Publisher: American Diabetes Association   (Total: 4 journals)   [Sort alphabetically]

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Diabetes Care     Full-text available via subscription   (Followers: 448, SJR: 6.693, CiteScore: 8)
Diabetes     Full-text available via subscription   (Followers: 389, SJR: 4.435, CiteScore: 6)
Clinical Diabetes     Full-text available via subscription   (Followers: 40, SJR: 0.741, CiteScore: 1)
Diabetes Spectrum     Full-text available via subscription   (Followers: 17, SJR: 0.623, CiteScore: 1)
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Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 389  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • MRI Metrics of Cerebral Endothelial Cell–Derived Exosomes for the
           Treatment of Cognitive Dysfunction Induced in Aging Rats Subjected to Type
           2 Diabetes

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      Authors: Ding G; Li L, Zhang L, et al.
      Pages: 873 - 880
      Abstract: Ongoing neurovascular dysfunction contributes to type 2 diabetes mellitus (T2DM)-induced cognitive deficits. However, it is not known whether early post onset of T2DM interventions may reduce evolving neurovascular dysfunction and thereby lead to diminution of T2DM-induced cognitive deficits. Using multiple MRI metrics, we evaluated neurovascular changes in T2DM rats treated with exosomes derived from cerebral endothelial cells (CEC-Exos). Two months after induction of T2DM in middle-aged male rats by administration of streptozotocin nicotinamide, rats were randomly treated with CEC-Exos twice weekly or saline for 4 consecutive weeks (n = 10/group). MRI measurements were performed at the end of the treatment, which included cerebral blood flow (CBF), contrast-enhanced T1-weighted imaging, and relaxation time constants T1 and T2. MRI analysis showed that compared with controls, the CEC-Exo–treated T2DM rats exhibited significant elevation of T2 and CBF in white matter and significant augmentation of T1 and reduction of blood-brain barrier permeability in gray matter. In the hippocampus, CEC-Exo treatment significantly increased T1 and CBF. Furthermore, CEC-Exo treatment significantly reduced T2DM-induced cognitive deficits measured by the Morris water maze and odor recognition tests. Collectively, our corresponding MRI data demonstrate that treatment of T2DM rats with CEC-Exos robustly reduced neurovascular dysfunction in gray and white matter and the hippocampus.
      PubDate: Thu, 17 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0754
      Issue No: Vol. 71, No. 5 (2022)
       
  • Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular
           Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise
           

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      Authors: MacDonald TL; Pattamaprapanont P, Cooney EM, et al.
      Pages: 881 - 893
      Abstract: Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium–glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test–derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.
      PubDate: Wed, 02 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0934
      Issue No: Vol. 71, No. 5 (2022)
       
  • Alteration of the Individual Metabolic Network of the Brain Based on
           Jensen-Shannon Divergence Similarity Estimation in Elderly Patients With
           Type 2 Diabetes Mellitus

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      Authors: Li Y; Wu J, Ma J, et al.
      Pages: 894 - 905
      Abstract: The aim of this study was to investigate the interactive effect between aging and type 2 diabetes mellitus (T2DM) on brain glucose metabolism, individual metabolic connectivity, and network properties. Using a 2 × 2 factorial design, 83 patients with T2DM (40 elderly and 43 middle-aged) and 69 sex-matched healthy control subjects (HCs) (34 elderly and 35 middle-aged) underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance scanning. Jensen-Shannon divergence was applied to construct individual metabolic connectivity and networks. The topological properties of the networks were quantified using graph theoretical analysis. The general linear model was used to mainly estimate the interaction effect between aging and T2DM on glucose metabolism, metabolic connectivity, and network. There was an interaction effect between aging and T2DM on glucose metabolism, metabolic connectivity, and regional metabolic network properties (all P < 0.05). The post hoc analyses showed that compared with elderly HCs and middle-aged patients with T2DM, elderly patients with T2DM had decreased glucose metabolism, increased metabolic connectivity, and regional metabolic network properties in cognition-related brain regions (all P < 0.05). Age and fasting plasma glucose had negative correlations with glucose metabolism and positive correlations with metabolic connectivity. Elderly patients with T2DM had glucose hypometabolism, strengthened functional integration, and increased efficiency of information communication mainly located in cognition-related brain regions. Metabolic connectivity pattern changes might be compensatory changes for glucose hypometabolism.
      PubDate: Tue, 08 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0600
      Issue No: Vol. 71, No. 5 (2022)
       
  • Illumination of the Endogenous Insulin-Regulated TBC1D4 Interactome in
           Human Skeletal Muscle

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      Authors: Larsen JK; Larsen MR, Birk JB, et al.
      Pages: 906 - 920
      Abstract: Insulin-stimulated muscle glucose uptake is a key process in glycemic control. This process depends on the redistribution of glucose transporters to the surface membrane, a process that involves regulatory proteins such as TBC1D1 and TBC1D4. Accordingly, a TBC1D4 loss-of-function mutation in human skeletal muscle is associated with an increased risk of type 2 diabetes, and observations from carriers of a TBC1D1 variant associate this protein to a severe obesity phenotype. Here, we identified interactors of the endogenous TBC1D4 protein in human skeletal muscle by an unbiased proteomics approach. We detected 76 proteins as candidate TBC1D4 interactors. The binding of 12 of these interactors was regulated by insulin, including proteins known to be involved in glucose metabolism (e.g., 14-3-3 proteins and α-actinin-4 [ACTN4]). TBC1D1 also coprecipitated with TBC1D4 and vice versa in both human and mouse skeletal muscle. This interaction was not regulated by insulin or exercise in young, healthy, lean individuals. Similarly, the exercise- and insulin-regulated phosphorylation of the TBC1D1-TBC1D4 complex was intact. In contrast, we observed an altered interaction as well as compromised insulin-stimulated phosphoregulation of the TBC1D1-TBC1D4 complex in muscle of obese individuals with type 2 diabetes. Altogether, we provide a repository of TBC1D4 interactors in human and mouse skeletal muscle that serve as potential regulators of TBC1D4 function and, thus, insulin-stimulated glucose uptake in human skeletal muscle.
      PubDate: Tue, 22 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0855
      Issue No: Vol. 71, No. 5 (2022)
       
  • Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity Via
           Inhibiting USP33-Mediated ADRB2 Deubiquitination

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      Authors: Niu Y; Jiang H, Yin H, et al.
      Pages: 921 - 933
      Abstract: Chronic inflammation in liver induces insulin resistance systemically and in other tissues, including the skeletal muscle (SM); however, the underlying mechanisms remain largely unknown. RNA sequencing of primary hepatocytes from wild-type mice fed long-term high-fat diet (HFD), which have severe chronic inflammation and insulin resistance revealed that the expression of hepatokine endoplasmic reticulum aminopeptidase 1 (ERAP1) was upregulated by a HFD. Increased ERAP1 levels were also observed in interferon-γ–treated primary hepatocytes. Furthermore, hepatic ERAP1 overexpression attenuated systemic and SM insulin sensitivity, whereas hepatic ERAP1 knockdown had the opposite effects, with corresponding changes in serum ERAP1 levels. Mechanistically, ERAP1 functions as an antagonist-like factor, which interacts with β2 adrenergic receptor (ADRB2) and reduces its expression by decreasing ubiquitin-specific peptidase 33–mediated deubiquitination and thereby interrupts ADRB2-stimulated insulin signaling in the SM. The findings of this study indicate ERAP1 is an inflammation-induced hepatokine that impairs SM insulin sensitivity. Its inhibition may provide a therapeutic strategy for insulin resistance–related diseases, such as type 2 diabetes.
      PubDate: Tue, 22 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0857
      Issue No: Vol. 71, No. 5 (2022)
       
  • Sleep Disturbance and Changes in Energy Intake and Body Composition During
           Weight Loss in the POUNDS Lost Trial

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      Authors: Li A; Li X, Zhou T, et al.
      Pages: 934 - 944
      Abstract: To examine associations between sleep disturbance and changes in weight and body composition and the mediating role of changes of appetite and food cravings in the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) 2-year weight-loss diet intervention trial, this study included 810 overweight or obese individuals with baseline sleep disturbance assessment who were randomly assigned one of four diets varying in macronutrient composition. Changes in body weight and fat distribution were assessed by DEXA and computed tomography during the 2-year intervention. Participants were asked to provide sleep disturbance levels (no, slight, moderate, or great) at baseline and to recall their sleep disturbances since last visit at 6, 12, 18, and 24 months. Weight loss during the first 6 months was followed by 1.5 years of steady weight regain. Participants with greater sleep disturbance from baseline to 6 months showed significant losses of body weight (Ptrend <0.001) and waist circumference (Ptrend = 0.002) at 6 months, after multivariate adjustment. Compared with individuals without sleep disturbance at all from baseline to 6 months, those with slight, moderate, or great sleep disturbance showed an elevated risk of failure to lose weight (−5% or more loss) at 6 months, when the maximum weight loss was achieved, with an odds ratio of 1.24 (95% CI 0.87, 1.78), 1.27 (95% CI 0.75, 2.13), or 3.12 (95% CI 1.61, 6.03), respectively. In addition, we observed that the repeatedly measured levels of sleep disturbance over 2 years were inversely associated with the overall weight loss rate (weight changes per 6 months) (Ptrend <0.001). Further, sleep disturbances during weight loss from baseline to 6 months and weight regain from 6 months to 24 months were significantly predictive of total fat, total fat mass percent, and trunk fat percent changes during the 2 years. Our results also indicated that food cravings for carbohydrates/starches, fast food fats, and sweets; cravings, prospective consumption, hunger of appetite measurements; and dietary restraint, disinhibition, and hunger subscales measured at 6 months significantly mediated the effects of sleep disturbance on weight loss. In conclusion, our results suggested that more severe sleep disturbance during weight loss was associated with an elevated risk of failure to lose weight during the dietary intervention. Food cravings and eating behaviors may partly mediate these associations.
      PubDate: Thu, 24 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0699
      Issue No: Vol. 71, No. 5 (2022)
       
  • Gut Microbiota Regulate Pancreatic Growth, Exocrine Function, and Gut
           Hormones

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      Authors: Girdhar K; Soto M, Huang Q, et al.
      Pages: 945 - 960
      Abstract: Growing evidence indicates an important link between gut microbiota, obesity, and metabolic syndrome. Alterations in exocrine pancreatic function are also widely present in patients with diabetes and obesity. To examine this interaction, C57BL/6J mice were fed a chow diet, a high-fat diet (HFD), or an HFD plus oral vancomycin or metronidazole to modify the gut microbiome. HFD alone leads to a 40% increase in pancreas weight, decreased glucagon-like peptide 1 and peptide YY levels, and increased glucose-dependent insulinotropic peptide in the plasma. Quantitative proteomics identified 138 host proteins in fecal samples of these mice, of which 32 were significantly changed by the HFD. The most significant of these were the pancreatic enzymes. These changes in amylase and elastase were reversed by antibiotic treatment. These alterations could be reproduced by transferring gut microbiota from donor C57BL/6J mice to germ-free mice. By contrast, antibiotics had no effect on pancreatic size or exocrine function in C57BL/6J mice fed the chow diet. Further, 1 week vancomycin administration significantly increased amylase and elastase levels in obese men with prediabetes. Thus, the alterations in gut microbiota in obesity can alter pancreatic growth, exocrine function, and gut endocrine function and may contribute to the alterations observed in patients with obesity and diabetes.
      PubDate: Fri, 25 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0382
      Issue No: Vol. 71, No. 5 (2022)
       
  • YY1 Regulates Glucose Homeostasis Through Controlling Insulin
           Transcription in Pancreatic β-Cells

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      Authors: Liu D; Yang KY, Chan VW, et al.
      Pages: 961 - 977
      Abstract: To date, identification of nonislet-specific transcriptional factors in the regulation of insulin gene expression has been little studied. Here, we report that the expression level of the transcription factor YY1 is increased dramatically in both human and mouse pancreatic β-cells after birth. Nevertheless, the physiological role of YY1 during β-cell development and its regulatory mechanism in β-cell function remain largely unknown. After β-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced β-cell mass in neonatal and adult mice. These mice also had hypoinsulinemia with normal insulin sensitivity compared with their wild-type littermates, manifesting as a type 1 diabetic phenotype. Mechanistically, genome-wide RNA sequencing has defined dysregulated insulin signaling and defective glucose responsiveness in β-cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation assays targeting YY1, and histone modifications, including H3K4me1, H3K27ac, and H3K27me3, have further identified Ins1 and Ins2 as direct gene targets of YY1. Luciferase reporter assays and loss- and gain-of-function experiments also demonstrated that YY1 binds to the enhancer regions in exon 2 of Ins1 and Ins2, activating insulin transcription and, therefore, proinsulin and insulin production in pancreatic β-cells. YY1 also directly interacts with RNA polymerase II, potentially stabilizing the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings suggest a role for YY1 as a transcriptional activator of insulin gene expression, assisting β-cell maturation and function after birth. These analyses may advance our understanding of β-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes.
      PubDate: Thu, 03 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0695
      Issue No: Vol. 71, No. 5 (2022)
       
  • The Essential Role of Pancreatic α-Cells in Maternal Metabolic
           Adaptation to Pregnancy

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      Authors: Qiao L; Saget S, Lu C, et al.
      Pages: 978 - 988
      Abstract: Pancreatic α-cells are important in maintaining metabolic homeostasis, but their role in regulating maternal metabolic adaptations to pregnancy has not been studied. The objective of this study was to determine whether pancreatic α-cells respond to pregnancy and their contribution to maternal metabolic adaptation. With use of C57BL/6 mice, the findings of our study showed that pregnancy induced a significant increase of α-cell mass by promoting α-cell proliferation that was associated with a transitory increase of maternal serum glucagon concentration in early pregnancy. Maternal pancreatic GLP-1 content also was significantly increased during pregnancy. Using the inducible Cre/loxp technique, we ablated the α-cells (α-null) before and during pregnancy while maintaining enteroendocrine L-cells and serum GLP-1 in the normal range. In contrast to an improved glucose tolerance test (GTT) before pregnancy, significantly impaired GTT and remarkably higher serum glucose concentrations in the fed state were observed in α-null dams. Glucagon receptor antagonism treatment, however, did not affect measures of maternal glucose metabolism, indicating a dispensable role of glucagon receptor signaling in maternal glucose homeostasis. However, the GLP-1 receptor agonist improved insulin production and glucose metabolism of α-null dams. Furthermore, GLP-1 receptor antagonist Exendin (9-39) attenuated pregnancy-enhanced insulin secretion and GLP-1 restored glucose-induced insulin secretion of cultured islets from α-null dams. Together, these results demonstrate that α-cells play an essential role in controlling maternal metabolic adaptation to pregnancy by enhancing insulin secretion.
      PubDate: Fri, 11 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0923
      Issue No: Vol. 71, No. 5 (2022)
       
  • Nrf2 Regulates β-Cell Mass by Suppressing β-Cell Death and Promoting
           β-Cell Proliferation

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      Authors: Baumel-Alterzon S; Katz LS, Brill G, et al.
      Pages: 989 - 1011
      Abstract: Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here, we generated β-cell–specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation, and mass. Depletion of Nrf2 in β-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high-fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell–specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing reactive oxygen species levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting β-cell mass in diabetes.
      PubDate: Tue, 22 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0581
      Issue No: Vol. 71, No. 5 (2022)
       
  • T-Cell Receptor/HLA Humanized Mice Reveal Reduced Tolerance and Increased
           Immunogenicity of Posttranslationally Modified GAD65 Epitope

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      Authors: Jing Y; Kong Y, McGinty J, et al.
      Pages: 1012 - 1022
      Abstract: Accumulating evidence supports a critical role for posttranslationally modified (PTM) islet neoantigens in type 1 diabetes. However, our understanding regarding thymic development and peripheral activation of PTM autoantigen-reactive T cells is still limited. Using HLA-DR4 humanized mice, we observed that deamidation of GAD65115–127 generates a more immunogenic epitope that recruits T cells with promiscuous recognition of both the deamidated and native epitopes and reduced frequency of regulatory T cells. Using humanized HLA/T-cell receptor (TCR) mice, we observed that TCRs reactive to the native or deamidated GAD65115–127 led to efficient development of CD4+ effector T cells; however, regulatory T-cell development was reduced in mice expressing the PTM-reactive TCR, which was partially restored with exogenous PTM peptide. Upon priming, both the native-specific and the deamidated-specific T cells accumulated in pancreatic islets, suggesting that both specificities can recognize endogenous GAD65 and contribute to anti–β-cell responses. Collectively, our observations in polyclonal and single TCR systems suggest that while effector T-cell responses can exhibit cross-reactivity between native and deamidated GAD65 epitopes, regulatory T-cell development is reduced in response to the deamidated epitope, pointing to regulatory T-cell development as a key mechanism for loss of tolerance to PTM antigenic targets.
      PubDate: Fri, 18 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0993
      Issue No: Vol. 71, No. 5 (2022)
       
  • Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic
           Regulation and Metabolic Control

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      Authors: Kozuka C; Efthymiou V, Sales VM, et al.
      Pages: 1023 - 1033
      Abstract: Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4–related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism.
      PubDate: Mon, 31 Jan 2022 00:00:00 GMT
      DOI: 10.2337/db21-0574
      Issue No: Vol. 71, No. 5 (2022)
       
  • PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic
           Reticulum–Mitochondria Contact and Mitophagy in Diabetic Nephropathy

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      Authors: Li C; Li L, Yang M, et al.
      Pages: 1034 - 1050
      Abstract: Mitochondria-associated endoplasmic reticulum membrane (MAM) may have a role in tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, and PACS-2 expression is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PTs) aggravates albuminuria and tubular injury in a streptozotocin-induced mouse model of diabetes. Mitochondrial fragmentation, MAM disruption, and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic proteins, including Drp1 and Becn1, are observed in tubules of diabetic mice; these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose concentrations through blocking mitochondrial recruitment of DRP1 and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM, where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.
      PubDate: Tue, 08 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0983
      Issue No: Vol. 71, No. 5 (2022)
       
  • Müller Glial Expression of REDD1 Is Required for Retinal
           Neurodegeneration and Visual Dysfunction in Diabetic Mice

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      Authors: Miller WP; Toro AL, Sunilkumar S, et al.
      Pages: 1051 - 1062
      Abstract: Clinical studies support a role for the protein regulated in development and DNA damage response 1 (REDD1) in ischemic retinal complications. To better understand how REDD1 contributes to retinal pathology, we examined human single-cell sequencing data sets and found specificity of REDD1 expression that was consistent with markers of retinal Müller glia. Thus, we investigated the hypothesis that REDD1 expression specifically in Müller glia contributes to diabetes-induced retinal pathology. The retina of Müller glia-specific REDD1 knockout (REDD1-mgKO) mice exhibited dramatic attenuation of REDD1 transcript and protein expression. In the retina of streptozotocin-induced diabetic control mice, REDD1 protein expression was enhanced coincident with an increase in oxidative stress. In the retina of diabetic REDD1-mgKO mice, there was no increase in REDD1 protein expression, and oxidative stress was reduced compared with diabetic control mice. In both Müller glia within the retina of diabetic mice and human Müller cell cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the gliosis marker glial fibrillary acidic protein. The effect of REDD1 deletion in preventing gliosis was associated with suppression of oxidative stress and required the antioxidant transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2). In contrast to diabetic control mice, diabetic REDD1-mgKO mice did not exhibit retinal thinning, increased markers of neurodegeneration within the retinal ganglion cell layer, or deficits in visual function. Overall, the findings support a key role for Müller glial REDD1 in the failed adaptive response of the retina to diabetes that includes gliosis, neurodegeneration, and impaired vision.
      PubDate: Tue, 15 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0853
      Issue No: Vol. 71, No. 5 (2022)
       
  • N -Hydroxyethyl-1-Deoxynojirimycin (Miglitol) Restores the
           Counterregulatory Response to Hypoglycemia Following Antecedent
           Hypoglycemia

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      Authors: Jokiaho AJ; Winchester M, Donovan CM.
      Pages: 1063 - 1072
      Abstract: Antecedent hypoglycemia suppresses the counterregulatory responses to subsequent hypoglycemic episodes, which can be prevented by normalizing portal-mesenteric vein (PMV) glycemia alone during the antecedent bout. Since the sodium–glucose transporter 3 receptor has been implicated in PMV glucosensing, we hypothesized that PMV infusion of the sodium–glucose cotransporter 3 receptor agonist N-hydroxyethyl-1-deoxynojirimycin (miglitol) would rescue the sympathoadrenal response to subsequent hypoglycemia. Rats underwent hyperinsulinemic-hypoglycemic clamps on 2 consecutive days without miglitol infusion (antecedent hypoglycemia without miglitol [HYPO]) or with miglitol infused upstream in the PMV, perfusing the glucosensors, or adjacent to the liver, bypassing PMV glucosensors, on day 1 or day 2. Control animals underwent day 1 euglycemic clamps, followed by hypoglycemic clamps on day 2. Peak epinephrine (EPI) responses for HYPO on day 2 were significantly blunted when compared with controls. Miglitol infusion on day 1 proved ineffective in restoring the EPI response following antecedent hypoglycemia, but day 2 miglitol infusion restored EPI responses to control levels. As norepinephrine and glucagon demonstrated similar responses, day 2 administration of miglitol effectively restored the counterregulatory response following antecedent hypoglycemia. In subsequent experiments, we demonstrate similar results with reduced miglitol infusion doses, approaching those currently prescribed for type 2 diabetes (correcting for rodent size), as well as the efficacy of oral miglitol administration in restoring the counterregulatory responses following antecedent hypoglycemia.
      PubDate: Fri, 18 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0859
      Issue No: Vol. 71, No. 5 (2022)
       
  • pdx1 Knockout Leads to a Diabetic Nephropathy– Like Phenotype in
           Zebrafish and Identifies Phosphatidylethanolamine as Metabolite Promoting
           Early Diabetic Kidney Damage

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      Authors: Wiggenhauser LM; Metzger L, Bennewitz K, et al.
      Pages: 1073 - 1080
      Abstract: The pdx1−/− zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. In this study, we investigate whether knockout of pdx1 also leads to diabetic kidney disease (DKD). pdx1−/− larvae exhibit several signs of early DKD, such as glomerular hypertrophy, impairments in the filtration barrier corresponding to microalbuminuria, and glomerular basement membrane (GBM) thickening. Adult pdx1−/− mutants show progressive GBM thickening in comparison with the larval state. Heterozygous pdx1 knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the pdx1−/− larvae. RNA sequencing of adult pdx1+/− kidneys uncovered regulations in multiple expected diabetic pathways related to podocyte disruption and hinting at early vascular dysregulation without obvious morphological alterations. Metabolome analysis and pharmacological intervention experiments revealed the contribution of phosphatidylethanolamine in the early establishment of kidney damage. In conclusion, this study identified the pdx1 mutant as a novel model for the study of DKD, showing signs of the early disease progression already in the larval stage and several selective features of later DKD in adult mutants.
      PubDate: Mon, 31 Jan 2022 00:00:00 GMT
      DOI: 10.2337/db21-0645
      Issue No: Vol. 71, No. 5 (2022)
       
  • Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory
           Phenotype Impair Cardiac Regeneration and Function Independently of Age

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      Authors: Marino F; Scalise M, Salerno N, et al.
      Pages: 1081 - 1098
      Abstract: Diabetes mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared senescent T2DM-hCSCs in vitro, restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs’ regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function.
      PubDate: Wed, 02 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0536
      Issue No: Vol. 71, No. 5 (2022)
       
  • Restoration of Autophagic Flux Improves Endothelial Function in Diabetes
           Through Lowering Mitochondrial ROS-Mediated eNOS Monomerization

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      Authors: Zhao L; Zhang C, He L, et al.
      Pages: 1099 - 1114
      Abstract: Endothelial nitric oxide synthase (eNOS) monomerization and uncoupling play crucial roles in mediating vascular dysfunction in diabetes, although the underlying mechanisms are still incompletely understood. Increasing evidence indicates that autophagic dysregulation is involved in the pathogenesis of diabetic endothelial dysfunction; however, whether autophagy regulates eNOS activity through controlling eNOS monomerization or dimerization remains elusive. In this study, autophagic flux was impaired in the endothelium of diabetic db/db mice and in human endothelial cells exposed to advanced glycation end products or oxidized low-density lipoprotein. Inhibition of autophagic flux by chloroquine or bafilomycin A1 were sufficient to induce eNOS monomerization and lower nitric oxide bioavailability by increasing mitochondrial reactive oxygen species (mtROS). Restoration of autophagic flux by overexpressing transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, decreased endothelial cell oxidative stress, increased eNOS dimerization, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Inhibition of mammalian target of rapamycin kinase (mTOR) increased TFEB nuclear localization, reduced mtROS accumulation, facilitated eNOS dimerization, and enhanced EDR in db/db mice. Moreover, calorie restriction also increased TFEB expression, improved autophagic flux, and restored EDR in the aortas of db/db mice. Taken together, the findings of this study reveal that mtROS-induced eNOS monomerization is closely associated with the impaired TFEB-autophagic flux axis leading to endothelial dysfunction in diabetic mice.
      PubDate: Fri, 18 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0660
      Issue No: Vol. 71, No. 5 (2022)
       
  • GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White
           Adipose Tissue

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      Authors: Campbell JE; Beaudry JL, Svendsen B, et al.
      Pages: 1115 - 1127
      Abstract: The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet β-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain. We used mouse genetics to target Gipr expression within adipocytes. Surprisingly, targeting Cre expression to adipocytes using the adiponectin (Adipoq) promoter did not produce meaningful reduction of WAT Gipr expression in Adipoq-Cre:Giprflx/flx mice. In contrast, adenoviral expression of Cre under the control of the cytomegalovirus promoter, or transgenic expression of Cre using nonadipocyte-selective promoters (Ap2/Fabp4 and Ubc) markedly attenuated WAT Gipr expression. Analysis of single-nucleus RNA-sequencing, adipose tissue data sets localized Gipr/GIPR expression predominantly to pericytes and mesothelial cells rather than to adipocytes. Together, these observations reveal that adipocytes are not the major GIPR+ cell type within WAT—findings with mechanistic implications for understanding how GIP and GIP-based co-agonists control adipose tissue biology.
      PubDate: Tue, 22 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-1166
      Issue No: Vol. 71, No. 5 (2022)
       
  • Evaluation of Evidence for Pathogenicity Demonstrates That BLK , KLF11 ,
           and PAX4 Should Not Be Included in Diagnostic Testing for MODY

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      Authors: Laver TW; Wakeling MN, Knox O, et al.
      Pages: 1128 - 1136
      Abstract: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7), and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (cosegregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n = 1,227) compared with a control population (UK Biobank [n = 185,898]). For comparison we analyzed well-established causes of MODY, HNF1A, and HNF4A. The published variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (combined logarithm of the odds [LOD] scores ≤1.2), compared with HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95 × 10−5). Ultra-rare missense and protein-truncating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV P > 0.05, missense P > 0.1 for all three genes) while HNF1A and HNF4A were enriched (P < 10−6). Findings of sensitivity analyses with different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11, or PAX4 as a cause of MODY. They should not be included in MODY diagnostic genetic testing.
      PubDate: Wed, 02 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0844
      Issue No: Vol. 71, No. 5 (2022)
       
  • Systematic Heritability and Heritability Enrichment Analysis for Diabetes
           Complications in UK Biobank and ACCORD Studies

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      Authors: Kim J; Jensen A, Ko S, et al.
      Pages: 1137 - 1148
      Abstract: Diabetes-related complications reflect longstanding damage to small and large vessels throughout the body. In addition to the duration of diabetes and poor glycemic control, genetic factors are important contributors to the variability in the development of vascular complications. Early heritability studies found strong familial clustering of both macrovascular and microvascular complications. However, they were limited by small sample sizes and large phenotypic heterogeneity, leading to less accurate estimates. We take advantage of two independent studies—UK Biobank and the Action to Control Cardiovascular Risk in Diabetes trial—to survey the single nucleotide polymorphism heritability for diabetes microvascular (diabetic kidney disease and diabetic retinopathy) and macrovascular (cardiovascular events) complications. Heritability for diabetic kidney disease was estimated at 29%. The heritability estimate for microalbuminuria ranged from 24 to 60% and was 41% for macroalbuminuria. Heritability estimates of diabetic retinopathy ranged from 6 to 33%, depending on the phenotype definition. More severe diabetes retinopathy possessed higher genetic contributions. We show, for the first time, that rare variants account for much of the heritability of diabetic retinopathy. This study suggests that a large portion of the genetic risk of diabetes complications is yet to be discovered and emphasizes the need for additional genetic studies of diabetes complications.
      PubDate: Tue, 08 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0839
      Issue No: Vol. 71, No. 5 (2022)
       
  • Endothelial Phospholipase Cγ2 Improves Outcomes of Diabetic Ischemic Limb
           Rescue Following VEGF Therapy

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      Authors: Rustagi Y; Abouhashem AS, Verma P, et al.
      Pages: 1149 - 1165
      Abstract: Therapeutic vascular endothelial growth factor (VEGF) replenishment has met with limited success for the management of critical limb-threatening ischemia. To improve outcomes of VEGF therapy, we applied single-cell RNA sequencing (scRNA-seq) technology to study the endothelial cells of the human diabetic skin. Single-cell suspensions were generated from the human skin followed by cDNA preparation using the Chromium Next GEM Single-cell 3′ Kit v3.1. Using appropriate quality control measures, 36,487 cells were chosen for downstream analysis. scRNA-seq studies identified that although VEGF signaling was not significantly altered in diabetic versus nondiabetic skin, phospholipase Cγ2 (PLCγ2) was downregulated. The significance of PLCγ2 in VEGF-mediated increase in endothelial cell metabolism and function was assessed in cultured human microvascular endothelial cells. In these cells, VEGF enhanced mitochondrial function, as indicated by elevation in oxygen consumption rate and extracellular acidification rate. The VEGF-dependent increase in cell metabolism was blunted in response to PLCγ2 inhibition. Follow-up rescue studies therefore focused on understanding the significance of VEGF therapy in presence or absence of endothelial PLCγ2 in type 1 (streptozotocin-injected) and type 2 (db/db) diabetic ischemic tissue. Nonviral topical tissue nanotransfection technology (TNT) delivery of CDH5 promoter–driven PLCγ2 open reading frame promoted the rescue of hindlimb ischemia in diabetic mice. Improvement of blood flow was also associated with higher abundance of VWF+/CD31+ and VWF+/SMA+ immunohistochemical staining. TNT-based gene delivery was not associated with tissue edema, a commonly noted complication associated with proangiogenic gene therapies. Taken together, our study demonstrates that TNT-mediated delivery of endothelial PLCγ2, as part of combination gene therapy, is effective in diabetic ischemic limb rescue.
      PubDate: Tue, 22 Feb 2022 00:00:00 GMT
      DOI: 10.2337/db21-0830
      Issue No: Vol. 71, No. 5 (2022)
       
  • Issues and Events

    • Free pre-print version: Loading...

      Pages: 1166 - 1166
      PubDate: Wed, 20 Apr 2022 00:00:00 GMT
      DOI: 10.2337/db22-ie05
      Issue No: Vol. 71, No. 5 (2022)
       
 
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