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| Open AccessIntradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.
- Li-Ming Gan
- , Maria Lagerström-Fermér
- & Regina Fritsche-Danielson
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Article
| Open AccessInhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production
The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
- T. M. Zaved Waise
- , Mozhgan Rasti
- & Tony K. T. Lam
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Article
| Open AccessGenome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism
Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.
- Armand Valsesia
- , Qiao-Ping Wang
- & Jörg Hager
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Article
| Open AccessTAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression
Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
- Jun-Ha Hwang
- , A Rum Kim
- & Jeong-Ho Hong
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Article
| Open AccessInsulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.
- Elisa Vergari
- , Jakob G. Knudsen
- & Patrik Rorsman
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| Open AccessLong term but not short term exposure to obesity related microbiota promotes host insulin resistance
Gut microbiota impact host metabolism and gut microbiome composition reflects dietary habits. Here the authors show that, in animals fed obesogenic diets, changes in gut microbiota precede changes in glucose homeostasis. Importantly, long term exposure of the host to the changed microbiota is required to impair glucose homeostasis.
- Kevin P. Foley
- , Soumaya Zlitni
- & Jonathan D. Schertzer
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Article
| Open AccessThe signalling conformation of the insulin receptor ectodomain
The insulin receptor plays a key role in many physiological processes, yet how insulin effects receptor signaling at the structural level remains incomplete. Here the authors present a high-resolution cryo-EM structure of a high-affinity form of the insulin-bound insulin receptor ectodomain that sheds light on the mechanism of signal transduction.
- Felix Weis
- , John G. Menting
- & Michael C. Lawrence
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| Open AccessDiscovering human diabetes-risk gene function with genetics and physiological assays
The function of genes linked to type 2 diabetes is poorly characterized. Here the authors combine Drosophila genetics and physiology with human islet biology to identify new regulators of insulin secretion including BCL11A.
- Heshan Peiris
- , Sangbin Park
- & Seung K. Kim
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Article
| Open AccessGenome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
- Angli Xue
- , Yang Wu
- & Jian Yang
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Article
| Open AccessDiscovery of a drug candidate for GLIS3-associated diabetes
GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes. Here, the authors generate mono-hormonal glucose-responding pancreatic β-like cells in vitro and through a screen identify a drug that rescues pancreatic β-like cell death in GLIS3 mutants by inhibiting the abnormally activated TGFβ pathway.
- Sadaf Amin
- , Brandoch Cook
- & Shuibing Chen
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Article
| Open AccessCaffeine-inducible gene switches controlling experimental diabetes
Control of transgene expression should ideally be easy and with minimal side effects. Here the authors present a synthetic biology-based approach in which the caffeine in coffee regulates a genetic circuit controlling glucagon-like peptide 1 expression in diabetic mice.
- Daniel Bojar
- , Leo Scheller
- & Martin Fussenegger
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Article
| Open AccessGenetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
- Viktoria Gusarova
- , Colm O’Dushlaine
- & Jesper Gromada
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Article
| Open AccessLaminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing
Laminins are important regulators of epidermal wound healing. Here, the authors show that laminins bind to multiple growth factors via their heparin-binding domains, and that incorporation of these domains into fibrin matrices increases growth factor retention, promoting wound healing in type 2 diabetic mouse models.
- Jun Ishihara
- , Ako Ishihara
- & Jeffrey A. Hubbell
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Article
| Open AccessDeficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders
Hyperinsulinemia can precede the development of insulin resistance. Here the authors identify a PKD2 mutation that leads to hyperinsulinemia and insulin resistance in Rhesus monkey and show that PKD2 deficiency promotes beta cell insulin secretion by activating L-type Ca2+ channels.
- Yao Xiao
- , Can Wang
- & Xiuqin Zhang
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| Open AccessContrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models
Non-invasive techniques to assess the progression of type 1 diabetes prior to clinical onset are needed. Here the authors apply a contrast-enhanced ultrasound measurement of mouse pancreatic blood flow to detect changes in the islet microvasculature that undergoes rearrangements during diabetes and predict disease progression.
- Joshua R. St Clair
- , David Ramirez
- & Richard K. P. Benninger
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Article
| Open AccessStructural basis for GPR40 allosteric agonism and incretin stimulation
GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism.
- Joseph D. Ho
- , Betty Chau
- & Chafiq Hamdouchi
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Article
| Open AccessReduced oxidative capacity in macrophages results in systemic insulin resistance
M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.
- Saet-Byel Jung
- , Min Jeong Choi
- & Minho Shong
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| Open AccessLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus
Type 1 diabetes mellitus (T1DM) is characterized by beta cell loss because of an autoimmune attack. Here the authors show that an agonist for LRH-1/NR5A2, a nuclear receptor known to be protective against beta cell apoptosis, inhibits immune-mediated inflammation and hyperglycemia in T1DM mouse models.
- Nadia Cobo-Vuilleumier
- , Petra I. Lorenzo
- & Benoit R. Gauthier
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| Open AccessAKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus
Patients suffering from congenital nephrogenic diabetes insipidus (NDI) fail to concentrate urine due to mutations in vasopressin type 2 receptor (V2R). Here Ando et al. show that agents disrupting the interaction between PKA and AKAPs restore aquaporin-2 activity downstream of V2R, offering a therapeutic approach for the treatment of NDI.
- Fumiaki Ando
- , Shuichi Mori
- & Shinichi Uchida
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| Open AccessA novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes
Autophagy plays an important role in metabolic functions and increased autophagic activity may be beneficial for metabolic disorders. Here the authors screen a chemical library for enhancer of autophagic flux and identify small molecules that improve the metabolic profile by increasing lysosomial functions.
- Hyejin Lim
- , Yu-Mi Lim
- & Myung-Shik Lee
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| Open AccessThe beta secretase BACE1 regulates the expression of insulin receptor in the liver
A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.
- Paul J. Meakin
- , Anna Mezzapesa
- & Franck Peiretti
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| Open AccessDe novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity
Adipocyte hyperplasia is thought to have beneficial metabolic effects in obesity, but definitive evidence is lacking. Here, Shao et al. promote de novo formation of adipocytes in visceral white adipose tissue (WAT) of adult mice through inducible overexpression of Pparg in Pdgfrβ+ preadipocytes and show that this protects from pathological WAT remodeling.
- Mengle Shao
- , Lavanya Vishvanath
- & Rana K. Gupta
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| Open AccessRe-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.
- Sílvia Bonàs-Guarch
- , Marta Guindo-Martínez
- & David Torrents
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| Open Access20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1
FFAR1 receptor is highly expressed in beta cells and its activation has been suggested as therapy against type-2 diabetes. Here, Tunaru et al. show that 20-hydroxyeicosatetraenoic acid, produced within the islets upon glucose stimulation, acts in an autocrine manner to stimulate insulin secretion via FFAR1 activation.
- Sorin Tunaru
- , Remy Bonnavion
- & Stefan Offermanns
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| Open AccessGLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose
The sweetener D-allulose has beneficial metabolic effects in animal models, but its mechanism of action was unclear. Here the authors report that D-allulose triggers GLP-1 release in the gut and GLP-1R signaling on vagal afferents, counteracting arrhythmic overeating, obesity and diabetes.
- Yusaku Iwasaki
- , Mio Sendo
- & Toshihiko Yada
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Article
| Open AccessSirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein
During diabetes, postprandial hyperglycemia is caused by impaired glucose uptake. Here, Watanabe and colleagues show that impaired hepatic glucose uptake during obesity is caused by a reduction in Sirt2 activity, which promotes glucokinase regulatory protein acetylation and its dissociation from glucokinase.
- Hitoshi Watanabe
- , Yuka Inaba
- & Hiroshi Inoue
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Article
| Open AccessDiabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages
Type 2 diabetes is associated with impaired wound healing, which can lead to limb loss. Here, the authors show that in Type 2 diabetic mouse models, Dnmt1 is upregulated in hematopoietic stem cells, leading to impaired differentiation towards macrophages, reduced macrophage infiltration in the wound and skewed M1/M2 polarization.
- Jinglian Yan
- , Guodong Tie
- & Louis M. Messina
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| Open AccessA miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning
White adipocytes can be stimulated to express thermogenic genes in a process known as beiging. Here, the authors show that miR-327 is downregulated during beiging, which releases FGF10 from inhibition and supports beige adipocyte formation via signaling through FGFR2.
- Carina Fischer
- , Takahiro Seki
- & Yihai Cao
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Article
| Open AccessNeuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism
Neuronal signals, in particular those transmitted via the vagal nerve, regulate both β-cell function and proliferation. Here, Yamamoto et al. show that the forkhead box M1 pathway is required for vagal signal-mediated induction of β-cell proliferation during obesity.
- Junpei Yamamoto
- , Junta Imai
- & Hideki Katagiri
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Article
| Open AccessHepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
During obesity, chronic inflammation leads to insulin resistance and diabetes. Here, Brenachot et al. show that Protein Tyrosine Phosphatase Receptor Gamma is upregulated in obesity by inflammatory signals and correlates with insulin resistance in humans. Its deletion in mouse models of obesity and inflammation ameliorates insulin resistance by suppressing glucose production.
- Xavier Brenachot
- , Giorgio Ramadori
- & Roberto Coppari
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Article
| Open AccessVps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism
Vps34 is a lipid kinase conserved from yeast to humans and involved in in intracellular vesicular trafficking and autophagy. Here Bilanges et al. show that inhibition of this kinase in mice improves glucose tolerance and diet-induced steatosis by modulating mitochondrial respiration and metabolism.
- Benoit Bilanges
- , Samira Alliouachene
- & Bart Vanhaesebroeck
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Article
| Open AccessAnalyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment
The authors examine the effects of antidiabetic medication on the gut microbiome and bile acid composition and show that these data can be used to stratify treatment regimens for type 2 diabetes.
- Yanyun Gu
- , Xiaokai Wang
- & Weiqing Wang
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| Open AccessStress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function
Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.
- Georgia Balsevich
- , Alexander S. Häusl
- & Mathias V. Schmidt
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| Open AccessSelenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models
Selenoprotein P is secreted by the liver and when present in excess it promotes development of type 2 diabetes. Here the authors develop neutralizing antibodies to target human and mouse selenoprotein P, and show that they improve insulin secretion and glucose tolerance in mouse models.
- Yuichiro Mita
- , Kaho Nakayama
- & Yoshiro Saito
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| Open AccessA mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance
Dysregulation of insulin secretion dynamics plays a role in diabetes development. Here, the authors build a mathematical model of hepatic insulin signaling and propose a sequential model of post-meal control of glucose and lipids, according to which delayed aPKC suppression would contribute to selective hepatic insulin resistance.
- Gang Zhao
- , Dagmar Wirth
- & Michael Meyer-Hermann
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Article
| Open AccessHeterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance
Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
- Kashyap A. Patel
- , Jarno Kettunen
- & Michael N. Weedon
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Article
| Open AccessMKK6 controls T3-mediated browning of white adipose tissue
Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure.
- Nuria Matesanz
- , Edgar Bernardo
- & Guadalupe Sabio
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| Open AccessInsights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas
Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.
- Huan Wang
- , Aaron Bender
- & Andrew F. Stewart
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Article
| Open AccessGCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis
Hepatic gluconeogenesis is tightly regulated at transcriptional level and is essential for survival during prolonged fasting. Here Wang et al. show that the mitochondrial enriched GCN5-like 1 protein controls hepatic glucose production by regulating FoxO1 protein levels via proteasome-dependent degradation and, in turn, gluconeogenic gene expression.
- Lingdi Wang
- , Iain Scott
- & Michael N. Sack
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Article
| Open AccessInhibition of Y1 receptor signaling improves islet transplant outcome
Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.
- Kim Loh
- , Yan-Chuan Shi
- & Herbert Herzog
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Article
| Open AccessFas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function
Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.
- Flurin Item
- , Stephan Wueest
- & Daniel Konrad
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Article
| Open AccessRetinol saturase coordinates liver metabolism by regulating ChREBP activity
Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.
- Steffi Heidenreich
- , Nicole Witte
- & Michael Schupp
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Article
| Open AccessGlycoprotein 2 is a specific cell surface marker of human pancreatic progenitors
Pancreatic progenitors (PPs) can be derived from human pluripotent stem cells in vitro but efficiency of differentiation varies, making it hard to sort for insulin-producing cells. Here, the authors use a proteomic approach to identify the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ PPs.
- Kathryn F. Cogger
- , Ankit Sinha
- & M. Cristina Nostro
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Article
| Open AccessEndotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
- Jia Cao
- , Jinghua Peng
- & Ling He
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Article
| Open AccessAdipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells
Obesity is associated with inflammation in adipose tissue, characterized by a shift in local T cell subsets. Here the authors show that loss of MHCII expression on adipocytes increases levels of immunosuppressive regulatory T cells in adipose tissue, which enhances insulin sensitivity.
- Tuo Deng
- , Joey Liu
- & Willa A. Hsueh
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Article
| Open AccessLoss of mTORC1 signalling impairs β-cell homeostasis and insulin processing
Deregulation of mTORC1 pathway has been associated with several human diseases including diabetes, neurodegeneration and cancer. Here Blandino-Rosanoet al. show that mTORC1 signalling controls insulin secretion and β-cell maintenance by regulation of β-cell proliferation, apoptosis and autophagy and insulin processing.
- Manuel Blandino-Rosano
- , Rebecca Barbaresso
- & Ernesto Bernal-Mizrachi
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Article
| Open AccessRaptor regulates functional maturation of murine beta cells
mTORC1 regulates beta cell survival, function and adaptation to physiologic and pathological stimuli. Here Niet al. demonstrate that that deficiency of Raptor, a component of mTORC1 complex, impairs insulin secretion and glucose tolerance in mice by affecting maturation of beta cells during the postnatal period.
- Qicheng Ni
- , Yanyun Gu
- & Qidi Wang
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Article
| Open AccessSox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
Type 2 diabetes (T2D) is a heterogeneous disorder characterized by insulin resistance and impaired insulin secretion. Here Axelssonet al. show that Sox5, which is reduced in diabetes, regulates a set of differentially expressed genes in T2D and its genetic and pharmacological induction improves insulin secretion by diabetic islets.
- A. S. Axelsson
- , T. Mahdi
- & A. H. Rosengren
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Article
| Open AccessSuccinate and its G-protein-coupled receptor stimulates osteoclastogenesis
Bone loss is common in patients with diabetes, but the underlying molecular and cellular mechanisms are unclear. Here the authors show high succinate levels in mice with type 2 diabetes and that succinate can signal through succinate receptor 1 on osteoclasts to induce bone resorption.
- Yuqi Guo
- , Chengzhi Xie
- & Xin Li