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SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation
Katherine R. Tuttle, Frank C. Brosius, Matthew A. Cavender, Paola Fioretto, Kevin J. Fowler, Hiddo J.L. Heerspink, Tom Manley, Darren K. McGuire, Mark E. Molitch, Amy K. Mottl, Leigh Perreault, Sylvia E. Rosas, Peter Rossing, Laura Sola, Volker Vallon, Christoph Wanner and Vlado Perkovic
doi : 10.2337/dbi20-0040
Diabetes 2021 Jan; 70 (1): 1-16.
Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed.
Deciphering the Complex Communication Networks That Orchestrate Pancreatic Islet Function
Jonathan Weitz, Danusa Menegaz and Alejandro Caicedo
doi : 10.2337/dbi19-0033
Diabetes 2021 Jan; 70 (1): 17-26.
Pancreatic islets are clusters of hormone-secreting endocrine cells that rely on intricate cell-cell communication mechanisms for proper function. The importance of multicellular cooperation in islet cell physiology was first noted nearly 30 years ago in seminal studies showing that hormone secretion from endocrine cell types is diminished when these cells are dispersed. These studies showed that reestablishing cellular contacts in so-called pseudoislets caused endocrine cells to regain hormone secretory function. This not only demonstrated that cooperation between islet cells is highly synergistic but also gave birth to the field of pancreatic islet organoids. Here we review recent advances related to the mechanisms of islet cell cross talk. We first describe new developments that revise current notions about purinergic and GABA signaling in islets. Then we comment on novel multicellular imaging studies that are revealing emergent properties of islet communication networks. We finish by highlighting and discussing recent synthetic approaches that use islet organoids of varied cellular composition to interrogate intraislet signaling mechanisms. This reverse engineering of islets not only will shed light on the mechanisms of intraislet signaling and define communication networks but also may guide efforts aimed at restoring islet function and ?-cell mass in diabetes.
Lifting the Veil on the “Phosphate Flush,” a Cryptic Phenomenon of Experimental Pancreatic Islet Physiology
Franz Matschinsky and David Wilson
doi : 10.2337/dbi20-0038
Diabetes 2021 Jan; 70 (1): 27-28.
“Treasure Your Exceptions”—Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture
Stephen O’Rahilly
doi : 10.2337/dbi19-0037
Diabetes 2021 Jan; 70 (1): 29-38.
The study of humans with genetic mutations which lead to a substantial disturbance of physiological processes has made a contribution to biomedical science that is disproportionate to the rarity of affected individuals. In this lecture, I discuss examples of where such studies have helped to illuminate two areas of human metabolism. First, the control of insulin sensitivity and its disruption in states of insulin resistance and second, the regulation of energy balance and its disturbances in obesity.
Linking Kidney and Cardiovascular Complications in Diabetes—Impact on Prognostication and Treatment: The 2019 Edwin Bierman Award Lecture
Peter Rossing, Frederik Persson, Marie Frimodt-M?ller and Tine Willum Hansen
doi : 10.2337/dbi19-0038
Diabetes 2021 Jan; 70 (1): 39-50.
In diabetes, increasing albuminuria and decreasing glomerular filtration rate are hallmarks of chronic kidney disease in diabetes and increase the risk of atherosclerotic cardiovascular events and mortality as well as the risk for end-stage kidney disease. For two decades, standard of care has been controlling risk factors, such as glucose, blood pressure, lipids, and lifestyle factors, and specifically use of agents blocking the renin-angiotensin system. This has improved outcome, but a large unmet need has been obvious. After many failed attempts to advance the therapeutic options, the past few years have provided several new promising treatment options such as sodium–glucose cotransporter 2 inhibitors, endothelin receptor antagonists, glucagon-like peptide 1 agonists, and nonsteroidal mineralocorticoid receptor antagonists. The benefits and side effects of these agents demonstrate the link between kidney and heart; some have beneficial effects on both, whereas for other potentially renoprotective agents, development of heart failure has been a limiting factor. They work on different pathways such as hemodynamic, metabolic, inflammatory, and fibrotic targets. We propose that treatment may be personalized if biomarkers or physiological investigations assessing activity in these pathways are applied. This could potentially pave the way for precision medicine, where treatment is optimized for maximal benefit and minimal adverse outcomes. At least it may help prioritizing agents for an individual subject.
Cardiac Autophagy Deficiency Attenuates ANP Production and Disrupts Myocardial-Adipose Cross Talk, Leading to Increased Fat Accumulation and Metabolic Dysfunction
Erfei Song, Daniel Da Eira, Shailee Jani, Diane Sepa-Kishi, Vivian Vu, Howard Hunter, Mi Lai, Michael B. Wheeler, Rolando B. Ceddia and Gary Sweeney
doi : 10.2337/db19-0762
Diabetes 2021 Jan; 70 (1): 51-61.
Increased myocardial autophagy has been established as an important stress-induced cardioprotective response. Three weeks after generating cardiomyocyte-specific autophagy deficiency, via inducible deletion of autophagy-related protein 7 (Atg7), we found that these mice (AKO) had increased body weight and fat mass without altered food intake. Glucose and insulin tolerance tests indicated reduced insulin sensitivity in AKO mice. Metabolic cage analysis showed reduced ambulatory activity and oxygen consumption with a trend of elevated respiratory exchange ratio in AKO mice. Direct analysis of metabolism in subcutaneous and visceral adipocytes showed increased glucose oxidation and reduced ATGL expression and HSL phosphorylation with no change in lipid synthesis or fatty acid oxidation. Importantly, we found AKO mice had reduced myocardial and circulating levels of atrial natriuretic peptide (ANP), an established mediator of myocardial-adipose cross talk. When normal ANP levels were restored to AKO mice with use of osmotic pump, the metabolic dysfunction evident in AKO mice was corrected. We conclude that cardiac autophagy deficiency alters myocardial-adipose cross talk via decreased ANP levels with adverse metabolic consequences.
Central Regulation of Branched-Chain Amino Acids Is Mediated by AgRP Neurons
Ritchel B. Gannaban, Cherl NamKoong, Henry H. Ruiz, Hyung Jin Choi and Andrew C. Shin
doi : 10.2337/db20-0510
Diabetes 2021 Jan; 70 (1): 62-75.
Circulating branched-chain amino acids (BCAAs) are elevated in obesity and diabetes, and recent studies support a causal role for BCAAs in insulin resistance and defective glycemic control. The physiological mechanisms underlying BCAA regulation are poorly understood. Here we show that insulin signaling in the mediobasal hypothalamus (MBH) of rats is mandatory for lowering plasma BCAAs, most probably by inducing hepatic BCAA catabolism. Insulin receptor deletion only in agouti-related protein (AgRP)–expressing neurons (AgRP neurons) in the MBH impaired hepatic BCAA breakdown and suppression of plasma BCAAs during hyperinsulinemic clamps in mice. In support of this, chemogenetic stimulation of AgRP neurons in the absence of food significantly raised plasma BCAAs and impaired hepatic BCAA degradation. A prolonged fasting or ghrelin treatment recapitulated designer receptors exclusively activated by designer drugs–induced activation of AgRP neurons and increased plasma BCAAs. Acute stimulation of vagal motor neurons in the dorsal motor nucleus was sufficient to decrease plasma BCAAs. Notably, elevated plasma BCAAs were associated with impaired glucose homeostasis. These findings suggest a critical role of insulin signaling in AgRP neurons for BCAA regulation and raise the possibility that this control may be mediated primarily via vagal outflow. Furthermore, our results provide an opportunity to closely examine the potential mechanistic link between central nervous system–driven BCAA control and glucose homeostasis.
Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy
Camille Gamblin, Christine Rouault, Amélie Lacombe, Francina Langa-Vives, Dominique Farabos, Antonin Lamaziere, Karine Clément, Emmanuel L. Gautier, Laurent Yvan-Charvet and Isabelle Dugail
doi : 10.2337/db20-0578
Diabetes 2021 Jan; 70 (1): 76-90.
Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes, is unclear. We show that the isolated adipocyte fraction, but not the total undigested adipose tissue (ATs), from obese patients has decreased LAL expression compared with that from nonobese people. Lentiviral-mediated LAL knockdown in the 3T3L1 mouse cell line to mimic the obese adipocytes condition did not affect lysosome density or autophagic flux, but it did increase triglyceride storage and disrupt endoplasmic reticulum cholesterol, as indicated by activated SREBP.
Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans
Anne-Marie Lundsgaard, Andreas M. Fritzen, Kim A. Sj?berg, Maximilian Kleinert, Erik A. Richter and Bente Kiens
doi : 10.2337/db20-0582
Diabetes 2021 Jan; 70 (1): 91-98.
Medium-chain fatty acids (MCFAs) have in rodents been shown to have protective effects on glucose homeostasis during high-fat overfeeding. In this study, we investigated whether dietary MCFAs protect against insulin resistance induced by a hypercaloric high-fat diet in humans. Healthy, lean men ingested a eucaloric control diet and a 3-day hypercaloric high-fat diet (increase of 75% in energy, 81–83% energy [E%] from fat) in randomized order. For one group (n = 8), the high-fat diet was enriched with saturated long-chain FAs (LCSFA-HFD), while the other group (n = 9) ingested a matched diet, but with ?30 g (5E%) saturated MCFAs (MCSFA-HFD) in substitution for a corresponding fraction of the saturated long-chain fatty acids (LCFAs). A hyperinsulinemic-euglycemic clamp with femoral arteriovenous balance and glucose tracer was applied after the control and hypercaloric diets. In LCSFA-HFD, whole-body insulin sensitivity and peripheral insulin-stimulated glucose disposal were reduced. These impairments were prevented in MCSFA-HFD, accompanied by increased basal fatty acid oxidation, maintained glucose metabolic flexibility, increased nonoxidative glucose disposal related to lower starting glycogen content, and increased glycogen synthase activity, together with increased muscle lactate production. In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess.
Glucose Sensing Mediated by Portal Glucagon-Like Peptide 1 Receptor Is Markedly Impaired in Insulin-Resistant Obese Animals
Charles-Henri Malbert, Alain Chauvin, Michael Horowitz and Karen L. Jones
doi : 10.2337/db20-0361
Diabetes 2021 Jan; 70 (1): 99-110.
The glucose portal sensor informs the brain of changes in glucose inflow through vagal afferents that require an activated glucagon-like peptide 1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions, and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1–dependent portal glucose signaling was identified, in vivo, using a novel 68Ga-labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r–dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose.
XPR1 Mediates the Pancreatic ?-Cell Phosphate Flush
Christopher J. Barker, Fernando Henrique Galv?o Tessaro, Sabrina de Souza Ferreira, Rafael Simas, Thais S. Ayala, Martin K?hler, Subu Surendran Rajasekaran, Joilson O. Martins, Elisabetta Darè and Per-Olof Berggren
doi : 10.2337/db19-0633
Diabetes 2021 Jan; 70 (1): 111-118.
Glucose-stimulated insulin secretion is the hallmark of the pancreatic ?-cell, a critical player in the regulation of blood glucose concentration. In 1974, the remarkable observation was made that an efflux of intracellular inorganic phosphate (Pi) accompanied the events of stimulated insulin secretion. The mechanism behind this “phosphate flush,” its association with insulin secretion, and its regulation have since then remained a mystery. We recapitulated the phosphate flush in the MIN6m9 ?-cell line and pseudoislets. We demonstrated that knockdown of XPR1, a phosphate transporter present in MIN6m9 cells and pancreatic islets, prevented this flush. Concomitantly, XPR1 silencing led to intracellular Pi accumulation and a potential impact on Ca2+ signaling. XPR1 knockdown slightly blunted first-phase glucose-stimulated insulin secretion in MIN6m9 cells, but had no significant impact on pseudoislet secretion. In keeping with other cell types, basal Pi efflux was stimulated by inositol pyrophosphates, and basal intracellular Pi accumulated following knockdown of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, while it is unlikely that XPR1 directly affects exocytosis, it may protect Ca2+ signaling. Thus, we have revealed XPR1 as the missing mediator of the phosphate flush, shedding light on a 45-year-old mystery.
Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity
Xing Ming, Arthur C.K. Chung, Dandan Mao, Huanyi Cao, Baoqi Fan, Willy K.K. Wong, Chin Chung Ho, Heung Man Lee, Kristina Schoonjans, Johan Auwerx, Guy A. Rutter, Juliana C.N. Chan, Xiao Yu Tian and Alice P.S. Kong
doi : 10.2337/db20-0339
Diabetes 2021 Jan; 70 (1): 119-131.
Sirtuin 3 (SIRT3) is a protein deacetylase regulating ?-cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of ?-cell–specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs, are unknown. We found that glucose tolerance and glucose-stimulated insulin secretion were impaired in high-fat diet (HFD)-fed ?-cell–selective Sirt3 knockout (Sirt3f/f;Cre/+) mice. In addition, Sirt3f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3f/f mice upon HFD feeding. RNA sequencing of islets suggested that Sirt3 deficiency overactivated 5-hydroxytryptamine (5-HT) synthesis as evidenced by upregulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in ?-cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.
Adiponectin Promotes Maternal ?-Cell Expansion Through Placental Lactogen Expression
Liping Qiao, Sarah Saget, Cindy Lu, William W. Hay, Gerard Karsenty and Jianhua Shao
doi : 10.2337/db20-0471
Diabetes 2021 Jan; 70 (1): 132-142.
Hypoadiponectinemia is a risk factor of gestational diabetes mellitus (GDM). Our previous study reported that adiponectin gene knockout mice (Adipoq?/?) develop GDM due to insulin insufficiency. The main objective of this study was to elucidate the underlying mechanism through which adiponectin controls islet expansion during pregnancy. A significant reduction in ?-cell proliferation rates, ?-cell areas, and blood insulin concentrations was detected in Adipoq?/? mice at midpregnancy. Surprisingly, conditionally knocking down adiponectin receptor 1 (AdipoR1) or AdipoR2 genes in ?-cells during pregnancy did not reduce ?-cell proliferation rates or blood insulin concentrations. In vitro adiponectin treatment also failed to show any effect on ?-cell proliferation of isolated pancreatic islets. It was reported that placental lactogen (PL) plays a crucial role in pregnancy-induced maternal ?-cell proliferation. A significant decrease in phosphorylation of signal transducer and activator of transcription 5, a downstream molecule of PL signaling, was observed in islets from Adipoq?/? dams. The mRNA levels of mouse PL genes were robustly decreased in the placentas of Adipoq?/? dams. In contrast, adiponectin treatment increased PL expression in human placenta explants and JEG3 trophoblast cells. Most importantly, bovine PL injection restored ?-cell proliferation and blood insulin concentrations in Adipoq?/? dams. Together, these results demonstrate that adiponectin plays a vital role in pregnancy-induced ?-cell proliferation by promoting PL expression in trophoblast cells.
Induction of Core Circadian Clock Transcription Factor Bmal1 Enhances ?-Cell Function and Protects Against Obesity-Induced Glucose Intolerance
Kuntol Rakshit and Aleksey V. Matveyenko
doi : 10.2337/db20-0192
Diabetes 2021 Jan; 70 (1): 143-154.
Type 2 diabetes mellitus (T2DM) is characterized by ?-cell dysfunction as a result of impaired glucose-stimulated insulin secretion (GSIS). Studies show that ?-cell circadian clocks are important regulators of GSIS and glucose homeostasis. These observations raise the question about whether enhancement of the circadian clock in ?-cells will confer protection against ?-cell dysfunction under diabetogenic conditions. To test this, we used an approach by first generating mice with ?-cell–specific inducible overexpression of Bmal1 (core circadian transcription factor; ?-Bmal1OV). We subsequently examined the effects of ?-Bmal1OV on the circadian clock, GSIS, islet transcriptome, and glucose metabolism in the context of diet-induced obesity. We also tested the effects of circadian clock–enhancing small-molecule nobiletin on GSIS in mouse and human control and T2DM islets. We report that ?-Bmal1OV mice display enhanced islet circadian clock amplitude and augmented in vivo and in vitro GSIS and are protected against obesity-induced glucose intolerance. These effects were associated with increased expression of purported BMAL1-target genes mediating insulin secretion, processing, and lipid metabolism. Furthermore, exposure of isolated islets to nobiletin enhanced ?-cell secretory function in a Bmal1-dependent manner. This work suggests therapeutic targeting of the circadian system as a potential strategy to counteract ?-cell failure under diabetogenic conditions.
Translational Factor eIF4G1 Regulates Glucose Homeostasis and Pancreatic ?-Cell Function
Seokwon Jo, Amber Lockridge, Ramkumar Mohan, Nicholas Esch, Regina Schlichting, Neha Panigrahy, Ahmad Essawy, Eric Gustafson and Emilyn U. Alejandro
doi : 10.2337/db20-0057
Diabetes 2021 Jan; 70 (1): 155-170.
Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling is associated with diabetes in humans and mice. In the current study, we tested the hypothesis that eIF4G1 is critical for ?-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in ?-cells in vivo (?eIF4G1 knockout [KO]). Adult male and female ?eIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. ?-Cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in proliferation and apoptosis in ?-cells of ?eIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca2+ flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5? cap-binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single ?-cells or intact islets of ?eIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and ?-cell function.
InsB9-23 Gene Transfer to Hepatocyte-Based Combined Therapy Abrogates Recurrence of Type 1 Diabetes After Islet Transplantation
Fabio Russo, Antonio Citro, Giorgia Squeri, Francesca Sanvito, Paolo Monti, Silvia Gregori, Maria Grazia Roncarolo and Andrea Annoni
doi : 10.2337/db19-1249
Diabetes 2021 Jan; 70 (1): 171-181.
The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of a lentiviral vector enabling expression of insulin B chain 9-23 (InsB9-23) (LV.InsB) in hepatocytes arrests ?-cell destruction in prediabetic NOD mice by generating InsB9-23–specific FoxP3+ T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 monoclonal antibody (combined therapy [CT], 1 × 5 ?g [CT5]) reverts diabetes and prevents recurrence of autoimmunity after islet transplantation in ?50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, alloislets were transplanted after optimized CT tolerogenic conditioning (1 × 25 ?g [CT25]). Diabetic NOD mice conditioned with CT25 when glycemia was <500 mg/dL remained normoglycemic for 100 days after alloislet transplantation and displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T-cell unresponsiveness to InsB9-23 stimulation and increased Treg frequency in islet infiltration and pancreatic lymph nodes. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 costimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before alloislet transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous ?-cell mass.
Depletion of Adipocyte Becn1 Leads to Lipodystrophy and Metabolic Dysregulation
Young Jin, Yul Ji, Yaechan Song, Sung Sik Choe, Yong Geun Jeon, Heeju Na, Tae Wook Nam, Hye Jeong Kim, Hahn Nahmgoong, Sung Min Kim, Jae-woo Kim, Ki Taek Nam, Je Kyung Seong, Daehee Hwang, Chan Bae Park, In Hye Lee, Jae Bum Kim and Han-Woong Lee
doi : 10.2337/db19-1239
Diabetes 2021 Jan; 70 (1): 182-195.
Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.
The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes
Marie Louise Johansen, Jaime Ibarrola, Amaya Fern?ndez-Celis, Morten Schou, Mette Pauli Sonne, Maria Refsgaard Holm, Jon Rasmussen, Flemming Dela, Frederic Jaisser, Jens Faber, Patrick Rossignol, Natalia Lopez-Andres and Caroline Kistorp
doi : 10.2337/db20-0394
Diabetes 2021 Jan; 70 (1): 196-203.
Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association among the MR, fibrosis, and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present substudy, including 30 participants, was prespecified as part of the Mineralocorticoid Receptor Antagonist in Type 2 Diabetes (MIRAD) trial, which randomized patients to either high-dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examination and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen types I and VI, and the profibrotic factor ?-smooth muscle actin compared with placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusion, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.
Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance, and Insulin Sensitivity in Healthy Glucose-Tolerant Subjects
Aurora Merovci, Devjit Tripathy, Xi Chen, Ivan Valdez, Muhammad Abdul-Ghani, Carolina Solis-Herrera, Amalia Gastaldelli and Ralph A. DeFronzo
doi : 10.2337/db20-0039
Diabetes 2021 Jan; 70 (1): 204-213.
The aim of the current study was to evaluate the effect of sustained physiologic increase of ?50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH?) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h. First-phase insulin secretion (0–10 min) increased by 70%, while second-phase insulin secretion during the first (10–80 min) and second (90–160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 h of physiologic hyperglycemia. Insulin sensitivity during hyperglycemic clamp declined by ?30% and ?55% (both P < 0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (second clamp step) and by 62% following arginine (both P < 0.005) following 72-h glucose infusion. The effect of 72-h glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 h of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (P < 0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 h 1) increases absolute insulin secretion but impairs ?-cell function, 2) causes insulin resistance, and 3) reduces metabolic clearance rate of insulin.
ETV5 Regulates Hepatic Fatty Acid Metabolism Through PPAR Signaling Pathway
Zhuo Mao, Mingji Feng, Zhuoran Li, Minsi Zhou, Langning Xu, Ke Pan, Shaoxiang Wang, Wen Su and Weizhen Zhang
doi : 10.2337/db20-0619
Diabetes 2021 Jan; 70 (1): 214-226.
ETV5 is an ETS transcription factor that has been associated with obesity in genomic association studies. However, little is known about the role of ETV5 in hepatic lipid metabolism and nonalcoholic fatty liver disease. In the current study, we found that ETV5 protein expression was increased in diet- and genetically induced steatotic liver. ETV5 responded to the nutrient status in a mammalian target of rapamycin complex 1 (mTORC1)–dependent manner and in turn, regulated mTORC1 activity. Both viral-mediated and genetic depletion of ETV5 in mice led to increased lipid accumulation in the liver. RNA sequencing analysis revealed that peroxisome proliferator–activated receptor (PPAR) signaling and fatty acid degradation/metabolism pathways were significantly downregulated in ETV5-deficient hepatocytes in vivo and in vitro. Mechanistically, ETV5 could bind to the PPAR response element region of downstream genes and enhance its transactivity. Collectively, our study identifies ETV5 as a novel transcription factor for the regulation of hepatic fatty acid metabolism, which is required for the optimal ?-oxidation process. ETV5 may provide a therapeutic target for the treatment of hepatic steatosis.
Long Noncoding RNA MALAT1 and Regulation of the Antioxidant Defense System in Diabetic Retinopathy
Rakesh Radhakrishnan and Renu A. Kowluru
doi : 10.2337/db20-0375
Diabetes 2021 Jan; 70 (1): 227-239.
The retina experiences increased oxidative stress in diabetes, and the transcriptional activity of Nrf2, which is critical in regulating many antioxidant genes, is decreased. The nuclear movement/transcriptional activity of Nrf2 is mediated by its intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabetes. Gene expression is also regulated by long noncoding RNAs (LncRNAs). Our aim was to investigate the role of LncRNA MALAT1 in the regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy. LncRNA MALAT1 expression (quantitative real-time PCR, immunofluorescence, and RNA sequencing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription of the antioxidant response genes (immunofluorescence and nuclear RNA sequencing) were investigated in retinal endothelial cells exposed to high glucose. Glucose increased LncRNA MALAT1 levels by increasing Sp1 transcription factor binding at its promoter. Downregulation of LncRNA MALAT1 by its siRNA prevented glucose-induced increase in Keap1 and facilitated Nrf2 nuclear translocation and antioxidant gene transcription. Retinal microvessels from streptozotocin-induced diabetic mice and human donors with diabetic retinopathy also presented similar increases in LncRNA MALAT1 and its interactions with Keap1 and decreases in Nrf2-mediated antioxidant defense genes. Thus, LncRNA MALAT1, via Keap1-Nrf2, regulates antioxidant defense in diabetic retinopathy. Inhibition of LncRNA MALAT1 has potential to protect the retina from oxidative damage and to prevent or slow down diabetic retinopathy.
CD31+ Extracellular Vesicles From Patients With Type 2 Diabetes Shuttle a miRNA Signature Associated With Cardiovascular Complications
Francesco Prattichizzo, Valeria De Nigris, Jacopo Sabbatinelli, Angelica Giuliani, Carlos Casta?o, Marcelina P?rrizas, Isabel Crespo, Annalisa Grimaldi, Nicol? Baranzini, Rosangela Spiga, Elettra Mancuso, Maria Rita Rippo, Antonio Domenico Procopio, Anna Novials, Anna Rita Bonfigli, Silvia Garavelli, Lucia La Sala, Giuseppe Matarese, Paola de Candia, Fabiola Olivieri and Antonio Ceriello
doi : 10.2337/db20-0199
Diabetes 2021 Jan; 70 (1): 240-254.
Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications, but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead–based method to isolate plasma CD31+ EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31+ EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31+ EVs in a large (n = 218) cross-sectional cohort of patients categorized as having T2DM without complications, having T2DM with complications, and control subjects.
Novel Lipid Species for Detecting and Predicting Atrial Fibrillation in Patients With Type 2 Diabetes
Yow Keat Tham, Kaushala S. Jayawardana, Zahir H. Alshehry, Corey Giles, Kevin Huynh, Adam Alexander T. Smith, Jenny Y.Y. Ooi, Sophia Zoungas, Graham S. Hillis, John Chalmers, Peter J. Meikle and Julie R. McMullen
doi : 10.2337/db20-0653
Diabetes 2021 Jan; 70 (1): 255-261.
The incidence of atrial fibrillation (AF) is higher in patients with diabetes. The goal of this study was to assess if the addition of plasma lipids to traditional risk factors could improve the ability to detect and predict future AF in patients with type 2 diabetes. Logistic regression models were used to identify lipids associated with AF or future AF from plasma lipids (n = 316) measured from participants in the ADVANCE trial (n = 3,772). To gain mechanistic insight, follow-up lipid analysis was undertaken in a mouse model that has an insulin-resistant heart and is susceptible to AF. Sphingolipids, cholesteryl esters, and phospholipids were associated with AF prevalence, whereas two monosialodihexosylganglioside (GM3) ganglioside species were associated with future AF. For AF detection and prediction, addition of six and three lipids, respectively, to a base model (n = 12 conventional risk factors) increased the C-statistics (detection: from 0.661 to 0.725; prediction: from 0.674 to 0.715) and categorical net reclassification indices. The GM3(d18:1/24:1) level was lower in patients in whom AF developed, improved the C-statistic for the prediction of future AF, and was lower in the plasma of the mouse model susceptible to AF. This study demonstrates that plasma lipids have the potential to improve the detection and prediction of AF in patients with diabetes.
Dapagliflozin Suppresses ER Stress and Improves Subclinical Myocardial Function in Diabetes: From Bedside to Bench
Jhih-Yuan Shih, Yu-Wen Lin, Sudeshna Fisch, Juei-Tang Cheng, Nai-Wen Kang, Chon-Seng Hong, Zhih-Cherng Chen and Wei-Ting Chang
doi : 10.2337/db20-0840
Diabetes 2021 Jan; 70 (1): 262-267.
Dapagliflozin (DAPA), a sodium–glucose cotransporter 2 inhibitor, is approved for treatments of patients with diabetes. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial disclosed DAPA’s benefits in symptomatic heart failure, but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular functions including speckle tracking in patients with diabetes who were free from symptomatic heart failure post–DAPA treatment. Using a rat model with streptozotocin-induced diabetes, we measured the effects of DAPA on myocardial function. In patients with diabetes, following 6 months of DAPA treatment, despite no significant changes in left ventricular ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared with control, the diabetic rat heart developed pronounced fibrosis and a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose-lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species, and endoplasmic reticulum (ER) stress–associated proteins, which were attenuated by the coincubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis, and improved overall function. The results can lead to further improvement in management of left ventricular function in patients with diabetes.
Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Mellitus Implicated Through Clustering
Camille E. Powe, Miriam S. Udler, Sarah Hsu, Catherine Allard, Alan Kuang, Alisa K. Manning, Patrice Perron, Luigi Bouchard, William L. Lowe, Denise Scholtens, Jose C. Florez and Marie-France Hivert
doi : 10.2337/db20-0772
Diabetes 2021 Jan; 70 (1): 268-281.
Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational diabetes mellitus (GDM) is distinct from that underlying T2D. In this study of >5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced ?-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. The effect size for this cluster’s association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.
Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes: The TEDDY Study
Qian Li, Xiang Liu, Jimin Yang, Iris Erlund, ?ke Lernmark, William Hagopian, Marian Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar, Jeffrey P. Krischer and the TEDDY Study Group
doi : 10.2337/db20-0696
Diabetes 2021 Jan; 70 (1): 282-292.
Children’s plasma metabolome, especially lipidome, reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 newborns by screening of HLA-DR-DQ genotypes at six clinical centers in four countries, profiled metabolome, and measured concentrations of ascorbic acid, 25-hydroxyvitamin D [25(OH)D], and erythrocyte membrane fatty acids following birth until IA seroconversion under a nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or GAD (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared with nonprogressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, and alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA case subjects but not in matched control subjects, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
A Polygenic Score for Type 2 Diabetes Risk Is Associated With Both the Acute and Sustained Response to Sulfonylureas
Josephine H. Li, Lukasz Szczerbinski, Adem Y. Dawed, Varinderpal Kaur, Jennifer N. Todd, Ewan R. Pearson and Jose C. Florez
doi : 10.2337/db20-0530
Diabetes 2021 Jan; 70 (1): 293-300.
There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and BMI. A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year hemoglobin A1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study (P = 0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.
Erratum. Abrogation of MMP-9 Gene Protects Against the Development of Retinopathy in Diabetic Mice by Preventing Mitochondrial Damage. Diabetes 2011;60:3023–3033
Renu A. Kowluru, Ghulam Mohammad, Julia M. dos Santos and Qing Zhong
doi : 10.2337/db21-er01a
Diabetes 2021 Jan; 70 (1): 301.
