Identification of Novel Genes Involved in Hyperglycemia in Mice.

Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) , a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis.

Identification of four novel QTL linked to the metabolic syndrome in the Berlin Fat Mouse.

Background: The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome. This study aimed to identify genetic variants associated with impaired glucose metabolism using the obese lines BFMI861-S1 and BFMI861-S2, which are genetically closely related, but differ in several traits. BFMI861-S1 is insulin resistant and stores ectopic fat in the liver, whereas BFMI861-S2 is insulin sensitive.

Lipocalin 13 enhances insulin secretion but is dispensable for systemic metabolic control.

Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets.

Overexpression of Gjb4 impairs cell proliferation and insulin secretion in primary islet cells.

Objective: Altered gene expression contributes to the development of type 2 diabetes (T2D); thus, the analysis of differentially expressed genes between diabetes-susceptible and diabetes-resistant mouse models is an important tool for the determination of candidate genes that participate in the pathology. Based on RNA-seq and array data comparing pancreatic gene expression of diabetes-prone New Zealand Obese (NZO) mice and diabetes-resistant B6.V-ob/ob (B6-ob/ob) mice, the gap junction protein beta 4 (Gjb4) was identified as a putative novel T2D candidate gene.

Decreased Expression of Cilia Genes in Pancreatic Islets as a Risk Factor for Type 2 Diabetes in Mice and Humans.

An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice.

An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation.

Recently, a unimolecular tri-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tri-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists.

Palmitate and insulin counteract glucose-induced thioredoxin interacting protein (TXNIP) expression in insulin secreting cells via distinct mechanisms.

Glucose and palmitate synergistically stimulate insulin secretion, but chronically elevated they induce apoptotic β-cell death. The glucotoxic effect has been attributed, at least partly, to the upregulation of the oxidative stress marker thioredoxin interacting protein (TXNIP). Palmitate downregulates TXNIP expression, the functional significance of which is still under debate.

Distinct functions of the dual leucine zipper kinase depending on its subcellular localization.

The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals.

Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation.

Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets.

GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice.

Aims/hypothesis: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions.

Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9.

Excess circulating uric acid, a product of hepatic glycolysis and purine metabolism, often accompanies metabolic syndrome. However, whether hyperuricaemia contributes to the development of metabolic syndrome or is merely a by-product of other processes that cause this disorder has not been resolved. In addition, how uric acid is cleared from the circulation is incompletely understood.

Differential transcriptome analysis of diabetes-resistant and -sensitive mouse islets reveals significant overlap with human diabetes susceptibility genes.

Type 2 diabetes in humans and in obese mice is polygenic. In recent genome-wide association studies, genetic markers explaining a small portion of the genetic contribution to the disease were discovered. However, functional evidence linking these genes with the pathogenesis of diabetes is scarce.

Minor role of mitochondrial respiration for fatty-acid induced insulin secretion.

An appropriate insulin secretion by pancreatic beta-cells is necessary to maintain glucose homeostasis. A rise in plasma glucose leads to increased metabolism and an elevated cytoplasmic ATP/ADP ratio that finally triggers insulin granule exocytosis. In addition to this triggering pathway, one or more amplifying pathways-activated by amino acids or fatty acid-enhance secretion by promoting insulin granule recruitment to, and priming at, the plasma membrane.

Estrogen deficiency aggravates insulin resistance and induces β-cell loss and diabetes in female New Zealand obese mice.

In several rodent strains such as the New Zealand Obese (NZO) mouse, the incidence of obesity-associated diabetes mellitus is much higher in males than in females. In the present study, we investigated the effects of ovariectomy on glucose homeostasis in female NZO mice in order to elucidate the mechanism of their diabetes resistance. NZO females were ovariectomized at the age of 4 weeks, received a high-fat diet and body weight, body fat, glucose and insulin tolerance were investigated in comparison to sham-operated mice.

Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.

Aims/hypothesis: Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days.

Methods: Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks.

Diet dependence of diabetes in the New Zealand Obese (NZO) mouse: total fat, but not fat quality or sucrose accelerates and aggravates diabetes.

Background: Obesity and diabetes in mice can be modified by dietary variables. Here we systematically analysed the effect of the sucrose and fat content and of the fat quality in New Zealand Obese mice, a mouse model of the metabolic syndrome.

Results: Male NZO mice fed a semi-purified diet with sucrose exhibited an identical weight gain and diabetes incidence as controls without sucrose.

High-fat, carbohydrate-free diet markedly aggravates obesity but prevents beta-cell loss and diabetes in the obese, diabetes-susceptible db/db strain.

Objective: We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and beta-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of diets with and without carbohydrates on obesity and development of beta-cell failure in a second mouse model of type 2 diabetes, the db/db mouse.

Results: When kept on a carbohydrate-containing standard (SD; with (w/w) 5.