Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function

Kahn, Steven E.; Prigeon, Ronald L.; McCulloch, David K.; Boyko, Edward J.; Bergman, Richard N.; Schwartz, Michael W.; Neifing, J. L.; Ward, W. K.; Beard, J. C.; Palmer, Jerry P.; al, et

doi:10.2337/diabetes.42.11.1663

Cited by 587 publications

(540 citation statements)

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“…While plasma insulin concentrations, fasting or after glucose, did not clearly discriminate between progressors and non-progressors, insulin secretory rates were higher in the progressors. Nonetheless, dynamic indices of beta cell function, such as glucose sensitivity and beta cell compensation for insulin insensitivity [21], were significantly and markedly impaired (by~25%) in the progressors. Thus, insulin hypersecretion masked the fact that the intrinsic ability of the beta cell to acutely respond to glucose was already compromised in the progressors at baseline.…”

Section: Discussionmentioning

confidence: 98%

“…The insulinogenic index was calculated as the ratio of the insulin concentration increment to the glucose concentration increment at 30 min into the OGTT (ΔI 30 /ΔG 30 ). The ability of the beta cell to compensate for the extant degree of insulin resistance was estimated by calculating the product of insulin sensitivity and the insulinogenic index, analogous to the disposition index (DI, in units of ml min −1 m −2 pmol mmol −1 ) proposed by Kahn and colleagues [21].…”

Section: Discussionmentioning

confidence: 99%

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Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

et al. 2005

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Aims/hypothesis: The aim of this prospective study was to investigate predictors of deteriorating glucose tolerance in subjects of British extraction. Methods: A total of 156 non-diabetic subjects (86 with a family history of type 2 diabetes) underwent a 75-g OGTT and anthropometric assessment at baseline and 5 years later. Pancreatic beta cell function and whole-body insulin sensitivity were studied by model assessment. Subjects were classified as progressors if glucose tolerance moved one or more steps from normal, impaired fasting glucose, impaired glucose tolerance and diabetes over the follow-up period. Results: At baseline, the progressors (n=22) had increased adiposity and a higher proportion of familial diabetes and abnormal glucose tolerance than non-progressors. Baseline pancreatic beta cell sensitivity to changes in glucose (p<0.02) and whole-body insulin sensitivity (p<0.0001) were decreased in the progressors. Logistic regression revealed that baseline and follow-up changes in beta cell glucose sensitivity and insulin sensitivity, rather than the classical clinical predictors (adiposity, familial diabetes and glucose levels), were the key independent predictors of progression (explaining over 50% of the progression). Conclusions/ interpretation: Impaired pancreatic beta cell glucose sensing and whole-body insulin sensitivity predict progression to hyperglycaemia. Strikingly, these pathophysiological changes override the importance of the clinical risk factors and highlight potential metabolic targets for prevention strategies.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

et al. 2005

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“…2c, p=0.02 compared with those who had NGT), indicating that the changes in Si and AIRg did not follow the expected hyperbolic relationship [23] and were consistent with their decline in glucose tolerance. Haemochromatosis subjects with diabetes had lower AIRg and DI compared with those with NGT, but average Si was unchanged (Fig.…”

Section: Mechanism Of Glucose Intolerancementioning

confidence: 78%

“…Kahn has previously reported that these two variables follow a hyperbolic relationship in normal individuals; the solid and dashed lines indicate the mean, and 5th and 95th percentiles, for AIRg and Si in the healthy, non-diabetic population studied by Kahn [23]. Thus, for example, if insulin secretory capacity decreases but Si also increases within this normal relationship, NGT should be maintained; glucose intolerance develops when one variable or the other does not compensate and the individual departs from the normal hyperbolic relationship [23]. Control and haemochromatosis subjects with NGT have similar values for AIRg and Si (see Fig.…”

Section: Mechanism Of Glucose Intolerancementioning

confidence: 97%

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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Aims/hypothesis: The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects and methods: Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. Results: The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Conclusions/interpretation: Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

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“…Normoglycaemia is maintained in the majority of obese insulin-resistant individuals, as their islet beta cells compensate for insulin resistance with insulin hypersecretion [1,2]. Obesity-associated type 2 diabetes develops when beta cell compensation processes fail [3,4].…”

Section: Introductionmentioning

confidence: 99%

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

et al. 2006

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Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucosestimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l).Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpretationThe results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

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Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function

Cited by 587 publications

References 0 publications

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

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