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Pages: 1601 - 1602 Abstract: For the past 26 years, the American Diabetes Association and its professional constituents have had the great pleasure of working with Lynda (“Lyn”) Reynolds, the director of the ADA Editorial Office. Lyn first joined ADA’s publishing team in 1997, when she was hired by editor in chief Charles M. Clark, Jr., MD, to help manage the peer review operations for Diabetes Care. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db22-en08 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1603 - 1610 Abstract: Recent reports have revived interest in the active role that β-cells may play in type 1 diabetes pathogenesis at different stages of disease. In some studies, investigators suggested an initiating role and proposed that type 1 diabetes may be primarily a disease of β-cells and only secondarily a disease of autoimmunity. This scenario is possible and invites the search for environmental triggers damaging β-cells. Another major contribution of β-cells may be to amplify autoimmune vulnerability and to eventually drive it into an intrinsic, self-detrimental state that turns the T cell–mediated homicide into a β-cell suicide. On the other hand, protective mechanisms are also mounted by β-cells and may provide novel therapeutic targets to combine immunomodulatory and β-cell protective agents. This integrated view of autoimmunity as a disease of T-cell/β-cell cross talk will ultimately advance our understanding of type 1 diabetes pathogenesis and improve our chances of preventing or reversing disease progression. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/dbi21-0036 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1611 - 1613 Abstract: Understanding how insulin secretion is regulated and how the β-cells and islets become dysfunctional is critical to understanding and treating diabetes. The islets of Langerhans are highly vascularized, receiving ∼10–20% of the pancreas blood flow (as measured by microbead accumulation) despite representing ∼1% of its volume (1). Proper vascularization of the islets is critical. For example, transplanted islets need to revascularize to receive the appropriate oxygenation and nutrient delivery required for survival and insulin production. Blood flow to the islets is extensively regulated by glucose, insulin, and other signaling molecules (2,3) and is altered in models of type 1 and type 2 diabetes (4–6). However, it is unknown whether this altered blood flow could contribute to pathogenesis. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/dbi22-0016 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1614 - 1616 Abstract: Pancreatic β-cells secrete the hormone insulin, which is essential to maintain systemic glucose homeostasis. β-Cell insufficiency due to impaired function, loss of identity, and increased cell death is central to the pathogenesis of diabetes. β-Cells in adult life are postmitotic, with a limited capacity to replicate and expand, and this ability further declines with age (1–3). Cells like the adult β-cell must deploy robust strategies, such as efficient repair of DNA damage, to ensure their genomic integrity and survival throughout their lifespans. DNA damage can alter the genomic output (e.g., transcription) and trigger genomic instability, which can lead to cellular dysfunction and ultimately death. Cells possess a battery of mechanisms, collectively called the DNA damage response (DDR), that sense and repair DNA damage (4). The DDR is also intimately linked with cell cycle control, with the cell cycle checkpoints also serving as checkpoints for DNA structure (5). Although emerging evidence suggests that prolonged DDR can trigger β-cell dysfunction and death, very little is known about the molecular control of DDR in β-cells and its impact on β-cell proliferation and function. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/dbi22-0010 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1617 - 1619 Abstract: The extracellular matrix (ECM) not only provides a structural support network for the assembly of individual cells into tissues but also affects growth, recruitment, differentiation, and function of the composing cells. In obesity, adipose tissue ECM undergoes remodeling, with dramatic changes in the absolute amount and composition of the components, contributing to the development of adipose tissue dysfunction (1). Adipose tissue ECM contains multiple types of collagen but is most enriched with collagen VI (COL6) (2,3). COL6 is a collagenous glycoprotein composed of three chains (α1, α2, and α3, encoded by 6 genes, Col6a1 to Col6a6) forming heterotrimeric monomers, which can be further assembled into dimers or tetramers. The COL6 α3 subunit (COL6A3) is the longest subunit (with the chain length ranging from 2,500 to 3,100 amino acids), and the expression of COL6A3 is increased in obese mouse adipose tissue compared with that of lean mice. ob/ob mice lacking Col6a3 show reduced adipose tissue inflammation and improved glucose tolerance (4), suggesting that the accumulation of COL6A3 in obese adipose tissue contributes to the development of adipose tissue dysfunction, leading to systemic metabolic defects. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/dbi22-0008 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1620 - 1622 Abstract: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, affecting 2–22% of all pregnancies depending on diagnostic criteria and study populations (1). GDM reflects an increased risk of type 2 diabetes (T2D) and cardiovascular diseases after the index pregnancy in women (2–4). Offspring born to mothers with GDM have an elevated risk of developing T2D and cardiovascular diseases, likely before reaching reproductive age (5–8). Thus, GDM has been considered one of the key contributors to the vicious intergenerational cycle of cardiometabolic diseases and a major challenge in obstetric care. Currently, tools are lacking to identify women in early pregnancy with a higher risk of developing GDM. As a result, neither mothers nor fetuses are treated until late in the second trimester (usually 24–28 gestational weeks), when GDM is diagnosed. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/dbi22-0015 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1623 - 1635 Abstract: Bariatric surgery improves glucose homeostasis, but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium–glucose cotransporter 2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2-null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2-null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose-lowering effects of bariatric surgery. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0768 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1636 - 1648 Abstract: Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db22-0079 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1649 - 1659 Abstract: Preclinical rodent and nonhuman primate models investigating maternal obesity have highlighted the importance of the intrauterine environment in the development of insulin resistance in offspring; however, it remains unclear if these findings can be translated to humans. To investigate possible intrauterine effects in humans, we isolated mesenchymal stem cells (MSCs) from the umbilical cord tissue of infants born to mothers of normal weight or mothers with obesity. Insulin-stimulated glycogen storage was determined in MSCs undergoing myogenesis in vitro. There was no difference in insulin action based on maternal obesity. However, maternal free fatty acid (FFA) concentration, cord leptin, and intracellular triglyceride content were positively correlated with insulin action. Furthermore, MSCs from offspring born to mothers with elevated FFAs displayed elevated activation of the mTOR signaling pathway. Taken together, these data suggest that infants born to mothers with elevated lipid availability have greater insulin action in MSCs, which may indicate upregulation of growth and lipid storage pathways during periods of maternal overnutrition. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0812 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1660 - 1678 Abstract: Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. For determination of the role of PDE4 in diabetic cardiac dysfunction, mice fed with a high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle specific miRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD mice, despite persistence of hyperglycemia. Findings of gain- and loss-of-function studies of PDE4D in cardiomyocytes indicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling–induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling–mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts of individuals with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0898 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1679 - 1693 Abstract: The pancreatic islet depends on blood supply to efficiently sense plasma glucose levels and deliver insulin and glucagon into the circulation. Long believed to be passive conduits of nutrients and hormones, islet capillaries were recently found to be densely covered with contractile pericytes with the capacity to locally control blood flow. Here, we determined the contribution of pericyte regulation of islet blood flow to plasma insulin and glucagon levels and glycemia. Selective optogenetic activation of pericytes in intraocular islet grafts contracted capillaries and diminished blood flow. In awake mice, acute light-induced stimulation of islet pericytes decreased insulin and increased glucagon plasma levels, producing hyperglycemic effects. Interestingly, pericytes are the targets of sympathetic nerves in the islet, suggesting that sympathetic control of hormone secretion may occur in part by modulating pericyte activity and blood flow. Indeed, in vivo activation of pericytes with the sympathetic agonist phenylephrine decreased blood flow in mouse islet grafts, lowered plasma insulin levels, and increased glycemia. We further show that islet pericytes and blood vessels in living human pancreas slices responded to sympathetic input. Our findings indicate that pericytes mediate vascular responses in the islet that are required for adequate hormone secretion and glucose homeostasis. Vascular and neuronal alterations that are commonly seen in the islets of people with diabetes may impair regulation of islet blood flow and thus precipitate islet dysfunction. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-1104 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1694 - 1705 Abstract: Identifying the mechanisms behind the β-cell adaptation to failure is important to develop strategies to manage type 2 diabetes (T2D). Using db/db mice at early stages of the disease process, we took advantage of unbiased RNA sequencing to identify genes/pathways regulated by insulin resistance in β-cells. We demonstrate herein that islets from 4-week-old nonobese and nondiabetic leptin receptor–deficient db/db mice exhibited downregulation of several genes involved in cell cycle regulation and DNA repair. We identified the transcription factor Yin Yang 1 (YY1) as a common gene between both pathways. The expression of YY1 and its targeted genes was decreased in the db/db islets. We confirmed the reduction in YY1 expression in β-cells from diabetic db/db mice, mice fed a high-fat diet (HFD), and individuals with T2D. Chromatin immunoprecipitation sequencing profiling in EndoC-βH1 cells, a human pancreatic β-cell line, indicated that YY1 binding regions regulate cell cycle control and DNA damage recognition and repair. We then generated mouse models with constitutive and inducible YY1 deficiency in β-cells. YY1-deficient mice developed diabetes early in life due to β-cell loss. β-Cells from these mice exhibited higher DNA damage, cell cycle arrest, and cell death as well as decreased maturation markers. Tamoxifen-induced YY1 deficiency in mature β-cells impaired β-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for β-cell DNA repair and cell cycle progression. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0908 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1706 - 1720 Abstract: Hypoxia-induced islet cell death, caused by an insufficient revascularization of the grafts, is a major obstacle for successful pancreatic islet transplantation. Recently, it has been reported that the nucleotide-binding oligomerization domain–like receptor protein 3 (NLRP3) inflammasome is expressed in pancreatic islets and that its loss protects against hypoxia-induced cell death. Therefore, we hypothesized that the inhibition of NLRP3 in islets improves the survival and endocrine function of the grafts. The transplantation of Nlrp3−/− islets or wild-type (WT) islets exposed to the NLRP3 inhibitor CY-09 into mouse dorsal skinfold chambers resulted in an improved revascularization compared with controls. An increased insulin release after NLRP3 inhibition caused the enhanced angiogenic response. Moreover, the inhibition of NLRP3 in hypoxic β-cells triggered insulin gene expression by inducing the shuttling of MafA and pancreatic and duodenal homeobox-1 into the nucleus. This was mediated by a reduced interaction of NLRP3 with the thioredoxin-interacting protein (TXNIP). Transplantation of Nlrp3−/− islets or WT islets exposed to CY-09 under the kidney capsule of diabetic mice markedly improved the restoration of normoglycemia. These findings indicate that the inhibition of NLRP3 in isolated islets represents a promising therapeutic strategy to improve engraftment and function of the islets. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0851 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1721 - 1734 Abstract: Prevention of immune rejection without immunosuppression is the ultimate goal of transplant immunobiology. One way to achieve this in cellular transplantation, such as with islet transplantation, is to create a favorable local environment at the transplant site. In the current study, we found that C57BL/6 mice with streptozotocin-induced diabetes remained normoglycemic for >1 year after transplantation of BALB/c islets without immunosuppression when the inguinal subcutaneous white adipose tissue (ISWAT) was the site of transplantation and when the site was pretreated with basic fibroblast growth factor. Mechanistically, mesenchymal stem cells (MSCs) expanded in the ISWAT after the treatment was found to produce transforming growth factor-β (TGF-β), and prevention of islet allograft rejection could be achieved by cotransplantation with syngeneic MSCs isolated from the ISWAT after the treatment, which was abolished by anti–TGF-β antibody treatment. Importantly, TGF-β–producing cells remained present at the site of cotransplantation up to the end of observation period at 240 days after transplantation. These findings indicate that prevention of islet allograft rejection without immunosuppression is feasible with the use of syngeneic TGF-β–producing MSCs expanded in the ISWAT after the treatment with bFGF, providing a novel strategy for prevention of islet allograft rejection without immunosuppression. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0684 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1735 - 1745 Abstract: Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T-cell population. Hybrid peptides formed through transpeptidation within pancreatic β-cell lysosomes have been proposed as a new class of autoantigens in type 1 diabetes (T1D). While the production of hybrid peptides in the thymus has not been explored, due to the nature of their generation, it is thought to be highly unlikely. Therefore, hybrid peptide-reactive thymocytes may preferentially escape thymic selection and contribute significantly to T1D progression. Using an antibody-peptide conjugation system, we targeted the hybrid insulin peptide (HIP) 2.5HIP toward thymic resident Langerin-positive dendritic cells to enhance thymic presentation during the early neonatal period. Our results indicated that anti–Langerin-2.5HIP delivery can enhance T-cell central tolerance toward cognate thymocytes in NOD.BDC2.5 mice. Strikingly, a single dose treatment with anti–Langerin-2.5HIP during the neonatal period delayed diabetes onset in NOD mice, indicating the potential of antibody-mediated delivery of autoimmune neoantigens during early stages of life as a therapeutic option in the prevention of autoimmune diseases. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-1069 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1746 - 1762 Abstract: Dysregulation of extracellular matrix proteins in obese adipose tissue (AT) induces systemic insulin resistance. The metabolic roles of type VI collagen and its cleavage peptide endotrophin in obese AT are well established. However, the mechanisms regulating endotrophin generation remain elusive. Herein, we identified that several endotrophin-containing peptides (pre-endotrophins) were generated from the COL6A3 chain in a stepwise manner for the efficient production of mature endotrophin, partly through the action of hypoxia-induced matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP16. Hypoxia is an upstream regulator of COL6A3 expression and the proteolytic processing that regulates endotrophin generation. Hypoxia-inducible factor 1α (HIF1α) and the hypoxia-associated suppression of microRNA-29 (miR-29) cooperatively control the levels of COL6A3 and MMPs, which are responsible for endotrophin generation in hypoxic ATs. Adipocyte-specific Hif1α knock-out (APN-HIF1αKO) mice fed a chronic high-fat diet exhibited the significant amelioration of both local fibro-inflammation in AT and systemic insulin resistance compared with their control littermates, partly through the inhibition of endotrophin generation. Strikingly, adenovirus-mediated miR-29 overexpression in the ATs of APN-HIF1αKO mice in obesity significantly decreased endotrophin levels, suggesting that miR-29, combined with HIF1α inhibition in AT, could be a promising therapeutic strategy for treating obesity and related metabolic diseases. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0801 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1763 - 1771 Abstract: We evaluated the role of the p66Shc redox adaptor protein in pancreatic β-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate 1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired β-cell function and insulin resistance induced by saturated fatty acids and excess body fat. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-1066 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1772 - 1784 Abstract: Diabetes can damage both the peripheral sensory organs, causing retinopathy, and the central visual system, leading to contrast sensitivity and impaired color vision in patients without retinopathy. Orientation discrimination is important for shape recognition by the visual system. Our psychophysical findings in this study show diminished orientation discrimination in patients with diabetes without retinopathy. To reveal the underlying mechanism, we established a diabetic mouse model and recorded in vivo electrophysiological data in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1). Reduced orientation selectivity was observed in both individual and populations of neurons in V1 and dLGN, which increased in severity with disease duration. This diabetes-associated neuronal dysfunction appeared earlier in the V1 than dLGN. Additionally, neuronal activity and signal-to-noise ratio are reduced in V1 neurons of diabetic mice, leading to a decreased capacity for information processing by V1 neurons. Notably, the V1 in diabetic mice exhibits reduced excitatory neuronal activity and lower levels of phosphorylated mammalian target of rapamycin (mTOR). Our findings show that altered responses of both populations of and single V1 neurons may impair fine vision, thus expanding our understanding of the underlying causes of diabetes-related impairment of the central nervous system. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0715 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1785 - 1794 Abstract: In this cross-sectional study we aimed to quantify the somatosensory dysfunction in the hand in people with diabetes with distal symmetrical polyneuropathy (DSPN) in hands and explore early signs of nerve dysfunction in people with diabetes without DSPN in hands. The clinical diagnosis of DSPN was confirmed with electrodiagnosis and corneal confocal microscopy. Thermal and mechanical nerve function in the hand was assessed with quantitative sensory tests. Measurements were compared between healthy participants (n = 31), individuals with diabetes without DSPN (n = 35), individuals with DSPN in feet but not hands (DSPNFEET ONLY) (n = 31), and individuals with DSPN in hands and feet (DSPNHANDS & FEET) (n = 28) with one-way between-group ANOVA. The somatosensory profile of the hand in people with DSPNHANDS & FEET showed widespread loss of thermal and mechanical detection. This profile in hands is comparable with the profile in the feet of people with DSPN in feet. Remarkably, individuals with DSPNFEET ONLY already showed a similar profile of widespread loss of nerve function in their hands. People with diabetes without DSPN in feet already had some nerve dysfunction in their hands. These findings suggest that nerve function assessment in hands should become more routine in people with diabetes. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-1147 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1795 - 1799 Abstract: Apolipoprotein M (apoM), primarily carried by HDL, has been associated with several conditions, including cardiovascular disease and diabetic nephropathy. This study proposes to examine whether plasma apoM levels are associated with the development of diabetic kidney disease, assessed as progression to macroalbuminuria (MA) and chronic kidney disease (CKD). Plasma apoM was measured using an enzyme immunoassay in 386 subjects from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort at DCCT entry and closeout and the concentrations used to determine the association with risk of progression to kidney dysfunction from the time of measurement through 18 years of EDIC follow-up. apoM levels, at DCCT baseline, were higher in patients who developed CKD than in those who retained normal renal function. At DCCT closeout, participants who progressed to MA, CKD, or both MA and CKD also had significantly higher apoM levels than those who remained normal, and increased levels of apoM were associated with increased risk of progression to both MA (risk ratio [RR] 1.30 [95% CI 1.01, 1.66]) and CKD (RR 1.69 [95% CI 1.18, 2.44]). Our results strongly suggest that alterations in apoM and therefore in the composition and function of HDL in type 1 diabetes are present early in the disease process and are associated with the development of nephropathy. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0920 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1800 - 1806 Abstract: Patients with type 1 diabetes (T1D) may develop severe outcomes during coronavirus disease 2019 (COVID-19), but their ability to generate an immune response against the SARS-CoV-2 mRNA vaccines remains to be established. We evaluated the safety, immunogenicity, and glycometabolic effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in patients with T1D. A total of 375 patients (326 with T1D and 49 subjects without diabetes) who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at ASST Fatebenefratelli Sacco were included in this monocentric observational study. Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination, without statistical differences between them. While both patients with T1D and subjects without diabetes exhibited a parallel increase in anti-SARS-CoV-2 spike titers after vaccination, the majority of patients with T1D (70% and 78%, respectively) did not show any increase in the SARS-CoV-2–specific cytotoxic response compared with the robust increase observed in all subjects without diabetes. A reduced secretion of the T-cell–related cytokines interleukin-2 and tumor necrosis factor-α in vaccinated patients with T1D was also observed. No glycometabolic alterations were evident in patients with T1D using continuous glucose monitoring during follow-up. Administration of the SARS-CoV-2 mRNA vaccine is associated with an impaired cellular SARS-CoV-2–specific cytotoxic immune response in patients with T1D. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db22-0053 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1807 - 1817 Abstract: Gestational diabetes mellitus (GDM) predisposes pregnant individuals to perinatal complications and long-term diabetes and cardiovascular diseases. We developed and validated metabolomic markers for GDM in a prospective test-validation study. In a case-control sample within the PETALS cohort (GDM n = 91 and non-GDM n = 180; discovery set), a random PETALS subsample (GDM n = 42 and non-GDM n = 372; validation set 1), and a case-control sample within the GLOW trial (GDM n = 35 and non-GDM n = 70; validation set 2), fasting serum untargeted metabolomics were measured by gas chromatography/time-of-flight mass spectrometry. Multivariate enrichment analysis examined associations between metabolites and GDM. Ten-fold cross-validated LASSO regression identified predictive metabolomic markers at gestational weeks (GW) 10–13 and 16–19 for GDM. Purinone metabolites at GW 10–13 and 16–19 and amino acids, amino alcohols, hexoses, indoles, and pyrimidine metabolites at GW 16–19 were positively associated with GDM risk (false discovery rate <0.05). A 17-metabolite panel at GW 10–13 outperformed the model using conventional risk factors, including fasting glycemia (area under the curve: discovery 0.871 vs. 0.742, validation 1 0.869 vs. 0.731, and validation 2 0.972 vs. 0.742; P < 0.01). Similar results were observed with a 13-metabolite panel at GW 17–19. Dysmetabolism is present early in pregnancy among individuals progressing to GDM. Multimetabolite panels in early pregnancy can predict GDM risk beyond conventional risk factors. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-1093 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1818 - 1826 Abstract: We systematically investigated the bidirectional causality among HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), fasting insulin (FI), and glycated hemoglobin A1c (HbA1c) based on genome-wide association summary statistics of Europeans (n = 1,320,016 for lipids, 151,013 for FI, and 344,182 for HbA1c). We applied multivariable Mendelian randomization (MR) to account for the correlation among different traits and constructed a causal graph with 13 significant causal effects after adjusting for multiple testing (P < 0.0025). Remarkably, we found that the effects of lipids on glycemic traits were through FI from TGs (β = 0.06 [95% CI 0.03, 0.08] in units of 1 SD for each trait) and HDL-C (β = −0.02 [−0.03, −0.01]). On the other hand, FI had a strong negative effect on HDL-C (β = −0.15 [−0.21, −0.09]) and positive effects on TGs (β = 0.22 [0.14, 0.31]) and HbA1c (β = 0.15 [0.12, 0.19]), while HbA1c could raise LDL-C (β = 0.06 [0.03, 0.08]) and TGs (β = 0.08 [0.06, 0.10]). These estimates derived from inverse-variance weighting were robust when using different MR methods. Our results suggest that elevated FI was a strong causal factor of high TGs and low HDL-C, which in turn would further increase FI. Therefore, early control of insulin resistance is critical to reduce the risk of type 2 diabetes, dyslipidemia, and cardiovascular complications. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db21-0734 Issue No:Vol. 71, No. 8 (2022)
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Pages: 1827 - 1827 Abstract: In Fig. 3B of article cited above, for images of iWAT and eWAT, the labels “WT” and “LKO” were inadvertently transposed. LKO (Cpt1a knockout) should have been the label for the first set of images of adipose tissue, and WT (wild type) should have been the label for the second set of images. PubDate: Sun, 21 Aug 2022 00:00:00 GMT DOI: 10.2337/db22-er08a Issue No:Vol. 71, No. 8 (2022)
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