Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.

After the discovery of insulin, a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of a human β cell line, healthy and type 2 diabetic (T2D) human islets and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance.

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival.

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63 beta cells.

A novel variant in AFF3 underlying isolated syndactyly.

Isolated syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover a novel heterozygous missense variant c.2915G > C: p.

Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome.

Cenani-Lenz syndrome (CLS) is a rare autosomal-recessive congenital disorder affecting development of distal limbs. It is characterized mainly by syndactyly and/or oligodactyly, renal anomalies, and characteristic facial features. Mutations in the LRP4 gene, located on human chromosome 11p11.

SARS-CoV-2 infection induces beta cell transdifferentiation.

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines.

Male germ cells support long-term propagation of Zika virus.

Evidence of male-to-female sexual transmission of Zika virus (ZIKV) and viral RNA in semen and sperm months after infection supports a potential role for testicular cells in ZIKV propagation. Here, we demonstrate that germ cells (GCs) are most susceptible to ZIKV. We found that only GCs infected by ZIKV, but not those infected by dengue virus and yellow fever virus, produce high levels of infectious virus.

Multifunctional in vivo imaging of pancreatic islets during diabetes development.

Pancreatic islet dysfunction leading to insufficient glucose-stimulated insulin secretion triggers the clinical onset of diabetes. How islet dysfunction develops is not well understood at the cellular level, partly owing to the lack of approaches to study single islets longitudinally in vivo Here, we present a noninvasive, high-resolution system to quantitatively image real-time glucose metabolism from single islets in vivo, currently not available with any other method. In addition, this multifunctional system simultaneously reports islet function, proliferation, vasculature and macrophage infiltration in vivo from the same set of images.

Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice.

Although most adults can lose weight by dieting, a well-characterized compensatory decrease in energy expenditure promotes weight regain more than 90% of the time. Using mice with impaired hypothalamic leptin signaling as a model of early-onset hyperphagia and obesity, we explored whether this unfavorable response to weight loss could be circumvented by early intervention. Early-onset obesity was associated with impairments in the structure and function of brown adipose tissue mitochondria, which were ameliorated by weight loss at any age.

Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness.

Objective: Obesity is often accompanied by hyperactivity of the neuroendocrine stress axis and has been linked to an increased risk of psychiatric disorders. Insulin is reciprocally regulated with the stress hormone corticosterone (CORT), raising the possibility that insulin normally provides inhibitory tone to the hypothalamus-adrenal-pituitary (HPA) axis. Here we examined whether disrupting signaling via the insulin receptor (InsR) in hypothalamic subpopulations impacts the neuroendocrine response to acute psychological stress.

Distinct networks of leptin- and insulin-sensing neurons regulate thermogenic responses to nutritional and cold challenges.

Defense of core body temperature (Tc) can be energetically costly; thus, it is critical that thermoregulatory circuits are modulated by signals of energy availability. Hypothalamic leptin and insulin signals relay information about energy status and are reported to promote thermogenesis, raising the possibility that they interact to direct an appropriate response to nutritional and thermal challenges. To test this idea, we used an Nkx2.

Partial dissociation of PrP(Sc) deposition and vacuolation in the brains of scrapie and BSE experimentally affected goats.

The diagnosis of transmissible spongiform encephalopathies (TSEs) depends on the detection of vacuolation in brain sections taken from affected individuals and/or the identification of the disease-associated isoform of the PrP (prion) protein (PrP(Sc)). During the course of an investigation, goats clinically affected following experimental infection with three different sources of TSE (SSBP/1, CH1641 and BSE) developed widespread vacuolar degeneration in the brain. With BSE, PrP(Sc) was clearly recognized in affected goat brain by immunocytochemistry (icc) and Western blotting, but in contrast the experimental scrapie sources SSBP/1 and CH1641 showed almost no or very little PrP(Sc) by icc.