Role of Reduced Suppression of Glucose Production and Diminished Early Insulin Release in Impaired Glucose Tolerance

Mitrakou, Asimina; Kelley, David E.; Mokáň, Marián; Veneman, Thiemo F.; Pangburn, Thomas; Reilly, J.P.; Gerich, John E.

doi:10.1056/nejm199201023260104

Cited by 556 publications

(446 citation statements)

References 47 publications

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“…However, impaired pancreatic beta cell function is an essential element in the development of abnormal glucose tolerance. Indeed, altered beta cell function is a known predisposing factor for type 2 diabetes [4][5][6][7][8], while other studies have found that insulin insensitivity and abnormal beta cell function are independent predictors [9][10][11]. A major problem until now has been the lack of detailed information about the specific abnormalities of beta cell function that predispose to diabetes.…”

Section: Introductionmentioning

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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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: Introductionmentioning

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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“…Many of the manifestations of alpha cell dysfunction described above have been reported in subjects with IGT [6,43,44]. Furthermore, a prospective study of postmenopausal women found that the AGR arg at a clamped plasma glucose of 14 mmol/l was an independent predictor of glucose intolerance [45].…”

Section: Abnormalities Of Alpha Cell Function In Diabetesmentioning

confidence: 92%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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“…Impaired suppression of glucagon release can be detected in individuals with impaired glucose tolerance (IGT) and type 2 diabetes following intravenous [2] or oral glucose administration [3]. Fasting glucagon concentrations exert a tonic stimulatory influence on hepatic glucose output, which in the dog has been estimated to account for one-third of the fasting rate of glucose release [4].…”

Section: Introductionmentioning

confidence: 99%

Association of fasting glucagon and proinsulin concentrations with insulin resistance

et al. 2007

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Aims/hypothesis Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. Results In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p<0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for both glucagon (p=0.05) and proinsulin (p=0.02) and 0.36 for adiponectin (p<0.0001). Conclusions/interpretation Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.

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Role of Reduced Suppression of Glucose Production and Diminished Early Insulin Release in Impaired Glucose Tolerance

Cited by 556 publications

References 47 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

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Association of fasting glucagon and proinsulin concentrations with insulin resistance

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