Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio; Clemente, Gennaro; Hu, Jiang; Pontecorvi, Alfredo; Holst, Jens J.; Giaccari, Andrea; Kulkarni, Rohit

doi:10.2337/db13-1013

Cited by 173 publications

(167 citation statements)

References 46 publications

(56 reference statements)

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“…We refer to a recent review article describing beta cell pathophysiology in type 2 diabetes [115], describing beta cell failure as a central mechanism in both type 1 and type 2 diabetes. Interestingly, in non-diabetic humans, insulin resistance has been reported to contribute to increased beta cell number and islet size [116]. Recently, in a mouse model, beta cell dedifferentiation rather than accelerated death has been suggested as a key driver of beta cell failure [117,118].…”

Section: Islet Structure-function and Diabetesmentioning

confidence: 99%

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

et al. 2015

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The human genome project and its search for factors underlying human diseases has fostered a major human research effort. Therefore, unsurprisingly, in recent years we have observed an increasing number of studies on human islet cells, including disease approaches focusing on type 1 and type 2 diabetes. Yet, the field of islet and diabetes research relies on the legacy of rodent-based investigations, which have proven difficult to translate to humans, particularly in type 1 diabetes. Whole islet physiology and pathology may differ between rodents and humans, and thus a comprehensive cross-species as well as species-specific view on islet research is much needed. In this review we summarise the current knowledge of interspecies islet cytoarchitecture, and discuss its potential impact on islet function and future perspectives in islet pathophysiology research.

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Section: Islet Structure-function and Diabetesmentioning

confidence: 99%

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

et al. 2015

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“…Glucagon, insulin's counterregulatory hormone, plays a major role in maintaining glucose homeostasis by promoting glucose production via hepatic glycogenolysis and gluconeogenesis. Glucagon levels are elevated in insulin-resistant/nondiabetic T1D and T2D patients, leading to enhanced hepatic glucose output and thereby exacerbating hyperglycemia (1)(2)(3). On the contrary and much less understood is the failure of α cells to secrete glucagon in response to hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Bozadjieva¹,

Blandino-Rosano²,

Chase³

et al. 2017

Journal of Clinical Investigation

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Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissuespecific deletion of the mTORC1 regulator Raptor in α cells (αRaptor KO ), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 3 8 0 jci.org Volume 127 Number 12 December 2017 transcription of critical α cell genes. This work provides insights into how nutrient-dependent glucagon secretion and α cell mass are regulated and suggest that pharmacologic inhibition of this pathway using immunosuppressant medications, such as everolimus or rapamycin, could alter glucagon levels and glucose homeostasis. ResultsLack of mTORC1 signaling after deletion of Raptor in α cells. α Cell-specific deletion of Raptor was achieved by crossing glucagon-Cre and Raptor fl/fl mice (αRaptor KO ) (18,19). Deletion of flanked exon 6 exclusively in α cells from αRaptor KO mice was demonstrated by nested reverse transcription PCR (RT-PCR) for exon 6 using different tissues and single α cells ( Figure 1A) (19). Loss of mTORC1 signaling was confirmed by lack of phospho-S6 (Ser240) immunofluorescence staining only in glucagon-positive cells in dispersed islets from 1-month-old αRaptor KO mice ( Figure 1B). To validate the reduction in mTORC1 signaling in α cells from αRaptor KO mice, we assessed phospho-S6 (Ser240), glucagon, and insulin staining in dispersed islets by flow cytometry using quantitative mean fluorescence intensity (MFI). Figure 1C shows pS6 MFI levels in α cells (glucagon + cell count) and Figure 1D includes pS6 MFI levels in β cells (insulin + cell count). Phospho-S6 (Ser240) levels were nearly lost in glucagon-positive cells from αRaptor KO mice (red curve) compared with controls (black curve) (Figures 1C). In contrast, the MFI for phospho-S6 (Se240) was similar in insulin-positive cells from αRaptor ...

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“…Two processes have been implicated in islet compensation in response to obesity and insulin resistance: First, an increased functionality and insulin secretion rate of the individual b-cells, e.g., by enhancing glucose metabolism or insulin gene expression or translation (4)(5)(6). In addition, increased systemic insulin output can be achieved by a morphological enlargement of b-cell mass through proliferation (7,8), hypertrophy (5,8), or neogenesis (9,10). Whereas in rodents b-cell mass has been reported to increase substantially in response to insulin resistance (7,11), this seems to be less pronounced in humans (12)(13)(14).…”

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confidence: 99%

Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

et al. 2016

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Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of β-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of β-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of β-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.

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Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

Cited by 173 publications

References 46 publications

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

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