Diabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.

Aims/hypothesisPancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP).MethodsAffymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells.ResultsComparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes.Conclusions/interpretationThese studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.Electronic supplementary materialThe online version of this article (10.1007/s00125-017-4500-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

South Asians have high rates of diabetes and the highest rates of premature coronary artery disease in the world, both occuring about 10 years earlier than in other populations. The metabolic syndrome (MS), which appears to be the antecedent or “common soil” for both of these conditions, is also common among South Asians. Because South Asians develop metabolic abnormalities at a lower body mass index and waist circumference than other groups, conventional criteria underestimate the prevalence of MS by 25% to 50%. The proposed South Asian Modified National Cholesterol Education Program criteria that use abdominal obesity as an optional component and the South Asian‐specific waist circumference recommended by the International Diabetes Federation appear to be more appropriate in this population. Furthermore, Asian Indians have at least double the risk of coronary artery disease than that of whites, even when adjusted for the presence of diabetes and MS. This increased risk appears to be due to South Asian dyslipidemia, which is characterized by high serum levels of apolipoprotein B, lipoprotein (a), and triglycerides and low levels of apolipoprotein A1 and high‐density lipoprotein (HDL) cholesterol. In addition, the HDL particles are small, dense, and dysfunctional. MS needs to be recognized as a looming danger to South Asians and treated with aggressive lifestyle modifications beginning in childhood and at a lower threshold than in other populations.

FNASCOBJECTIVE -The objective of the study was to examine body fat distribution using computed tomography (CT), dual-energy X-ray absorptiometry (DEXA), and anthropometry in relation to type 2 diabetes in urban Asian Indians. RESEARCH DESIGN AND METHODS-This is a case-control study of 82 type 2 diabetic and 82 age-and sex-matched nondiabetic subjects from the Chennai Urban Rural Epidemiology Study, an ongoing epidemiological study in southern India. Visceral, subcutaneous, and total abdominal fat were measured using CT, while DEXA was used to measure central abdominal and total body fat. Anthropometric measures included BMI, waist circumference, sagittal abdominal diameter (SAD), and waist-to-hip ratio.RESULTS -Visceral and central abdominal fat showed a strong correlation with each other (P Ͻ 0.0001), and analysis revealed a fairly good agreement between tertiles of visceral and central abdominal fat ( ϭ 0.44, P Ͻ 0.0001). Diabetic subjects had significantly higher visceral (P ϭ 0.005) and central abdominal (P ϭ 0.011) fat compared with nondiabetic subjects. Waist circumference and SAD showed a strong correlation with visceral (P Ͻ 0.01) and central abdominal (P Ͻ 0.0001) fat in both diabetic and nondiabetic subjects. Logistic regression analysis revealed visceral (odds ratio [OR] 1.011, P ϭ 0.004) and central abdominal (OR 1.001, P ϭ 0.013) fat to be associated with diabetes, even after adjusting for age and sex.CONCLUSIONS -Visceral and central abdominal fat showed a strong association with type 2 diabetes. Both measures correlated well with each other and with waist circumference and SAD in diabetic and nondiabetic urban Asian Indians. Diabetes Care 27:2948 -2953, 2004A sian Indians have an increased susceptibility to type 2 diabetes and insulin resistance compared with Europeans (1-4). Recent studies indicate a rising prevalence of diabetes and insulin resistance in India (5-7). Although obesity is a major contributing factor to diabetes, Asian Indians are known to have lower BMIs than Europeans (8). However, for any given BMI, Asian Indians have greater waist-to-hip ratios and abdominal fat (8,9) than Europeans. There are very few studies on fat distribution in Indians (10,11) and virtually none comparing diabetic and nondiabetic subjects. Thus, the first objective of this study was to measure body fat distribution in Asian Indians in relation to type 2 diabetes.Computed tomography (CT) is widely used to assess visceral fat (12-14). Dual-energy X-ray absorptiometry (DEXA) is usually used to measure total body fat (15) but recently has also been used to measure central abdominal fat (16). The association of visceral fat measured by CT and central abdominal fat measured by DEXA has not been studied in an Asian-Indian population, and their relationship with anthropometric variables is also not clear. Thus, the second objective of our study was to correlate visceral and central abdominal fat with each other and with anthropometric parameters. RESEARCH DESIGN ANDMETHODS -This is a case-control study of diabetic...

Aims/hypothesis Previous work has demonstrated that beta cell amount (whether measured as beta cell mass, beta cell volume or insulin-positive area) is decreased in type 2 diabetes; however, recent findings suggest that mechanisms other than death may contribute to beta cell failure in this disease. To better characterise beta cell mass and function in type 2 diabetes, we performed morphological, ultra-structural and functional studies using histological samples and isolated islets. Methods Pancreases from ten non-diabetic (ND) and ten matched type 2 diabetic organ donors were studied by insulin, glucagon and chromogranin A immunocytochemistry and electron microscopy (EM). Glucose-stimulated insulin secretion was assessed using isolated islets and studies were performed using independent ND islet preparations after 24 h exposure to 22.2 mmol/l glucose. Results Immunocytochemistry showed that the fractional islet insulin-positive area was lower in type 2 diabetic islets (54.9± 6.3% vs 72.1±8.7%, p <0.01), whereas glucagon (23.3 ± 5.4% vs 20.2 ± 5.3%) and chromogranin A (86.4±6.1% vs 89.0±5.5%) staining was similar between the two groups. EM showed that the proportion of beta cells in type 2 diabetic islets was only marginally decreased; marked beta cell degranulation was found in diabetic beta cells; these findings were all reproduced after exposing isolated ND islets to high glucose. Glucose-stimulated insulin secretion was 40-50% lower from type 2 diabetic islets ( p <0.01), which again was mimicked by culturing non-diabetic islets in high glucose. Conclusions/interpretation These results suggest that, at least in subgroups of type 2 diabetic patients, the loss of beta cells as assessed so far might be overestimated, possibly due to changes in beta cell phenotype other than death, also contributing to beta cell failure in type 2 diabetes.

OBJECTIVEWe tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes.RESEARCH DESIGN AND METHODSFasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels.RESULTSAlthough absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05).CONCLUSIONSThese data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.

Highlights d Proteomics of cytokine-treated human islets identified GDF15 as a protective factor d GDF15 levels were reduced in cytokine-treated islets by translational blockade d GDF15 inhibited IL-1b+INF-g-induced apoptosis of human islets and a b-cell line d Administration of GDF15 prevented diabetes in non-obese diabetic mice

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