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Diabetes is a significant global public health issue with implications for vascular endothelial cells (ECs) dysfunction and the subsequent development and advancement of diabetes complications. This study aims to compare the cellular and molecular properties of the aorta in normal and streptozotocin (STZ)-induced diabetic mice, with a focus on elucidating potential mechanism underlying EC dysfunction. Here, we performed a single-cell RNA sequencing survey of 32,573 cells from the aorta of normal and STZ-induced diabetic mice. We found a compendium of 10 distinct cell types, mainly ECs, smooth muscle cells, fibroblast, pericyte, immune cells, and stromal cells. As the diabetes condition progressed, we observed a subpopulation of aortic ECs that exhibited significantly elevated expression of complement (C) molecule C1qa compared with their healthy counterparts. This increased expression of C1qa was found to induce reactive oxygen species (ROS) production, facilitate EC migration and increased permeability, and impair the vasodilation within the aortic segment of mice. Furthermore, AAV-Tie2-shRNA-C1qa was administered into diabetic mice by tail vein injection, showing that inhibition of C1qa in the endothelium led to a reduction in ROS production, decreased vascular permeability, and improved vasodilation. Collectively, these findings highlight the crucial involvement of C1qa in endothelial dysfunction associated with diabetes. Article Highlights: The molecular mechanisms and cellular heterogeneity of C1q in endothelial cells, which regulate vascular function, remain unclear. C1q is involved in the regulation of vascular function. C1q in vascular endothelial cells can regulate vascular function, including permeability, immunity, and diastolic function. C1q represents a promising therapeutic target for the treatment of endothelial dysfunction associated with diabetes. [ABSTRACT FROM AUTHOR]

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor–mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns. We found that IL-1α is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mφ Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mφs late post-injury and is induced by IL-1α from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3 f/f lyz2 Cre+), we demonstrate that JMJD3 controls Mφ-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1α/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mφs. These data also highlight the importance of cell cross-talk in wound tissues and identify JMJD3 and the IL-1R signaling cascade as important upstream therapeutic targets for Mφ NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds. Article Highlights: The molecular mechanism regulating macrophage (Mφ) NLRP3 inflammasome activity in diabetic wounds remains unclear. Diabetic wound keratinocytes induce Nlrp3 gene expression and enhance inflammasome activation in wound Mφs through IL-1 receptor–mediated signaling. IL-1α is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mφ Nlrp3 expression via histone demethylase, JMJD3. JMJD3 controls Mφ-mediated Nlrp3 expression during wound healing. [ABSTRACT FROM AUTHOR]

Insulin resistance is a risk factor for type 2 diabetes, and exercise can improve insulin sensitivity. However, following exercise, high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a crossover design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemic-euglycemic clamp 5 h after one-legged exercise with 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery. Article Highlights: Increased muscle insulin sensitivity following one-legged exercise is reduced by circulating fatty acid levels mimicking those observed in recovery from whole-body exercise. The fatty acid–induced inhibition of postexercise insulin action in muscle is alleviated by pharmacologically increasing PDC activation and flux to forcibly increase carbohydrate oxidation. Lipid infusion leading to fatty acid levels in the physiological range does not cause muscle insulin resistance in a rested leg. Muscle glucose uptake is linked to PDC activation state and flux during recovery from exercise in the presence of elevated plasma lipid availability. [ABSTRACT FROM AUTHOR]

Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus. [ABSTRACT FROM AUTHOR]

In December 2018, Diabetes and Diabetologia began requiring authors of papers reporting data obtained from studies on human islets to report critical characteristics of the human islets used for research. The islet community was asked to provide feedback on it. Here is the contribution by the European Consortium for Islet Transplantation. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the receptor isoforms in the negative regulation of insulin secretion by dopamine, which references a research paper by F. Uefune et al., published within the issue. It discusses the significant role of dopamine receptor in the dominant effect of dopamine on B-cells, and the use of overexpression systems to dissect the contributions of D1 nd D2 to dopamine signaling.

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat. Article Highlights: The relationship between excess adiposity and type 2 diabetes is complex. Can genetic subtypes of adiposity reveal distinct pathways linking adiposity with type 2 diabetes? Higher adiposity increases type 2 diabetes risk via different mechanisms (e.g., cholesterol pathways or inflammation) but decreases risk via other mechanisms (lower liver fat and improved insulin sensitivity, or increased body size and enhanced muscle quality). These insights could improve precision medicine for type 2 diabetes via treating adiposity. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DPP-4) and neprilysin (NEP) rapidly degrade glucagon-like peptide 1 (GLP-1) in mice. Commercially available sandwich ELISA kits may not accurately detect the degradation products, leading to potentially misleading results. We aimed to stabilize GLP-1 in mice, allowing reliable measurement with sensitive commercially available ELISA kits. Nonanesthetized male C57Bl/6JRj mice were subjected to an oral glucose tolerance test (OGTT; 2 g/kg glucose), and plasma total and intact GLP-1 were measured (Mercodia and Alpco ELISA kits, respectively). No GLP-1 increases were seen in samples taken beyond 15 min after the glucose load. Samples taken at 5 and 10 min after the OGTT showed a minor increase in total, but not intact, GLP-1. We then administered saline (control), or a DPP-4 inhibitor (valine pyrrolidide or sitagliptin) with or without an NEP-inhibitor (sacubitril), 30 min before the OGTT. In the inhibitor groups only, intact GLP-1 increased significantly during the OGTT. After injecting male C57Bl/6JRj mice with a known dose of GLP-1(7-36)NH2, peak GLP-1 levels were barely detectable after saline but were 5- to 10-fold higher during sitagliptin and the combination of sitagliptin/sacubitril. The half-life of the GLP-1 plasma disappearance increased up to sevenfold during inhibitor treatment. We conclude that reliable measurement of GLP-1 secretion is not possible in mice in vivo with commercially available sandwich ELISA kits, unless degradation is prevented by inhibition of DPP-4 and perhaps NEP. The described approach allows improved estimates of GLP-1 secretion for future studies, although it is a limitation that these inhibitors additionally influence levels of insulin and glucagon. Article Highlights: Reliable measurement of glucagon-like peptide 1 (GLP-1) in mice using commercially available ELISA kits is challenging because of rapid degradation by the enzymes dipeptidyl peptidase 4 and neprilysin. Total GLP-1 secretion can best be assessed early after giving a stimulus, yet at the risk of additionally measuring stress-induced GLP-1(1-36)NH2. Intact GLP-1 can only be measured with concomitant in vivo inhibition of dipeptidyl peptidase 4 and perhaps neprilysin. [ABSTRACT FROM AUTHOR]

For many years, it has been taught in medical textbooks that the endocrine and exocrine parts of the pancreas have separate blood supplies that do not mix. Therefore, they have been studied by different scientific communities, and patients with pancreatic disorders are treated by physicians in different medical disciplines, where endocrine and exocrine function are the focus of endocrinologists and gastroenterologists, respectively. The conventional model that every islet in each pancreatic lobule receives a dedicated arterial blood supply was first proposed in 1932, and it has been inherited to date. Recently, in vivo intravital recording of red blood cell flow in mouse islets as well as in situ structural analysis of 3D pancreatic vasculature from hundreds of islets provided evidence for preferentially integrated pancreatic blood flow in six mammalian species. The majority of islets have no association with the arteriole, and there is bidirectional blood exchange between the two segments. Such vascularization may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to a topologically and temporally specific plasma content, which could underlie an adaptive sensory function as well as common pathogeneses of both portions of the organ in pancreatic diseases, including diabetes. [ABSTRACT FROM AUTHOR]

The article discusses critical observations on metabolic physiology as of 2023. Topics covered include studies' suggestion that stimulatory actions of glucagon contribute to physiologic insulin secretion, and its promotion is independent of its effect to raise blood glucose. Also noted is the current active investigation of glucagon stimulation of B-cells.

The article discusses that the learning that certain representative immunoblot images in the above-cited paper may have been duplicated, authors Iria Nieto-Vázquez, Sonia Fernández-Veledo, Cristina M. Rondinone, and Ángela M. Valverde have decided to voluntarily retract the article.

This section presents abstracts of papers related to diabetes including "Mild Mitochondrial Dysfunction Increases Type I Diabetic Renal and Cardiac Damage," "PDGFR-Β Deletion Improves Diabetic Nephropathy in CaM Kinase IIα (Thr286Asp) Transgenic Mice," and "Increased Axl Receptor Tyrosine Kinase and Its Ligand in Glycoxidized-LDL-Induced Mesangial Cells and Diabetic Kidney."

Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like [Metrnl]) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing. Functionally, the recombinant protein Metrnl significantly accelerated wound closure in normal and diabetic mice models including db/db, high-fat diet/streptozotocin (HFD/STZ), and STZ mice. Mechanistically, keratinocytes secrete quantities of Metrnl to promote angiogenesis; increase endothelial cell proliferation, migration, and tube formation; and enhance macrophage polarization to the M2 type. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. Moreover, the keratinocyte- and macrophage-produced cytokine Metrnl drives postinjury angiogenesis and reepithelialization through activation of AKT phosphorylation (S473) in a KIT receptor tyrosine kinase (c-Kit)–dependent manner. In conclusion, our study suggests that Metrnl has a biological effect in accelerating wound closure through c-Kit–dependent angiogenesis and epithelialization. Article Highlights: The topical application of Metrnl hydrogel accelerates wound healing in both normal and diabetic mice. Metrnl has multiple roles in cell proliferation, migration, tube formation, and macrophage M2 polarization, and thus promotes angiogenesis and reepithelialization in mouse models. Metrnl drives postinjury angiogenesis and reepithelialization in a c-Kit/AKTS473–dependent manner. [ABSTRACT FROM AUTHOR]

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e−6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits. Article Highlights: Our goal was to create a resource of trait-gene expression associations on a genome-wide scale across several cardiometabolic traits that accounts for cell-type heterogeneity. We aimed to determine whether cell-type composition affects trait-gene associations. We found that adjusting for both BMI and cell-type proportion is the best-fitting model for most trait-gene expression associations in adipose tissue. We identified 2,664 significant associations for 1,252 genes and 14 traits using a linear model that accounts for cell-type composition and BMI. Our findings suggest that cell-type composition should be considered when assessing the association between adipose gene expression and cardiometabolic traits. [ABSTRACT FROM AUTHOR]

Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extracellular vesicles and some free proteins (e.g., fatty acid binding protein 4) that, in sum, affect adipose homeostasis as well as the development of metabolic disease. At the mechanistic level, lipolytic signals activate p53 in an adipose triglyceride lipase–dependent manner, and pharmacologic inhibition of p53 attenuates adipocyte-derived extracellular vesicle (AdEV) protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities, and redox control. Consistent with a role for p53 in adipocyte protein secretion, activation of p53 by the MDM2 antagonist nutlin potentiated AdEV particles and non-AdEV protein secretion from cultured 3T3-L1 or OP9 adipocytes while the levels of FABP4 and AdEV proteins were significantly reduced in serum from p53−/− mice compared with wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair–depleted ERCC1−/Δ–haploinsufficient mice expressed elevated p53 in adipose depots, along with significantly increased serum FABP4. In sum, these data suggest that lipolytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner. Article Highlights: This study was undertaken to discover mechanism(s) leading to regulated protein secretion by adipocytes. We tested the hypothesis that TP53/p53 is required for regulated protein secretion. Our studies identified that TP53/p53 is required for protein secretion and is regulated by several stress inducers, such as nutrient deprivation and/or DNA damage. These studies may provide a mechanistic link among TP53/p53 mutations, cancer, and obesity. [ABSTRACT FROM AUTHOR]

While type 2 diabetes mellitus (T2DM) is commonly considered a putative causal risk factor for stroke, the effect of stroke on T2DM remains unclear. The intrinsic link underlying T2DM and stroke has not been thoroughly examined. We aimed to evaluate the phenotypic and genetic relationships underlying T2DM and stroke. We evaluated phenotypic associations using data from the UK Biobank (N = 472,050). We then investigated genetic relationships by leveraging genomic data in European ancestry for T2DM, with and without adjusting (adj) for BMI (T2DM: n = 74,124 case subjects/824,006 control subjects; T2DMadjBMI: n = 50,409 case subjects/523,897 control subjects), and for stroke (n = 73,652 case subjects/1,234,808 control subjects). We performed additional analyses using genomic data in East Asian ancestry for T2DM (n = 77,418 case subjects/356,122 control subjects) and for stroke (n = 27,413 case subjects/237,242 control subjects). Observational analyses suggested a significantly increased hazard of stroke among individuals with T2DM (hazard ratio 2.28 [95% CI 1.97–2.64]), but a slightly increased hazard of T2DM among individuals with stroke (1.22 [1.03–1.45]) which attenuated to 1.14 (0.96–1.36) in sensitivity analysis. A positive global T2DM-stroke genetic correlation was observed (rg = 0.35; P = 1.46 × 10−27), largely independent of BMI (T2DMadjBMI-stroke: rg = 0.27; P = 3.59 × 10−13). This was further corroborated by 38 shared independent loci and 161 shared expression-trait associations. Mendelian randomization analyses suggested a putative causal effect of T2DM on stroke in Europeans (odds ratio 1.07 [95% CI 1.06–1.09]), which remained significant in East Asians (1.03 [1.01–1.06]). Conversely, despite a putative causal effect of stroke on T2DM also observed in Europeans (1.21 [1.07–1.37]), it attenuated to 1.04 (0.91–1.19) in East Asians. Our study provides additional evidence to underscore the significant relationship between T2DM and stroke. Article Highlights: Observational analyses suggest a doubled risk of stroke among individuals with type 2 diabetes mellitus (T2DM), but a slightly increased risk of T2DM among individuals with stroke that attenuates to nonsignificance in sensitivity analysis. Genetic analyses reveal that both traits share a genetic basis at global and local genomic levels, as well as at individual genetic variant and gene levels, independent of BMI. Mendelian randomization analyses suggest a putative causal effect of T2DM on stroke among Europeans that remains significant in East Asians, while the putative causal effect of stroke on T2DM among Europeans that attenuates to null in East Asians. [ABSTRACT FROM AUTHOR]

Exercise increases muscle glucose uptake independently of insulin signaling and represents a cornerstone for the prevention of metabolic disorders. Pharmacological activation of the exercise-responsive AMPK in skeletal muscle has been proven successful as a therapeutic approach to treat metabolic disorders by improving glucose homeostasis through the regulation of muscle glucose uptake. However, conflicting observations cloud the proposed role of AMPK as a necessary regulator of muscle glucose uptake during exercise. We show that glucose uptake increases in human skeletal muscle in the absence of AMPK activation during exercise and that exercise-stimulated AMPKγ3 activity strongly correlates to muscle glucose uptake in the postexercise period. In AMPKγ3-deficient mice, muscle glucose uptake is normally regulated during exercise and contractions but impaired in the recovery period from these stimuli. Impaired glucose uptake in recovery from exercise and contractions is associated with a lower glucose extraction, which can be explained by a diminished permeability to glucose and abundance of GLUT4 at the muscle plasma membrane. As a result, AMPKγ3 deficiency impairs muscle glycogen resynthesis following exercise. These results identify a physiological function of the AMPKγ3 complex in human and rodent skeletal muscle that regulates glucose uptake in recovery from exercise to recapture muscle energy stores. Article Highlights: Exercise-induced activation of AMPK in skeletal muscle has been proposed to regulate muscle glucose uptake in recovery from exercise. This study investigated whether the muscle-specific AMPKγ3-associated heterotrimeric complex was involved in regulating muscle glucose metabolism in recovery from exercise. The findings support that exercise-induced activation of the AMPKγ3 complex in human and mouse skeletal muscle enhances glucose uptake in recovery from exercise via increased translocation of GLUT4 to the plasma membrane. This work uncovers the physiological role of the AMPKγ3 complex in regulating muscle glucose uptake that favors replenishment of the muscle cellular energy stores. [ABSTRACT FROM AUTHOR]

The advanced cessation of lactation elevates the risk of programmed obesity and obesity-related metabolic disorders in adulthood. This study used multiomic analysis to investigate the mechanism behind this phenomenon and the effects of leucine supplementation on ameliorating programmed obesity development. Wistar/SD rat offspring were subjected to early weaning (EW) at day 17 (EWWIS and EWSD groups) or normal weaning at day 21 (CWIS and CSD groups). Half of the rats from the EWSD group were selected to create a new group with 2-month leucine supplementation at day 150. The results showed that EW impaired lipid metabolic gene expression and increased insulin, neuropeptide Y, and feed intake, inducing obesity in adulthood. Six lipid metabolism–related genes (Acot1, Acot2, Acot4, Scd, Abcg8, and Cyp8b1) were influenced by EW during the entire experimental period. Additionally, adult early-weaned rats exhibited cholesterol and fatty acid β-oxidation disorders, liver taurine reduction, cholestasis, and insulin and leptin resistance. Leucine supplementation partly alleviated these metabolic disorders and increased liver L-carnitine, retarding programmed obesity development. This study provides new insights into the mechanism of programmed obesity development and the potential benefits of leucine supplementation, which may offer suggestions for life planning and programmed obesity prevention. Article Highlights: Early-weaned adult rats showed excess lipid accumulation and metabolic defects. Early weaning disrupts lipid metabolism and secretion of neuropeptide Y and insulin. The altered lipid metabolic gene expression in this study is vital in programming. Leucine mitigates metabolic disorders and hampers programmed obesity development. [ABSTRACT FROM AUTHOR]

The article provides a summary of a white paper from the Keystone Islet Workshop held in April 2014 that was shared with the leadership of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the American Diabetes Association. Topics discusses include the reasons for increased pressure for research on the pipeline of human islets such as acceptance for an urgent need to directly address applicability of rodent findings to the pathophysiology for every type of diabetes.