Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption.

Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function.

Glucagon-producing α-cell transcriptional identity and reprogramming towards insulin production.

β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity.

Generation and Characterization of a Novel Mouse Model That Allows Spatiotemporal Quantification of Pancreatic β-Cell Proliferation.

Pancreatic β-cell proliferation has been gaining much attention as a therapeutic target for the prevention and treatment of diabetes. In order to evaluate potential β-cell mitogens, accurate and reliable methods for the detection and quantification of the β-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating β-cells as mVenus cells by using RIP-Cre; R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in β-cells.

GPR40 activation initiates store-operated Ca entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells.

The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. Previous studies demonstrated that GPR40 activation enhances Ca release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca release via the IP3 receptor is linked to GIIS potentiation.

Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice.

Aims/hypothesis: Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival.

A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D).

LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia.

Aims/hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear.

Targeting GLP-1 receptors for repeated magnetic resonance imaging differentiates graded losses of pancreatic beta cells in mice.

Aims/hypothesis: Non-invasive imaging of beta cells is a much-needed development but is one that faces significant biological and technological hurdles. A relevant imaging method should at least allow for an evaluation over time of the mass of beta cells under physiological and pathological conditions, and for an assessment of novel therapies. We, therefore, investigated the ability of a new MRI probe to repeatedly measure the loss of beta cells in a rodent model.

An essential role for insulin and IGF1 receptors in regulating sertoli cell proliferation, testis size, and FSH action in mice.

Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs.

Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice.

Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs.

Understanding the extrinsic and intrinsic signals involved in pancreas and β-cell development: from endoderm to β cells.

Purpose Of Review: To summarize recent progress in understanding of the extrinsic and intrinsic signals directing pancreas development from early endoderm.

Recent Findings: The pancreatic mesoderm was shown not only to play a permissive role in pancreas determination but also to control endocrine commitment and maturation through the interplay between Notch and fibroblast growth factor signaling. The requirement of Wnt (wingless-type)/β-catenin signaling in the expansion of the acinar cell lineage, and the spatial-temporal specificity of PDX1 (pancreatic and duodenal homeobox) activity, which is needed for proper acinar development, were also demonstrated.

Nestin expression in pancreatic exocrine cell lineages.

Expression of nestin has been suggested to be a characteristic of pancreatic islet stem cells. To determine whether nestin is indeed expressed in such putative cells during embryonic development, or in the adult pancreas after injury, we performed a cell lineage analysis using two independent lines of transgenic mice encoding Cre recombinase under the control of rat nestin cis-regulatory sequences, each crossed with loxP-bearing R26R mice. F1 animals produced the reporter molecule beta-galactosidase only upon Cre-mediated recombination, thus solely in cells using (or having used) the transgenic nestin promoter.

Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells.

Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells.

Homeostasis of blood glucose is maintained by hormone secretion from the pancreatic islets of Langerhans. Glucose stimulates insulin secretion from beta-cells but suppresses the release of glucagon, a hormone that raises blood glucose, from alpha-cells. The mechanism by which nutrients stimulate insulin secretion has been studied extensively: ATP has been identified as the main messenger and the ATP-sensitive potassium channel as an essential transducer in this process.