Insulin Secretion in Obesity

Kreisberg, Robert A.; Boshell, Buris R.; DiPlacido, John; Roddam, Roy F.

doi:10.1056/nejm196702092760603

Cited by 150 publications

(46 citation statements)

References 12 publications

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“…The significant correlation of the degree of obesity and fasting insulin levels is extremely important, since some studies appear to indicate a relation between fasting insulin levels and diabetes (11,12). However, when subjects with a wide range of glucose tolerance and body weight are examined, as in this study, only obesity and not carbohydrate intolerance is associated with elevated fasting insulin levels.…”

Section: Discussionmentioning

confidence: 70%

The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects*

Bagdade¹,

Bierman²,

Porte³

1967

J. Clin. Invest.

632

272

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Abstract. The level of insulin after an overnight fast (basal) in 37 obese and nonobese male subjects with normal and abnormal carbohydrate tolerance was directly related to the increase in insulin concentration during a 3 hr 100 g oral glucose tolerance test. Obesity, but not diabetes, was associated with an elevation of this basal insulin level. Thus obesity predicted with the magnitude of the insulin response to glucose ingestion. When the individual insulin values were expressed as per cent change from the basal level, this effect of obesity was excluded. The insulin levels of all subjects with normal carbohydrate tolerance promptly rose 5-7-fold, and reached peak values 1 hr after oral glucose. In contrast, the diabetic response (as per cent increase) was markedly reduced during the 1st hr, and maximal (but still subnormal) insulin levels were not attained until 2 hr. In all subjects the insulin response (quantitated by calculation of the area circumscribed by a plot of the per cent change in insulin with time) showed a significant inverse correlation with the glucose response. Thus increasing degrees of carbohydrate intolerance were associated with decreasing insulin responses. Elevated levels of insulin, in both the basal state and in response to glucose, were related to obesity.

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Section: Discussionmentioning

confidence: 70%

The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects*

Bagdade¹,

Bierman²,

Porte³

1967

J. Clin. Invest.

632

272

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“…The reason for the glucose intolerance in the third generation of the current study can be explained on the basis of insulin insensitivity in obese subjects (15). The high insulin to glucose ratio at various time points after oral glucose loading, i.e.…”

Section: Discussionmentioning

confidence: 76%

“…The higher insulin to glucose ratio at various time points during the glucose tolerance tests suggests that the glucose intolerance may be a result of peripheral insulin resistance rather than a decrease in insulin secretion (15,16).…”

Section: Discussionmentioning

confidence: 99%

The Cross-Generation Effect of Neonatal Macrosomia in Rat Pups of Streptozotocin-Induced Diabetes

Gelardi

Chung-Ja

1991

Pediatr Res

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ABSTRACT. To study the cross-generation effect of enhanced growth in macrosomic newborn rats, we induced mild hyperglycemia in 15 pregnant Sprague Dawley rats by intraperitoneal injection of streptozotocin, 35 mg/kg body weight, on the 5th d of gestation. As reported previously, we produced hyperinsulinemia and accelerated growth in the fetuses of hyperglycernic dams. We also showed that the macrosomic female pups (second generation) continued to have a higher growth rate through the first 12 wk of life. In this study, the second-generation female rats were mated with macrosomic second-generation males; they demonstrated glucose intolerance during late pregnancy and delivered pups (third generation) with higher birth weight and plasma insulin levels than the pups from control second-generation rats. When the macrosomic third-generation pups were raised under identical nutritional and environmental conditions as controls, the macrosomic rats showed accelerated growth and higher fat tissue weight during the first 12 wk of life. Furthermore, the macrosomia was associated with glucose intolerance and higher insulin to glucose ratios compared to controls. We also mated the offspring of second-generation streptozotocin-injected nonmacrosomic as well as the offspring of macrosomic pups of buffer-injected dams; none of the pups from these matings were significantly macrosomic. Therefore. we conclude that the ueruetuation of obesity and -.. .possibly glucose intolerance across generations in this rat model is predominantly a result of abnormal intrauterine metabolic environment rather than genetic factor driven. (Pediatr Res 29: 606-610, 1991) According to Pedersen's hypothesis (1), poorly controlled pregnant diabetics will have maternal hyperglycemia, which in turn induces fetal hyperglycemia and hyperinsulinemia. This abnormal metabolic and hormonal milieu results in several neonatal morbidities including neonatal macrosomia (2). Macrosomia is a result of accelerated fetal growth in the presence of an abundance of substrates and anabolic hormones such as insulin and somatomedin-c (3-5). In the human (6, 7) and experimental models (8), neonatal macrosomia is associated with accelerated postnatal growth through adulthood resulting in an increased propensity toward obesity. In the experimental model (8), the obesity is further associated with glucose intolerance, particularly in female subjects. An intriguing question is: "Will the rnacrosomic female offspring of diabetic mothers become glucose in- tolerant during pregnancy and will their fetuses show accelerated fetal growth and abnormal glucose metabolism?" The purpose of our study is to use an experimental model to answer this question. Our hypotheses are: 1 ) the female offspring of streptozotocin-induced mild hyperglycemic rats will exhibit glucose intolerance when they attain adulthood and become pregnant; 2) these second-generation macrosomic females will produce offspring (third generation) of higher birth weight; and 3) the third-generation macrosomic offsprin...

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“…Most obese patients are insulin resistant (1)(2)(3), and various animal models of obesity have also been described in which insulin resistance is a prominent feature (4,5). Decreased cellular insulin receptors have been observed in a variety of tissues from obese animals (6)(7)(8)(9)(10) and man (11)(12)(13)(14)(15), and the potential causal relationship between decreased insulin receptors and insulin resistance is obvious.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

Kolterman¹,

Insel²,

Saekow³

et al. 1980

J. Clin. Invest.

622

261

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A B S T R A C T To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulinglucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101+16 vs. 186+16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally ef: fective instulin concentration was 270+27 ,uU/ml for the obese coompared with 130±10 ,U/ml for controls. In nine of' the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the least hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest postreceptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppression in all subjects. The doseresponse curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. InReceived for publication 27 August 1979 and in revised form 30 January 1980. 1272 sulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significanit inverse linear relationship was demonstrated between insulin binding andl the serum instulin concentrationl re(luired f'or halfrmaximnal stimulation of glucose disposal. In conclusioni: (a) decreased cellular insulin receptors contrilbute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.

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Insulin Secretion in Obesity

Cited by 150 publications

References 12 publications

The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects*

The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects*

The Cross-Generation Effect of Neonatal Macrosomia in Rat Pups of Streptozotocin-Induced Diabetes

Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

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