Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy

Hosker, J. P.; Rudenski, A; Burnett, M. A.; Matthews, David R.; Turner, R. C.

doi:10.1016/0026-0495(89)90064-4

Cited by 121 publications

(89 citation statements)

References 24 publications

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“…When mildly Type II diabetic patients, treated by diet alone, were subjected to hyperglycaemic clamp, both phases of insulin secretion were considerably inhibited (Fig. 4) [13]. This was seen at glucose concentrations of 7.5, 10 and 15 mmol/l.…”

Section: Impaired Insulin Secretion In Type II Diabetes Mellitusmentioning

confidence: 93%

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Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

176

149

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In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ concentration in the mitochondrial matrix activating Ca 2+ -sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca 2+ -stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca 2+ -induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1a (HNF-1a) also displayed deletion of glucose-induced but not Ca 2+ -induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease. [Diabetologia (2000) 43: 265±277]

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Section: Impaired Insulin Secretion In Type II Diabetes Mellitusmentioning

confidence: 93%

“…B Control subjects. Modified and reprinted with permission from Hosker et al [13] A B cell (Fig. 6).…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

176

149

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“…Data suggest that some second-generation sulphonylureas could exert a stimulatory effect on first-phase insulin secretion. A study [30] showed that first-phase insulin secretion in response to different degrees of hyperglycaemia was enhanced though not normalized by gliclazide. In our experience [31], the acute administration of gliclazide in newly diagnosed patients before receiving a constant infusion of glucose was associated with an improvement in glucose tolerance, expressed as the incremental plasma glucose area above baseline compared with placebo (354±42 vs 461±52 mmom/240 min).…”

Section: Restoration Of Early Insulin Release In Type 2 Diabetic Patimentioning

confidence: 99%

Loss of early insulin secretion leads to postprandial hyperglycaemia

2003

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Aims/Hypothesis. A loss of early-phase insulin response is common in Type 2 diabetic patients and in people with impaired glucose metabolism. It is hypothesized that this alteration is not simply a marker for the risk of developing diabetes, rather it is a an important pathogenetic mechanism causing excessive postprandial hyperglycaemia. Methods. Relevant literature on the epidemiology, physiopathology, and therapeutic intervention related to loss of early insulin secretion and postprandial hyperglycaemia has been analysed. Results. In response to intravenous glucose, insulin secretion is biphasic. This behaviour translates as a rapid release of insulin into the blood stream in response to the ingestion of carbohydrates or a mixed meal. The rapid increase in portal insulin concentration and the avid binding of the hormone to its receptor on liver cell membranes, account for a prompt suppression of endogenous glucose production and reduction of the rate of increase in plasma glucose concentrations. This has been supported by experimental studies carried out in both animals and humans: the selective abolition of early insulin secretion in healthy subjects results in impaired glucose tolerance, excessive glucose excursions, and possible hampering of the thermic effects of ingested carbohydrates. In nondiabetic subjects, the loss of early insulin secretion is a determinant for developing diabetes. The critical role of the early-phase insulin response in determining postprandial hyperglycaemia, is supported by an amelioration of glucose tolerance by restoring the acute rise in plasma insulin concentrations after the ingestion of both glucose and a mixed meal. This amelioration in plasma glucose profile can prevent late hyperglycaemia and hyperinsulinaemia. Conclusion/interpretation. Therapeutic approaches aimed at restoring a physiological pattern of insulin secretion could prove effective in reducing postprandial glucose excursions particularly in the early stage of Type 2 diabetes. [Diabetologia (2003)

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“…In patients with T2D, the second phase is strongly reduced and the first phase is nearly abolished (7). Multiple factors contribute to the biphasic nature of glucose-stimulated insulin secretion (GSIS), including distinct pools of insulin granules, metabolic signaling, and actin cytoskeleton remodeling (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%