Quantitation of Insulin-stimulated Glucose Disposal in Patients with Non-insulin-dependent Diabetes Mellitus

Donner, C. C.; Fraze, E.; Chen, Y D I; Reaven, G. M.

doi:10.2337/diab.34.9.831

Cited by 21 publications

(9 citation statements)

References 6 publications

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“…At maximally stimulating insulin concentrations, capacity for glucose disposal is independent of the effect of insulin sensitivity (3). Our results before weight loss agree with previously published data demonstrating that increments of plasma insulin within phys-iologic range have little effect on glucose disposal in subjects with NIDDM, particularly if fasting glucose concentration exceeds 200 mg/dl (10,39). Changes in capacity, at any given insulin and glucose concentrations, probably reflect changes in intracellular defects of insulin action, e.g., changes in enzyme activity, in the number of functional glucose transporter systems, or in coupling if there is a ratelimiting step (7,37,38).…”

Section: Discussionsupporting

confidence: 92%

Insulin Action in Obese Non-Insulin-Dependent Diabetics and in Their Isolated Adipocytes Before and After Weight Loss

1987

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To determine the effects of weight loss on insulin action in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in their isolated adipocytes, we studied nine weight-stabilized Pima Indians [7 females and 2 males; age 39 +/- 3 yr; wt 99.9 +/- 8.2 kg; body fat 39 +/- 2% (means +/- SE)] before and after a 6.7 +/- 1.3-kg weight loss and decrease in fasting plasma glucose from 250 +/- 11 to 148 +/- 15 mg/dl. In vivo insulin action was measured during a 3-insulin-step, hyperglycemic (approximately 310 mg/dl) clamp with somatostatin (250 micrograms/h). At a clamp plasma insulin concentration of 10 microU/ml, glucose disposal rates did not change after weight loss; at approximately 100 microU/ml, glucose disposal rates increased by 21% [from 4.3 +/- 0.2 to 5.3 +/- 0.4 mg X min-1 X kg-1 of fat-free mass (FFM), P less than .01] mostly due to increased carbohydrate oxidation rates (2.0 +/- 0.3 to 2.8 +/- 0.3 mg X min-1 X kg-1 FFM, P less than .02); at 2400 microU/ml, glucose disposal rates increased by 37% (11.4 +/- 0.6 to 15.6 +/- 1.4 mg X min-1 X kg-1 FFM, P less than .02) mostly due to increased nonoxidative carbohydrate disposal rates or storage (7.5 +/- 0.6 to 10.9 +/- 1.3 mg X min-1 X kg-1 FFM, P less than .04). Sensitivity of glucose disposal to insulin in the physiologic range (measured as change in glucose disposal rate per unit change in insulin concentration between clamps at approximately 10 and approximately 100 microU/ml) was very low in these diabetic subjects and did not change after weight loss. Adipocyte cell size, basal and maximal insulin-stimulated glucose transport, and half-maximal rate for transport did not change after weight loss. The data suggest that insulin in the physiologic range has no apparent effect on glucose disposal in patients with NIDDM before or after weight loss. However, a moderate weight loss is associated with enhanced capacity to transport and metabolize glucose in vivo. The discrepancy between in vivo and in vitro results suggests that the adipocyte may not always reflect in vivo insulin action. Diabetes 36:227-36, 1987.

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Section: Discussionsupporting

confidence: 92%

Insulin Action in Obese Non-Insulin-Dependent Diabetics and in Their Isolated Adipocytes Before and After Weight Loss

1987

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“…It is now well established that skeletal muscle in normal man plays a fundamental role in the disposal of glucose (27), and it is the site responsible for postprandial hyperglycemia in insulin resistant states such as obesity and NIDDM (12,13). However, the mechanism(s) of these abnormalities has remained largely unexplored for several reasons: (a) obtaining human muscle biopsies from subjects with NIDDM is difficult; (b) the methodology for studying insulin receptor structure and function in muscle has only recently been developed; and (c) an in vitro insulin responsive human muscle cell preparation has not yet been developed.…”

Section: Discussionmentioning

confidence: 99%

“…The overall insulin resistance in NIDDM, with or without obesity, has been well demonstrated with the use of several in vivo techniques (6)(7)(8)(9)(10)(11)(12). Quantitatively, the most important site of insulin action resides in the muscle, which plays the predominant role in insulin-mediated glucose utilization (13).…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes.

F¹,

Sinha²,

Raju³

et al. 1987

J. Clin. Invest.

337

161

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We have studied the structure and function of the insulin receptors in obese patients with and without noninsulin dependent diabetes mellitus (NIDDM) and in nonobese controls using partially purified receptors from muscle biopsies.Insulin binding was decreased in obesity due to reduced number of binding sites but no differences were observed in insulin binding between obese subjects with or without NIDDM. The structural characteristics of the receptors, as determined by affinity labeling methods and electrophoretic mobility of the 6-subunit, were not altered in obese or NIDDM compared to normal weight subjects. Furthermore, the ability of insulin to stimulate the autophosphorylation of the #-subunit and the phosphoamino acid composition of the phosphorylated receptor were the same in all groups. However, insulin receptor kinase activity was decreased in obesity using Glu4:Tyrl as exogenous phosphoacceptor without any appreciable additional defect when obesity was associated with NIDDM.Thus, our data are supportive of the hypothesis that in muscle of obese humans, insulin resistance is partially due to decreased insulin receptors and insulin receptor kinase activity. In NIDDM the defect(s) in muscle is probably distal to the insulin receptor kinase.

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“…The overall insulin resistance in NIDDM, with or without obesity, has been well demonstrated with the use of several in vivo techniques (6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

F¹,

Ittoop²,

Pories³

et al. 1986

J. Clin. Invest.

212

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We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man. Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submaximal insulin concentration in comparison to nonobese controls. Insulin binding per cell number was similar in all groups. However, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger. In addition, the pool of detergent-extractable receptor was further decreased in diabetics. Insulin receptors in all groups were unaltered as determined by affinity-labeling methods. However, insulin-stimulated insulin receptor kinase activity was decreased in diabetics. Thus, in obesity, decreased surface binding could explain resistance to submaximal insulin concentrations. In diabetes, diminished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver.

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Quantitation of Insulin-stimulated Glucose Disposal in Patients with Non-insulin-dependent Diabetes Mellitus

Cited by 21 publications

References 6 publications

Insulin Action in Obese Non-Insulin-Dependent Diabetics and in Their Isolated Adipocytes Before and After Weight Loss

Insulin Action in Obese Non-Insulin-Dependent Diabetics and in Their Isolated Adipocytes Before and After Weight Loss

Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes.

Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

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