Islet Insulin Secretion, β-Cell Mass, and Energy Balance in a Polygenic Mouse Model of Type 2 Diabetes With Obesity

Mao, Xia; Dillon, Kristy; McEntee, Michael F.; Saxton, Arnold M.; Kim, Jung Han

doi:10.1177/2326409814528153

Cited by 8 publications

(8 citation statements)

References 32 publications

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“…Longitudinal studies show that individuals who progressed to diabetes did not have compensatory increases in insulin secretion; in contrast, those that did, did not progress [ 18 , 35 ]. Consistent with this, animal models of diabetes also show increased insulin secretion in early disease [ 11 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 57%

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Changes in beta cell function occur in prediabetes and early disease in the Lepr db mouse model of diabetes

et al. 2016

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Aims/hypothesis Type 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. Methods The Lepr db 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. Results We 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/interpretation Beta cell function is altered in prediabetes and there are further changes in the progression to early disease.

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Section: Discussionmentioning

confidence: 57%

“…There is indirect evidence that compensatory increases in beta cell number can occur in obese humans [ 8 , 9 ] and in animal models such as prediabetic Zucker diabetic fatty rats [ 10 ], TALLYHO diabetic mice [ 11 ], ob / ob mice [ 12 ] and animals fed a high-fat diet [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Changes in beta cell function occur in prediabetes and early disease in the Lepr db mouse model of diabetes

et al. 2016

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“…Heat production, respiratory exchange ratio (RER), food intake, and locomotor activity were measured in mice using an 8-chamber Comprehensive Laboratory Animal Monitoring System (CLAMS) (Columbus Instruments, Columbus, OH, USA) as described previously [11]. Locomotor activity was determined as ambulatory count, the number of times different infrared beams were broken in either the x-or y-axes during an interval.…”

Section: Indirect Calorimetry Locomotor Activity and Food Intakementioning

confidence: 99%

Genotype-dependent Metabolic Responses to Semi-Purified High-Sucrose High-Fat Diets in the TALLYHO/Jng vs. C57BL/6 Mouse during the Development of Obesity and Type 2 Diabetes

Parkman

Mao

Dillon

et al. 2016

Exp Clin Endocrinol Diabetes

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The co-epidemic of obesity and type 2 diabetes is associated with increased morbidity and mortality. Genetic factors are highly involved in the development of these diseases, in the form of interactions of multiple genes within obesogenic and diabetogenic environments, such as a high fat diet. The TALLYHO/Jng (TH) mouse is an inbred polygenic model for human obesity and type 2 diabetes. In order to further develop the TH mouse as a clinically relevant model, we investigated diet dependence of obesity and type 2 diabetes in TH mice vs. C57BL/6 (B6) mice. TH and B6 mice were weaned onto a standard rodent chow, semi-purified high-sucrose low-fat (HSLF), or semi-purified high-sucrose high-fat (HSHF) diet and maintained on these diets throughout the study. Despite similar fat contents in HSLF diets and chow, both B6 and TH mice responded to HSLF diets, with increases in adiposity. TH mice, but not B6 mice, exhibited significantly higher adiposity with severely aggravated glucose intolerance and hyperglycemia on HSHF diets compared to the other diets. HSLF diets also advanced diabetes in TH mice compared to chow, but it did not surpass the effects of HSHF diets. The severe glucose intolerance and hyperglycemia in TH mice on both HSLF and HSHF diets were accompanied by significantly reduced mRNA levels compared to B6 mice. The present data demonstrate that diets are important modulators of genetic susceptibility to type 2 diabetes and obesity in TH mice. The interplay between heredity and dietary environment in TH mice appears to amplify insulin resistance, contributing to severe glucose intolerance and diabetes.

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“…In support of this, longitudinal studies show that subjects who progressed to diabetes did not have compensatory increases in insulin secretion, in contrast those with increased secretion did not progress (Weyer, Bogardus et al 1999;Festa, Williams et al 2006). Consistent with this human data, animal models of diabetes also show increased insulin secretion in early disease (Kaneko, Ueki et al 2010;Mao, Dillon et al 2014).…”

Section: Discussionsupporting

confidence: 60%

“…Further support for an increase in beta-cell number, comes from animal models where, increased beta-cell mass, or islet size, have been shown in pre-diabetic Zucker Diabetic Fatty rats (Pick, Clark et al 1998), Tallyho diabetic mice (Mao, Dillon et al 2014), ob/ob mice (Irles, Neco et al 2015) and animals fed a high fat diet (Hull, Kodama et al 2005;Terauchi, Takamoto et al 2007;Gonzalez, Merino et al 2013). …”

Section: Introductionmentioning

confidence: 96%

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

Hoang¹

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It is well established that changes in insulin secretion play an important role in the pathogenesis of type 2 diabetes. However, the underlying mechanisms of secretory changes occurring at the pancreatic beta-cell level are not fully elucidated. Therefore, this thesis focuses on the modulation of beta-cell function, particularly insulin granule exocytosis, during the progression of type 2 diabetes using the BKS.Cg-Dock7m+/+Lepr db /J (Lepr db mice) as a model of disease.I applied a variety of in vivo and in vitro methods to this project and further refined a livecell two-photon assay which I used to measure the numbers and kinetics of granule fusion events within intact islets.Using this latter technique, in the first part of the project I aimed to test a prevalent hypothesis that granule fusion behaviour changes in disease. Three indices of the post-fusion granule behaviour were compared between islets from animals with overt diabetes (db/db) and wild type. There was no difference in two indices of the fusion-granule behaviour; lifetime of granule fusion and post-fusion fluorescence intensity. The only change was a small increase in the percentage of recaptured granules (or "kiss-and-run" exocytosis) in db/db islets. In contrast to this minor change in granule fusion kinetics, further work showed that the main secretory deficit of frank diabetes, in db/db islets, is due to the loss of responding beta-cells and a reduction in the numbers of exocytic fusing granules in the remaining responsive cells.In the second part of the project I studied disease progression in the Lepr db model. Based on the area under the curve of the glucose tolerance tests, each db/db mouse was classified into one of four stages of disease, ranging from pre-diabetes (stage 1) to severe diabetes (stage 4). The results indicated that changes in islet size and insulin content occurred across all stages of disease severity.At stage 1, there was an increase in islet insulin content due to both an increased number of betacells and increased insulin content in each cell, whereas at stages 2-4, there was a progressive loss of islet insulin content that is a reflection of loss of content from individual beta-cells.Finally, in terms of beta-cell function, the data revealed that modulation of function characterised all stages of disease severity in db/db mice. In stage 1 there was an upregulation in the number of fusion of insulin-containing granules as well as the prevalence of compound exocytosis.At later disease stages there was a loss of glucose-induced insulin-granule fusion which my data indicated was due to impairment in glucose sensing. This work demonstrates that beta-cell function is intimately associated with pre-diabetes and progression to diabetes and adds weight to clinical strategies for therapeutic intervention as early as possible. Page | iiIn summary, the results show that the major factors in the disease phenotype are changes in the numbers of responding beta-cells and the numbers of fusing granules rather than the kinetic...

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Islet Insulin Secretion, β-Cell Mass, and Energy Balance in a Polygenic Mouse Model of Type 2 Diabetes With Obesity

Cited by 8 publications

References 32 publications

Changes in beta cell function occur in prediabetes and early disease in the Lepr db mouse model of diabetes

Changes in beta cell function occur in prediabetes and early disease in the Lepr db mouse model of diabetes

Genotype-dependent Metabolic Responses to Semi-Purified High-Sucrose High-Fat Diets in the TALLYHO/Jng vs. C57BL/6 Mouse during the Development of Obesity and Type 2 Diabetes

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

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