycemic...

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Section: Discussionsupporting

confidence: 92%

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Pendergrass¹,

Bertoldo

Bonadonna

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Decreased insulin-stimulated glucose uptake is a characteristic of insulin resistance in obesity and diabetes (46) and defects in the glucose transport system could represent a significant contribution to the mechanisms of insulin resistance in liver and muscle (47,48). The obese Zucker rat does not normally develop overt diabetes and is a better model of impaired glucose tolerance than diabetes (21).…”

Section: Discussionmentioning

confidence: 99%

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Alemzadeh

Holshouser²,

Massey³

et al. 2002

European Journal of Endocrinology

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Objectives: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucosemediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused downregulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. Methods: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. Results: DZ-treated animals showed lower fasting plasma insulin levels ðP , 0:001Þ than their controls. Plasma glucose levels were lower in DZ obese rats than in controls ðP , 0:001Þ; without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase ðP , 0:001Þ and glucose-6-phosphatase ðP , 0:0001Þ and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls ðP , 0:001Þ: However, DZ-treated lean rats demonstrated higher PEPCK activity than controls ðP , 0:002Þ: DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content ðP , 0:01Þ; glycogen synthase activity ðP , 0:0001Þ and glycogen content ðP , 0:02Þ compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals ðP , 0:02Þ: Conclusions: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.

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“…In insulin-sensitive tissues, insulin stimulates glucose transport by translocation of glucose transporters to the plasma membrane from a large intracellular pool (see Cushman and Simpson 1985). The reduction in glucose uptake by hind limb muscle in the last period of infusion of insulin can be explained by mechanisms suggested by Kubo and Foley (1986). These workers considered that at physiological concentrations of glucose, in the presence of insulin concentrations that stimulate maximally, the rate-limiting step for insulin-mediated uptake of glucose and for glucose metabolism in muscle shifts from glucose transport to some step beyond transport.…”

Section: Discussionmentioning

confidence: 99%

Insulin Affects Glucose Uptake by Muscle and Mammary Tissues of Lactating Ewes

Leenanuruksa¹,

Niumsup²,

McDowell³

1988

Aust. Jnl. Of Bio. Sci.

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Effects of insulin on exchanges of glucose across skeletal muscle and mammary tissue were measured in short-term studies in lactating ewes. Insulin secretion was suppressed by a primed/continuous infusion of somatostatin, then insulin was administered by continuous intravenous infusion of doses that were increased, in a step-wise manner, from 0 to 2 U h -I. Plasma glucose was maintained essentially constant by frequent monitoring and intravenous administration of exogenous glucose.Somatostatin suppressed but did not completely inhibit insulin secretion as shown by maintenance of plasma concentration of C-peptide. As plasma insulin was increased, while arterial glucose was maintained stable, uptake of glucose by skeletal muscle increased and glucose uptake by the mammary gland decreased. These observations confirm the role of insulin in regulating glucose uptake by skeletal muscle and raise the possibility that insulin also regulates glucose uptake by the mammary gland.

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Rate-limiting steps for insulin-mediated glucose uptake into perfused rat hindlimb

Cited by 84 publications

References 15 publications

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Insulin Affects Glucose Uptake by Muscle and Mammary Tissues of Lactating Ewes

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