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Human duct cells contribute to ? cell compensation in insulin resistance.

ABSTRACT: The identification of new sources of ? cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in ? cell mass. To explore the existence of a dynamic ? cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits ? cell hyperplasia and used lineage tracing to track the source of new ? cells. Although both control and LIRKO mice displayed increased ? cell mass in response to the relative insulin resistance of pregnancy, the further increase in mass in the latter supported a dynamic source that could be traced to pancreatic ducts. Two observations support the translational significance of these findings. First, NOD/SCID-? LIRKO mice that became pregnant following cotransplantation of human islets and human ducts under the kidney capsule showed enhanced ? cell proliferation and an increase in ductal cells positive for transcription factors expressed during ? cell development. Second, we identified duct cells positive for immature ? cell markers in pancreas sections from pregnant humans and in individuals with T2D. Taken together, during increased insulin demand, ductal cells contribute to the compensatory ? cell pool by differentiation/neogenesis.

SUBMITTER: Dirice E

PROVIDER: S-EPMC6538348 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Human duct cells contribute to β cell compensation in insulin resistance.

Dirice Ercument E De Jesus Dario F DF Kahraman Sevim S Basile Giorgio G Ng Raymond Ws RW El Ouaamari Abdelfattah A Teo Adrian Kee Keong AKK Bhatt Shweta S Hu Jiang J Kulkarni Rohit N RN

JCI insight 20190418 8

The identification of new sources of β cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in β cell mass. To explore the existence of a dynamic β cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits β cell hyperplasia and used ...[more]

PMID: 30996131

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Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

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Human duct cells contribute to ? cell compensation in insulin resistance.

Publications

Human duct cells contribute to β cell compensation in insulin resistance.

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