Abstract
Aims/hypothesisType 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease.MethodsThe Leprdb mouse (age 13–18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells.ResultsWe identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule–granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose.Conclusions/interpretationBeta cell function is altered in prediabetes and there are further changes in the progression to early disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3942-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Type 2 diabetes is a chronic, progressive disease characterised by loss of glucose homeostasis and leading to morbidity and premature mortality [1,2,3,4]
Conclusions/interpretation Beta cell function is altered in prediabetes and there are further changes in the progression to early disease
In early disease there can be an increase in insulin secretion that might be explained by an increase in beta cell mass; it is unknown whether beta cell function changes
Summary
Type 2 diabetes is a chronic, progressive disease characterised by loss of glucose homeostasis and leading to morbidity and premature mortality [1,2,3,4]. In early disease there can be an increase in insulin secretion that might be explained by an increase in beta cell mass; it is unknown whether beta cell function changes. We have used the Leprdb mouse model of diabetes to investigate beta cell function in early disease. Prior to overt type 2 diabetes, a prediabetic state can be identified by impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) after a glucose tolerance test (GTT). A study of prediabetic individuals (identified by IFG) showed increased insulin secretion in response to an OGTT [6]. Some studies have shown that individuals with IGT have enhanced insulin secretion [6, 7], but it is not known whether this is due to upregulation of beta cell secretion or an increased number of beta cells [3]
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