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Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade., (© 2023 by the American Diabetes Association.)

The islets of Langerhans are well embedded within the exocrine pancreas (the latter comprised of ducts and acini), but the nature of interactions between these pancreatic compartments and their role in determining normal islet function and survival are poorly understood. However, these interactions appear to be critical, as when pancreatic exocrine disease occurs, islet function and insulin secretion frequently decline to the point that diabetes ensues, termed pancreatogenic diabetes. The most common forms of pancreatogenic diabetes involve sustained exocrine disease leading to ductal obstruction, acinar inflammation, and fibro-fatty replacement of the exocrine pancreas that predates the development of dysfunction of the endocrine pancreas, as seen in chronic pancreatitis-associated diabetes and cystic fibrosis-related diabetes and, more rarely, MODY type 8. Intriguingly, a form of tumour-induced diabetes has been described that is associated with pancreatic ductal adenocarcinoma. Here, we review the similarities and differences among these forms of pancreatogenic diabetes, with the goal of highlighting the importance of exocrine/ductal homeostasis for the maintenance of pancreatic islet function and survival and to highlight the need for a better understanding of the mechanisms underlying these diverse conditions. Graphical abstract.

Hyaluronan (HA) is an extracellular matrix (ECM) component that is present in mouse and human islet ECM. HA is localized in peri-islet and intra-islet regions adjacent to microvessels. HA normally exists in a high molecular weight form, which is anti-inflammatory. However, under inflammatory conditions, HA is degraded into fragments that are proinflammatory. HA accumulates in islets of human subjects with recent onset type 1 diabetes (T1D), and is associated with myeloid and lymphocytic islet infiltration, suggesting a possible role for HA in insulitis. A similar accumulation of HA, in amount and location, occurs in non-obese diabetic (NOD) and DORmO mouse models of T1D. Furthermore, HA accumulates in follicular germinal centers and in T-cell areas in lymph nodes and spleen in both human and mouse models of T1D, as compared with control tissues. Whether HA accumulates in islets in type 2 diabetes (T2D) or models thereof has not been previously described. Here we show evidence that HA accumulates in a mouse model of islet amyloid deposition, a well-known component of islet pathology in T2D. In summary, islet HA accumulation is a feature of both T1D and a model of T2D, and may represent a novel inflammatory mediator of islet pathology., (© The Author(s) 2015.)

Aims/hypothesisPrevious studies on isolated islets have demonstrated tight coupling between calcium (Ca(2+)) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca(2+)/metabolic coupling process [CMCP]) by Ca(2+) mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes.MethodsGlucose- and Ca(2+)-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia.ResultsGlucose stimulation of cytosolic Ca(2+) and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca(2+) channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia.Conclusions/interpretationThese results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca(2+) influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.