Dataset Information

Adaptive changes of human islets to an obesogenic environment in the mouse.

ABSTRACT:

Aims/hypothesis

In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.

Methods

Non-diabetic Rag2 (-/-) mice (n = 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA(lc) or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.

Results

Transplanted mice on an HFD gained significantly more weight (p < 0.001) and had higher fasting glycaemia (2-12 weeks; p = 0.0002) and consistently higher fasting human C-peptide levels (2-12 weeks; p = 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (p < 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (p < 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.

Conclusions/interpretation

This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.

SUBMITTER: Gargani S

PROVIDER: S-EPMC3536990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Obesity is closely associated with adipose tissue inflammation and insulin resistance. Dysglycemia and type 2 diabetes results when islet β cells fail to maintain appropriate insulin secretion in the face of insulin resistance. To clarify the early transcriptional events leading to β-cell failure in the setting of obesity, we fed male C57BL/6J mice an obesogenic, high-fat diet (60% kcal from fat) or a control diet (10% kcal from fat) for one week, and islets from these mice (from four high-fat- and three control-fed mice) were subjected to single-cell RNA sequencing (sc-RNAseq) analysis. Islet endocrine cell types (α cells, β cells, δ cells, PP cells) and other resident cell types (macrophages, T cells) were annotated by transcript profiles and visualized using Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) plots. UMAP analysis revealed distinct cell clusters (11 for β cells, 5 for α cells, 3 for δ cells, PP cells, ductal cells, endothelial cells), emphasizing the heterogeneity of cell populations in the islet. Collectively, the clusters containing the majority of β cells showed the fewest gene expression changes, whereas clusters harboring the minority of β cells showed the most changes. We identified that distinct β-cell clusters downregulate genes associated with the endoplasmic reticulum stress response and upregulate genes associated with insulin secretion, whereas others upregulate genes that impair insulin secretion, cell proliferation, and cell survival. Moreover, all β-cell clusters negatively regulate genes associated with immune response activation. Glucagon-producing α cells exhibited patterns similar to β cells but, again, in clusters containing the minority of α cells. Our data indicate that an early transcriptional response in islets to an obesogenic diet reflects an attempt by distinct populations of β cells to augment or impair cellular function and/or reduce inflammatory responses as possible harbingers of ensuing insulin resistance.