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Abstract Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function.

A survey on antibiotic literacy in terms of the use and abuse of antibiotics to track and understand antibiotic consumption is crucial to optimize the use of antibiotics and minimizing antimicrobial resistance (AMR). Purposive random sampling, using the snow-ball questionnaire technique, was adopted to ensure that the respondents distributed across India, coming from rural and urban settings, were adolescents as well as adults and had completed at least the higher secondary school level of education. Respondents were divided into five subcategories. The questionnaire was distributed between April 2021 and July 2021, during the second COVID-19 wave in India. The survey questionnaire included 34 questions, comprising multiple-choice and 5-point Likert scale-type questions. This study composed of 972 respondents. Most respondents considered antibiotics safe and frequently failed to discriminate between the symptoms of bacterial and viral infections, most often leading to self-prescription. About 34% of the rural participants and 50% of the urban participants considered antibiotic resistance a serious health concern. Antibiotic prescriptions by the medical or paramedical practitioner were largely empirical. At least 95% of participants acknowledged having heard about antibiotics; nearly 20% of antibiotic consumption came from nonprescription users, while 30% had not completed their antibiotic therapy for a variety of reasons. Sixty-two percent consumed antibiotics to treat cold and flu symptoms. Results from the survey suggest the presence of a crucial gap between the respondents’ perception of antibiotics and levels of information regarding antibiotic use and misuse. The present study may serve as a benchmark that strongly recommends a financially feasible policy, which includes educating society regarding the spread of AMR and its severe consequences by incorporating AMR into the curriculum at the levels of senior secondary school and higher education.

Adult beta cells, which are highly specialised insulin-secreting cells, rarely replicate. Puri et al. demonstrate that beta cell proliferative capacity is inversely correlated with their functionality and differentiation state, by inducing proliferation of adult cells with ectopic overexpression of the cell cycle regulator c-Myc.

Organ formation is achieved through the complex interplay between signaling pathways and transcriptional cascades. The canonical Wnt signaling pathway plays multiple roles during embryonic development including patterning, proliferation and differentiation in distinct tissues. Previous studies have established the importance of this pathway at multiple stages of pancreas formation as well as in postnatal organ function and homeostasis. In mice, gain-of-function experiments have demonstrated that activation of the canonical Wnt pathway results in pancreatic hypoplasia, a phenomenon whose underlying mechanisms remains to be elucidated. Here, we show that ectopic activation of epithelial canonical Wnt signaling causes aberrant induction of gastric and intestinal markers both in the pancreatic epithelium and mesenchyme, leading to the development of gut-like features. Furthermore, we provide evidence that β -catenin-induced impairment of pancreas formation depends on Hedgehog signaling. Together, our data emphasize the developmental plasticity of pancreatic progenitors and further underscore the key role of precise regulation of signaling pathways to maintain appropriate organ boundaries.

Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development. In mice, depletion of Vhlh in pancreatic ß-cells causes perturbed glucose homeostasis, but the role of this gene in other pancreatic cells is poorly understood. To investigate the function of VHL/HIF pathway in pancreatic cells, we inactivated Vhlh in the pancreatic epithelium as well as in the endocrine and exocrine lineages. Our results show that embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia. The hypoglycemia is recapitulated in mice with endocrine-specific removal of Vhlh, while animals with loss of Vhlh predominantly in the exocrine compartment survive to adulthood with no overt defects in glucose metabolism. Mice with hypoglycemia display diminished insulin release in response to elevated glucose. Significantly, the glucagon response is impaired both in vivo (circulating glucagon levels) as well as in an in vitro secretion assay in isolated islets. Hypoxia also impairs glucagon secretion in a glucagon-expressing cell line in culture. Our results reveal a novel role for the hypoxia/HIF pathway in islet hormone secretion and maintenance of the fine balance that allows for the establishment of normoglycemia.