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Emerging Role of Bone Morphogenetic Protein 4 in Metabolic Disorders
Ritesh K. Baboota, Matthias Blüher and Ulf Smith
doi : 10.2337/db20-0884
Diabetes 2021 Feb; 70 (2): 303-312
Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the TGF-? superfamily. Initially discovered for their ability to induce bone formation, BMPs are known to play a diverse and critical array of biological roles. We here focus on recent evidence showing that BMP4 is an important regulator of white/beige adipogenic differentiation with important consequences for thermogenesis, energy homeostasis, and development of obesity in vivo. BMP4 is highly expressed in, and released by, human adipose tissue, and serum levels are increased in obesity. Recent studies have now shown BMP4 to play an important role not only for white/beige/brown adipocyte differentiation and thermogenesis but also in regulating systemic glucose homeostasis and insulin sensitivity. It also has important suppressive effects on hepatic glucose production and lipid metabolism. Cellular BMP4 signaling/action is regulated by both ambient cell/systemic levels and several endogenous and systemic BMP antagonists. Reduced BMP4 signaling/action can contribute to the development of obesity, insulin resistance, and associated metabolic disorders. In this article, we summarize the pleiotropic functions of BMP4 in the pathophysiology of these diseases and also consider the therapeutic implications of targeting BMP4 in the prevention/treatment of obesity and its associated complications.
Modulation of Leukocytes of the Innate Arm of the Immune System as a Potential Approach to Prevent the Onset and Progression of Type 1 Diabetes
Alessandra Petrelli, Mark A. Atkinson, Massimo Pietropaolo and Nick Giannoukakis
doi : 10.2337/dbi20-0026
Diabetes 2021 Feb; 70 (2): 313-322
Type 1 diabetes (T1D) is characterized by insulin deficiency resulting from the selective destruction of pancreatic ?-cells by self-reactive T cells. Recent evidence demonstrates that innate immune responses substantially contribute to the pathogenesis of T1D, as they represent a first line of response to danger/damage signals. Here we discuss evidence on how, in a relapsing-remitting pattern, pancreas remodeling, diet, microbiota, gut permeability, and viral/bacterial infections induce the accumulation of leukocytes of the innate arm of the immune system throughout the pancreas. The subsequent acquisition and presentation of endocrine and exocrine antigens to the adaptive arm of the immune system results in a chronic progression of pancreatic damage. This process provides for the generation of self-reactive T-cell responses; however, the relative weight that genetic and environmental factors have on the etiopathogenesis of T1D is endotype imprinted and patient specific. With this Perspectives in Diabetes, our goal is to encourage the scientific community to rethink mechanisms underlying T1D pathogenesis and to consider therapeutic approaches that focus on these processes in intervention trials within new-onset disease as well as in efforts seeking the disorder’s prevention in individuals at high risk.
Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
Sona Kang
doi : 10.2337/dbi20-0041
Diabetes 2021 Feb; 70 (2): 323-325
Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
Andrew S. Terker, Ming-Zhi Zhang and Raymond C. Harris
doi : 10.2337/dbi20-0042
Diabetes 2021 Feb; 70 (2): 326-327
Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: The 2020 Edwin Bierman Award Lecture
Rama Natarajan
doi : 10.2337/dbi20-0030
Diabetes 2021 Feb; 70 (2): 328-337
Macrovascular complications such as atherosclerosis, myocardial infarction and stroke, and microvascular complications such as nephropathy, retinopathy, and neuropathy are the major causes of increased morbidity and mortality in both type 1 and type 2 diabetes. Increased inflammation, oxidative stress, and fibrosis are common features in most diabetes complications. Although extensive studies have examined the biochemical pathways leading to the expression of inflammatory, profibrotic, and other pathological genes, as well as genetic factors related to diabetes and associated complications, much less is known about the contribution of epigenetic changes that occur without alterations in the DNA sequence. Environmental factors, lifestyles, and improper diet implicated in diabetes can affect epigenetic states. Epigenetic modifications, including DNA methylation and histone modifications, can alter gene transcription in response to environmental stimuli and cooperate with noncoding RNAs. These epigenetic modifications have been observed in various target cells under diabetic conditions. Moreover, epigenetics has also been implicated in the phenomenon of metabolic memory observed in clinic trials and animal studies, in which prior episodes of poor glycemic control can confer continued risk of complications despite subsequent glucose normalization. Epigenome-wide association studies in cohorts with diabetes are uncovering epigenotype variations that provide new insights into diabetic vascular complications. Here, I discuss the role of epigenetics and noncoding RNAs in diabetes complications and metabolic memory, and their translation potential to serve as biomarkers and drug targets to improve clinical management of diabetic vascular complications.
A Journey in Diabetes: From Clinical Physiology to Novel Therapeutics: The 2020 Banting Medal for Scientific Achievement Lecture
Ele Ferrannini
doi : 10.2337/dbi20-0028
Diabetes 2021 Feb; 70 (2): 338-346
Insulin resistance and ?-cell dysfunction are the core pathophysiological mechanisms of all hyperglycemic syndromes. Advances in in vivo investigative techniques have made it possible to quantify insulin resistance in multiple sites (skeletal and myocardial muscle, subcutaneous and visceral fat depots, liver, kidney, vascular tissues, brain and intestine), to clarify its consequences for tissue substrate selection, and to establish its relation to tissue perfusion. Physiological modeling of ?-cell function has provided a uniform tool to measure ?-cell glucose sensitivity and potentiation in response to a variety of secretory stimuli, thereby allowing us to establish feedbacks with insulin resistance, to delineate the biphasic time course of conversion to diabetes, to gauge incretin effects, and to identify primary insulin hypersecretion. As insulin resistance also characterizes several of the comorbidities of diabetes (e.g., obesity, hypertension, dyslipidemia), with shared genetic and acquired influences, the concept is put forward that diabetes is a systemic disease from the outset, actually from the prediabetic stage. In fact, early multifactorial therapy, particularly with newer antihyperglycemic agents, has shown that the burden of micro- and macrovascular complications can be favorably modified despite the rising pressure imposed by protracted obesity.
Building Biomimetic Potency Tests for Islet Transplantation
Aaron L. Glieberman, Benjamin D. Pope, Douglas A. Melton and Kevin Kit Parker
doi : 10.2337/db20-0297
Diabetes 2021 Feb; 70 (2): 347-363
Diabetes is a disease of insulin insufficiency, requiring many to rely on exogenous insulin with constant monitoring to avoid a fatal outcome. Islet transplantation is a recent therapy that can provide insulin independence, but the procedure is still limited by both the availability of human islets and reliable tests to assess their function. While stem cell technologies are poised to fill the shortage of transplantable cells, better methods are still needed for predicting transplantation outcome. To ensure islet quality, we propose that the next generation of islet potency tests should be biomimetic systems that match glucose stimulation dynamics and cell microenvironmental preferences and rapidly assess conditional and continuous insulin secretion with minimal manual handing. Here, we review the current approaches for islet potency testing and outline technologies and methods that can be used to arrive at a more predictive potency test that tracks islet secretory capacity in a relevant context. With the development of potency tests that can report on islet secretion dynamics in a context relevant to their intended function, islet transplantation can expand into a more widely accessible and reliable treatment option for individuals with diabetes.
Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance
Tarekegn Geberhiwot, Shanat Baig, Cathy Obringer, Dorothée Girard, Charlotte Dawson, Konstantinos Manolopoulos, Nadia Messaddeq, Pierre Bel Lassen, Karine Clement, Jeremy W. Tomlinson, Richard P. Steeds, Hélène Dollfus, Nikolai Petrovsky and Vincent Marion
doi : 10.2337/db20-0647
Diabetes 2021 Feb; 70 (2): 364-376
Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Almsflin/flin; Adipo-Cre+/?) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.
Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance
Amalia Gastaldelli, Muhammad Abdul Ghani and Ralph A. DeFronzo
doi : 10.2337/db19-1152
Diabetes 2021 Feb; 70 (2): 377-385
With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ? min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ? m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = ?0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.
Ablation of AMPK-Related Kinase MPK38/MELK Leads to Male-Specific Obesity in Aged Mature Adult Mice
Hyun-A Seong and Hyunjung Ha
doi : 10.2337/db20-0436
Diabetes 2021 Feb; 70 (2): 386-399
Murine protein serine-threonine kinase 38 (MPK38)/maternal embryonic leucine zipper kinase (MELK) is implicated in diverse biological processes, including the cell cycle, apoptosis, and tumorigenesis; however, its physiological role is unknown. Using mice lacking MPK38 (MPK38?/?), we found that MPK38?/? male, but not female, mice (7 months of age) became obese while consuming a standard diet, displayed impairments in metabolism and inflammation, became more obese than wild-type mice while consuming a high-fat diet, and exhibited no castration/testosterone replacement–induced metabolic changes. The adenoviral restoration of MPK38 ameliorated the obesity-induced adverse metabolic profile of the obese male, but not female, mice. Seven-month-old MPK38?/? males displayed typical postcastration concentrations of serum testosterone with an accompanying decrease in serum luteinizing hormone (LH) levels, suggesting a role for MPK38 in the age-related changes in serum testosterone in aged mature adult male mice. The stability and activity of MPK38 were increased by dihydrotestosterone but reduced by estradiol (E2). These findings suggest MPK38 as a therapeutic target for obesity-related metabolic disorders in males.
Deletion of the Brain-Specific ? and ? Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity
Jessica L. Cote, Lawrence S. Argetsinger, Anabel Flores, Alan C. Rupp, Joel M. Cline, Lauren C. DeSantis, Alexander H. Bedard, Devika P. Bagchi, Paul B. Vander, Abrielle M. Cacciaglia, Erik S. Clutter, Gowri Chandrashekar, Ormond A. MacDougald, Martin G. Myers and Christin Carter-Su
doi : 10.2337/db20-0687
Diabetes 2021 Feb; 70 (2): 400-414
Mice lacking SH2B1 and humans with variants of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively spliced SH2B1 isoforms, SH2B1? and SH2B1? exhibit ubiquitous expression, whereas SH2B1? and SH2B1? are essentially restricted to the brain. To understand the roles for SH2B1? and SH2B1? in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (?? knockout [??KO] mice). ??KO mice exhibit decreased food intake, protection from weight gain on standard and high-fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, ??KO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1? and/or SH2B1? relative to the other SH2B1 isoforms likely shifts energy balance toward a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively spliced isoforms of SH2B1 perform different functions in vivo.
CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity
Philippe Zizzari, Rongjun He, Sarah Falk, Luigi Bellocchio, Camille Allard, Samantha Clark, Thierry Lesté-Lasserre, Giovanni Marsicano, Christoffer Clemmensen, Diego Perez-Tilve, Brian Finan, Daniela Cota and Carmelo Quarta
doi : 10.2337/db20-0162
Diabetes 2021 Feb; 70 (2): 415-422
Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists.
Acyl-Ghrelin Influences Pancreatic ?-Cell Function by Interference with KATP Channels
Julia Kaiser, Peter Krippeit-Drews and Gisela Drews
doi : 10.2337/db20-0231
Diabetes 2021 Feb; 70 (2): 423-435
The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects ?-cell function, with particular attention to the role of ATP-sensitive K+ (KATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+]c and glucose-stimulated insulin secretion (GSIS). These effects were abolished in ?-cells from SUR1-knockout (KO) mice. AG increased KATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic–cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2–5 antagonist H6056. These data indicate that AG indirectly opens KATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+]c and GSIS. The experiments with SUR1-KO ?-cells point to a direct effect of AG on ?-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from ?-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors.
Pancreatic ?-Cell–Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion
Christian H. Burns, Belinda Yau, Anjelica Rodriguez, Jenna Triplett, Drew Maslar, You Sun An, Reini E.N. van der Welle, Ross G. Kossina, Max R. Fisher, Gregory W. Strout, Peter O. Bayguinov, Tineke Veenendaal, David Chitayat, James A.J. Fitzpatrick, Judith Klumperman, Melkam A. Kebede and Cedric S. Asensio
doi : 10.2337/db20-0454
Diabetes 2021 Feb; 70 (2): 436-448
Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (HOPS) complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic ?-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule-regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in ?-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.
Retinol-Binding Protein 4 Activates STRA6, Provoking Pancreatic ?-Cell Dysfunction in Type 2 Diabetes
Rong Huang, Xinxiu Bai, Xueyan Li, Xiaohui Wang and Lina Zhao
doi : 10.2337/db19-1241
Diabetes 2021 Feb; 70 (2): 449-463
Pancreatic ?-cell dysfunction plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes, although its effect on ?-cell function remains elusive, and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic ?-cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose-stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4’s only known specific membrane receptor, is expressed in ?-cells and mediates the inhibitory effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore ?-cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic ?-cell dysfunction, which provides new insight into the diabetogenic effect of RBP4.
SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates ?-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients
Tina Fløyel, Kira Meyerovich, Michala C. Prause, Simranjeet Kaur, Caroline Frørup, Henrik B. Mortensen, Lotte B. Nielsen, Flemming Pociot, Alessandra K. Cardozo and Joachim Størling
doi : 10.2337/db20-0092
Diabetes 2021 Feb; 70 (2): 464-476
The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the ?-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual ?-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat ?-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-?B (NF-?B) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls ?-cell sensitivity to cytokines possibly by affecting the NF-?B–inducible nitric oxide synthase–endoplasmic reticulum stress pathway.
Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia
Nadejda Bozadjieva Kramer, Camila Lubaczeuski, Manuel Blandino-Rosano, Grant Barker, George K. Gittes, Alejandro Caicedo and Ernesto Bernal-Mizrachi
doi : 10.2337/db20-0440
Diabetes 2021 Feb; 70 (2): 477-491
Elevation of glucagon levels and increase in ?-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and ?-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in ?-cells (?TSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of ?-cell proliferation, cell size, and mass expansion. Hyperglucagonemia in ?TSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in ?TSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), PEPCK, and genes involved in amino acid metabolism and urea production. Glucagon resistance in ?TSC2KO mice was associated with improved glucose levels in streptozotocin-induced ?-cell destruction and high-fat diet–induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.
Loss of Furin in ?-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to ?-Cell Dysfunction
Bas Brouwers, Ilaria Coppola, Katlijn Vints, Bastian Dislich, Nathalie Jouvet, Leentje Van Lommel, Charlotte Segers, Natalia V. Gounko, Lieven Thorrez, Frans Schuit, Stefan F. Lichtenthaler, Jennifer L. Estall, Jeroen Declercq, Bruno Ramos-Molina and John W.M. Creemers
doi : 10.2337/db20-0474
Diabetes 2021 Feb; 70 (2): 492-503
FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, but its specific role in pancreatic ?-cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis. We show that FURIN is highly expressed in human islets, whereas PCs that potentially could provide redundancy are expressed at considerably lower levels. ?-cell–specific Furin knockout (?FurKO) mice are glucose intolerant as a result of smaller islets with lower insulin content and abnormal dense-core secretory granule morphology. mRNA expression analysis and differential proteomics on ?FurKO islets revealed activation of activating transcription factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). ?FurKO cells show impaired cleavage or shedding of vacuolar-type ATPase (V-ATPase) subunits Ac45 and prorenin receptor, respectively, and impaired lysosomal acidification. Blocking V-ATPase pharmacologically in ?-cells increased mTORC1 activity, suggesting involvement of the V-ATPase proton pump in the phenotype. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation and impaired lysosomal acidification in ?-cells lacking Furin, causing ?-cell dysfunction.
TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model
Sha Sha, James A. Pearson, Jian Peng, Youjia Hu, Juan Huang, Yanpeng Xing, Luyao Zhang, Ying Zhu, Hongyu Zhao, F. Susan Wong, Li Chen and Li Wen
doi : 10.2337/db20-0373
Diabetes 2021 Feb; 70 (2): 504-515
Toll-like receptor 9 (TLR9) is highly expressed in B cells, and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on ?-cell autoimmunity is not known. To fill this knowledge gap, we generated NOD mice with a B-cell–specific deficiency of TLR9 (TLR9fl/fl/CD19-Cre+ NOD). The B-cell–specific deletion of TLR9 resulted in near-complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of interleukin-10 (IL-10)–producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10–producing B cells. Molecular analysis revealed a network of TLR9 with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.
Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice
Fernanda M.C. Sodré, Samal Bissenova, Ylke Bruggeman, Ronak Tilvawala, Dana P. Cook, Claire Berthault, Santanu Mondal, Aïsha Callebaut, Sylvaine You, Raphael Scharfmann, Roberto Mallone, Paul R. Thompson, Chantal Mathieu, Mijke Buitinga and Lut Overbergh
doi : 10.2337/db20-0421
Diabetes 2021 Feb; 70 (2): 516-528
Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated glucose-regulated protein 78, and reduced spontaneous neutrophil extracellular trap formation of bone marrow–derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of interferon-?–producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.
Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes
Terri C. Thayer, Joanne Davies, James A. Pearson, Stephanie J. Hanna, Li Wen and F. Susan Wong
doi : 10.2337/db19-1050
Diabetes 2021 Feb; 70 (2): 529-537
Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8+ T cells, escaping central and peripheral tolerance, contribute to ?-cell destruction. Using G9C??/?CD8+ T cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the NOD mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9C??/?CD8+ T-cell cytotoxicity and dendritic cell–induced proliferation, they failed to sufficiently regulate T cells stimulated by anti-CD3/CD28. In contrast, non-MHC–matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.
Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation
Julia Braune, Andreas Lindhorst, Janine Fröba, Constance Hobusch, Peter Kovacs, Matthias Blüher, Jens Eilers, Ingo Bechmann and Martin Gericke
doi : 10.2337/db20-0293
Diabetes 2021 Feb; 70 (2): 538-548
Obesity is associated with chronic low-grade inflammation of visceral adipose tissue (AT) characterized by an increasing number of AT macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures, as ATMs accumulate around dying adipocytes, and the occurrence of multinucleated giant cells (MGCs). However, to date, the function of MGCs in obesity is unknown. Therefore, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrated that MGCs occurred in obese patients and after 24 weeks of a high-fat diet in mice, accompanying signs of AT inflammation and then representing ?3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggered MGC formation. Most importantly, MGCs in obese AT had a higher capacity to phagocytize oversized particles, such as adipocytes, as shown by live imaging of AT, 45-µm bead uptake ex vivo, and higher lipid content in vivo. Finally, we showed that interleukin-4 treatment was sufficient to increase the number of MGCs in AT, whereas other factors may be more important for endogenous MGC formation in vivo. Most importantly, our data suggest that MGCs are specialized for clearance of dead adipocytes in obesity.
CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPAR?
Mohamed A. Zayed, Xiaohua Jin, Chao Yang, Larisa Belaygorod, Connor Engel, Kshitij Desai, Nikolai Harroun, Omar Saffaf, Bruce W. Patterson, Fong-Fu Hsu and Clay F. Semenkovich
doi : 10.2337/db20-0635
Diabetes 2021 Feb; 70 (2): 549-561
De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator–activated receptor ? (PPAR?) in the liver. Fenofibrate, a PPAR? agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPAR? phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)–specific deletion of Cept1 via induced VE-cadherin-CreERT2–mediated recombination (Cept1Lp/LpCre+). Cept1Lp/LpCre+ ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre+ mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPAR? signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribonuclease-prepared siRNA decreased PPAR? phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+ mice, Cept1Lp/LpCre+Ppara?/? mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPAR?.
Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type 2 Diabetic Nephropathy
Yan Li, Yu Pan, Shirong Cao, Kensuke Sasaki, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Ming-Zhi Zhang and Raymond C. Harris
doi : 10.2337/db20-0660
Diabetes 2021 Feb; 70 (2): 562-576
Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (small interfering [si]EGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose–induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type 2 diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either db/db mice or nos3?/?; db/db mice, a model of accelerated type 2 DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression, and decreased profibrotic and fibrotic components in nos3?/?; db/db mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury.
A High-Fat Diet Attenuates AMPK ?1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo
Chenghui Yan, Xiaoxiang Tian, Jiayin Li, Dan Liu, Ding Ye, Zhonglin Xie, Yaling Han and Ming-Hui Zou
doi : 10.2337/db20-0146
Diabetes 2021 Feb; 70 (2): 577-588
Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (AT) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (NAFLD). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a high-fat diet (HFD) or treated with metformin or GW4869 and with AMPK?1-floxed (Prka?1fl/fl/wild-type [WT]), Prka?1?/?, liver tissue-specific Prka?1?/?, or AT-specific Prka?1?/? modification. In cultured adipocytes and white AT, the absence of AMPK?1 increased exosome release and exosomal proteins by elevating tumor susceptibility gene 101 (TSG101)–mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in Prka?1?/? and AT-specific Prka?1?/? mice than in WT and liver-specific Prka?1?/? mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver-specific Prka?1?/? mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in Prka?1?/? and adipocyte-specific Prka?1?/? mice. We conclude that HFD-mediated AMPK?1 inhibition promotes NAFLD by increasing numbers of AT CD36-containing exosomes.
Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease
Lu Zhang, Zichen Wang, Ruijie Liu, Zhengzhe Li, Jennifer Lin, Megan L. Wojciechowicz, Jiyi Huang, Kyung Lee, Avi Ma’ayan and John Cijiang He
doi : 10.2337/db20-0580
Diabetes 2021 Feb; 70 (2): 589-602
Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-?/NF-?B, JAK/STAT, and TGF-?/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-?B and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy
Fenfen Peng, Wangqiu Gong, Shuting Li, Bohui Yin, Chen Zhao, Wenting Liu, Xiaowen Chen, Congwei Luo, Qianying Huang, Ting Chen, Lingzhi Sun, Shun Fang, Weidong Zhou, Zhijian Li and Haibo Long
doi : 10.2337/db20-0203
Diabetes 2021 Feb; 70 (2): 603-615
Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose–induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.
CaM Kinase II-? Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy
Jessy Chen, Thomas Fleming, Sylvia Katz, Matthias Dewenter, Kai Hofmann, Alireza Saadatmand, Mariya Kronlage, Moritz P. Werner, Bianca Pokrandt, Friederike Schreiter, Jihong Lin, Daniel Katz, Jakob Morgenstern, Ahmed Elwakiel, Peter Sinn, Hermann-Josef Gröne, Hans-Peter Hammes, Peter P. Nawroth, Berend Isermann, Carsten Sticht, Britta Brügger, Hugo A. Katus, Marco Hagenmueller and Johannes Backs
doi : 10.2337/db19-0659
Diabetes 2021 Feb; 70 (2): 616-626
Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM kinase II-? (CaMKII?), which is known to be activated through diabetic metabolism. CaMKII? is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor–mutant mice to mice lacking CaMKII? globally. Remarkably, CaMKII?-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKII?-deficient diabetic mice developed the full picture of diabetic nephropathy, but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.
Polycystic Ovary Syndrome and Risk of Type 2 Diabetes, Coronary Heart Disease, and Stroke
Tiantian Zhu, Jinrui Cui and Mark O. Goodarzi
doi : 10.2337/db20-0800
Diabetes 2021 Feb; 70 (2): 627-637
Polycystic ovary syndrome (PCOS) has been associated with diabetes and cardiovascular disease; however, whether the relationship is causal is uncertain. We conducted a two-sample Mendelian randomization study to investigate the associations of PCOS with type 2 diabetes, coronary heart disease (CHD), and stroke. Association between PCOS and diabetes risk was examined in European and Asian cohorts, both sex specific and sex combined. Causal effects of PCOS on risks of CHD and stroke were evaluated in European cohorts. Stroke was analyzed as any stroke as well as four subtypes of stroke (ischemic, large artery, cardioembolic, small vessel). We found no association of genetically predicted PCOS with risk of diabetes, CHD, or stroke. This suggests that PCOS in and of itself does not increase the risk of these outcomes. Other features of PCOS (obesity, elevated testosterone, low sex hormone binding globulin) may explain the association between PCOS and cardiometabolic diseases. In light of these results, efforts to prevent cardiometabolic complications in PCOS should focus on women with high-risk features rather than all women with PCOS.
Baseline Assessment of Circulating MicroRNAs Near Diagnosis of Type 1 Diabetes Predicts Future Stimulated Insulin Secretion
Isaac Snowhite, Ricardo Pastori, Jay Sosenko, Shari Messinger Cayetano and Alberto Pugliese
doi : 10.2337/db20-0817
Diabetes 2021 Feb; 70 (2): 638-651
Type 1 diabetes is an autoimmune disease resulting in severely impaired insulin secretion. We investigated whether circulating microRNAs (miRNAs) are associated with residual insulin secretion at diagnosis and predict the severity of its future decline. We studied 53 newly diagnosed subjects enrolled in placebo groups of TrialNet clinical trials. We measured serum levels of 2,083 miRNAs, using RNA sequencing technology, in fasting samples from the baseline visit (<100 days from diagnosis), during which residual insulin secretion was measured with a mixed meal tolerance test (MMTT). Area under the curve (AUC) C-peptide and peak C-peptide were stratified by quartiles of expression of 31 miRNAs. After adjustment for baseline C-peptide, age, BMI, and sex, baseline levels of miR-3187-3p, miR-4302, and the miRNA combination of miR-3187-3p/miR-103a-3p predicted differences in MMTT C-peptide AUC/peak levels at the 12-month visit; the combination miR-3187-3p/miR-4723-5p predicted proportions of subjects above/below the 200 pmol/L clinical trial eligibility threshold at the 12-month visit. Thus, miRNA assessment at baseline identifies associations with C-peptide and stratifies subjects for future severity of C-peptide loss after 1 year. We suggest that miRNAs may be useful in predicting future C-peptide decline for improved subject stratification in clinical trials.
