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| Open AccessHyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
- Yulong Gong
- , Bingyuan Yang
- & Wenbiao Chen
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Article
| Open AccessEffect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial
β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents. Here the authors report that two-weeks of treatment with the β2-agonist clenbuterol improves insulin-stimulated glucose disposal in healthy young men in a double-blinded, randomized cross-over trial.
- Sten M. M. van Beek
- , Yvonne M. H. Bruls
- & Joris Hoeks
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| Open AccessThe urban built environment and adult BMI, obesity, and diabetes in Latin American cities
Latin America is the world’s most urbanized region and its heterogeneous urban development may impact chronic diseases. In this study, the authors evaluate the association of built environment characteristics with body mass index, obesity, and type 2 diabetes.
- Cecilia Anza-Ramirez
- , Mariana Lazo
- & J. Jaime Miranda
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| Open AccessImplantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats
Islet transplantation for type 1 diabetes management is hindered by the life-long need for immunosuppressive medications. Here, the authors report an islet encapsulation device with local anti-rejection drug release that achieves long-term diabetes reversal in male rats and reduces drug-related toxicity.
- Jesus Paez-Mayorga
- , Jocelyn Nikita Campa-Carranza
- & Alessandro Grattoni
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| Open AccessA randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes
Based on preclinical studies, gamma aminobutyric acid (GABA) and immunization for the enzyme that produces GABA glutamate decarboxylase (GAD) could be a potential therapy for type 1 diabetes. Here the authors report that in a placebo-controlled, double blind trial in children with new onset type 1 diabetes oral GABA plus GAD did not preserve beta-cell function measured as fasting/meal-stimulated c-peptide levels.
- Alexandra Martin
- , Gail J. Mick
- & Kenneth L. McCormick
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Article
| Open AccessDifferential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation
Interleukin-18 (IL18) has a pivotal role in interferon signalling and T cell development, but increasingly recognized as an adipokine that regulates energy metabolism in fat tissue. Authors here dissect the function of IL18 signalling in the adipose compartment by targeted genomic deletion of its two receptors individually and in combination in brown and white adipose tissues.
- Xian Zhang
- , Songyuan Luo
- & Guo-Ping Shi
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Article
| Open AccessThe dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.
- Alessandra Dall’Agnese
- , Jesse M. Platt
- & Richard A. Young
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Article
| Open AccessTargeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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Article
| Open AccessGPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages
G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.
- Jing Yan
- , Yuemei Zhang
- & Cheng Hu
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Article
| Open AccessMetabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population
Four T2D subtypes were previously identified: severe insulin deficient, severe insulin resistant, mild obesity-related, and mild age-related diabetes. Here, the authors show that these subtypes can be translated to an Arabic population and identify distinct subtype-specific metabolic and proteomic signatures.
- Shaza B. Zaghlool
- , Anna Halama
- & Karsten Suhre
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Article
| Open AccessCausal deep learning reveals the comparative effectiveness of antihyperglycemic treatments in poorly controlled diabetes
Current treatment guidelines for Type-2 diabetes endorse a massive number of potential anti-hyper-glycemic treatment options in various permutations and combinations. Here, the authors present a causal deep learning approach for more personalized recommendations of treatment selection.
- Chinmay Belthangady
- , Stefanos Giampanis
- & Beau Norgeot
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Article
| Open AccessAnalytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma
Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.
- Angela Criscuolo
- , Palina Nepachalovich
- & Maria Fedorova
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Article
| Open AccessUse of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes
Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression.
- Paul M. H. Tran
- , Fran Dong
- & Sharad Purohit
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| Open AccessPlasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis
Kang and colleagues find that plasma membrane flipping of Syntaxin-2 from inside (inhibitory) to outside (relief of inhibition) of pancreatic β-cells helps fine-tune insulin secretion. Increasing this flipping efficiency can alleviate the impaired insulin secretion in diabetes.
- Fei Kang
- , Li Xie
- & Herbert Y. Gaisano
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Article
| Open AccessStructural mechanism of SGLT1 inhibitors
SGLT1 is essential for glucose, galactose and water uptake from the intestine, and its inhibitors have broad therapeutic potential. Here, the authors describe the cryo-EM structure of human SGLT1 in complex with an inhibitor.
- Yange Niu
- , Wenhao Cui
- & Lei Chen
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Article
| Open AccessHepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
- Ying Yan
- , Zhoumin Niu
- & Hao Ying
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Article
| Open AccessThe type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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Article
| Open AccessFunctional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes
Here, by performing multi-omics microbiome analyses in a cohort of children with new-onset T1D, the authors characterize altered microbial functional and metabolic traits involved in T1D, which they validate in animal experiments, together providing potential avenues for microbiome-based interventions.
- Xiaoxiao Yuan
- , Ruirui Wang
- & Feihong Luo
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| Open AccessThe metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial
Combining a GLP-1 receptor agonist, to increase endogenous beta cell function, with exogenous insulin is a possible therapeutic option for the treatment of type 2 diabetes. Here, the authors show adding exenatide to basal insulin in early type 2 diabetes does not further enhance underlying pancreatic beta-cell function or the capacity to achieve diabetes remission, but may yield on-treatment glycemic benefits.
- Ravi Retnakaran
- , Chang Ye
- & Bernard Zinman
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Article
| Open AccessPhosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling
The insulin signalling cascade can be inhibited by phosphatases, including Ser/Thr protein phosphatase 2A (PP2A). Here the authors show that Alpha4, a regulator of the PP2A catalytic subunit, modulates insulin receptor tyrosine phosphorylation via the YBX-1/PTP1B pathway and is involved in maintenance of adipose tissue homeostasis and systemic metabolism.
- Masaji Sakaguchi
- , Shota Okagawa
- & Eiichi Araki
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| Open AccessA predictive computational platform for optimizing the design of bioartificial pancreas devices
Transplanting encapsulated insulin-producing cells may achieve a functional cure for type 1 diabetes, but efficacy is constrained by mass transfer limits. Here, the authors report a dynamic computational platform to investigate the therapeutic potency of such programmable bioartificial pancreas devices.
- Alexander U. Ernst
- , Long-Hai Wang
- & Minglin Ma
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Article
| Open AccessReducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
Retinal pigment epithelium (RPE) plays an important role in diabetic retinopathy (DR) progression. Here, the authors show AKT1 and AKT2 are reciprocally regulated in the RPE of DR donor tissue and diabetic mice, reducing Akt2 in RPE causing a compensatory increase in Akt1 and attenuating DR.
- Haitao Liu
- , Nadezda A. Stepicheva
- & Debasish Sinha
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| Open AccessDeletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice
Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.
- Takayoshi Sasako
- , Toshihiro Umehara
- & Kohjiro Ueki
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Article
| Open AccessLipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion
During hypoglycemia, glucagon secretion is part of the mechanism needed to restore normal blood glucose levels. Here, Strembitska et al. report that sensing of hypoglycemia by AgRP neurons requires Agpat5, an enzyme which prevents fatty acids from entering the mitochondria for ATP production, ensuring correct neuronal activation and glucagon secretion.
- Anastasiya Strembitska
- , Gwenaël Labouèbe
- & Bernard Thorens
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Article
| Open AccessDiabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder
Patients with diabetes have an increased susceptibility to infections. Here the authors show that high glucose impairs innate immunity through reduced levels of the antimicrobial peptide psoriasin and impaired epithelial barrier function, resulting in an increased risk of urinary tract infection.
- Soumitra Mohanty
- , Witchuda Kamolvit
- & Annelie Brauner
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open AccessEarly macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.
- L. Orliaguet
- , T. Ejlalmanesh
- & F. Alzaid
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| Open AccessAdipocytes control food intake and weight regain via Vacuolar-type H+ ATPase
Energy metabolism is dysregulated in obesity, and some if these changes persist after weight loss and may contribute to weight regain. Here the authors report that a vacuolar-type H+ ATPase, ATP6v0a1, is induced in adipocytes during obesity and persists after weight loss, and regulates food intake and weight gain in C. elegans and mice.
- Rizaldy C. Zapata
- , Maria Carretero
- & Olivia Osborn
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| Open AccessA Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes
Children with type 1 diabetes (T1D) are at risk for reduced cognitive ability and atypical brain development. This study shows that brain and cognitive measures can be improved in adolescents with T1D using a semi-automated insulin delivery system.
- Allan L. Reiss
- , Booil Jo
- & Juan Marrero
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| Open AccessAdaptation to chronic ER stress enforces pancreatic β-cell plasticity
Pancreatic β-cells are naturally prone to ER stress due to their role in insulin production and secretion. Here, the authors show that chronic ER stress adaptive exhaustion results in an irreversible loss of β-cell function leading to T1D pathogenesis
- Chien-Wen Chen
- , Bo-Jhih Guan
- & Maria Hatzoglou
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Article
| Open AccessMaladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
ChREBP is a glucose-responsive transcription factor, which regulates glucose-mediated proliferation and cell death in pancreatic β-cells. Here the authors show that the acute feed forward induction of ChREBPβ is required for adaptive β-cell expansion, that chronic overexpression of ChREBPβ is toxic to β-cells, and offer mitigation strategies
- Liora S. Katz
- , Gabriel Brill
- & Donald K. Scott
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| Open AccessPhenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ
Whether amino acids act on cellular insulin signaling remains unclear. Here, the authors find that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake and positively correlated with T2D onset.
- Qian Zhou
- , Wan-Wan Sun
- & Shi-Min Zhao
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| Open AccessA critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells
Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.
- Yingying Ye
- , Mohammad Barghouth
- & Erik Renström
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| Open AccessZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes
Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.
- Qing Ma
- , Yini Xiao
- & Weida Li
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| Open AccessHepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis
Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin.
- Gloria Ursino
- , Giorgio Ramadori
- & Roberto Coppari
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Article
| Open AccessRegulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor
Insulin sensitivity declines with age via unclear mechanisms. Here, the authors show that the activity of membrane type 1 matrix metalloproteinase (MT1-MMP) is increased with ageing, leading to cleavage of the insulin receptor, and show that metabolic effects can be rescued by MT1-MMP inhibition in mice.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessA phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes
Glucagon-like peptide-1 receptor (GLP1R) agonists are used to treat type 2 diabetes (T2D), and polyagonists targeting multiple hormone receptors are investigated as potential therapeutics for T2D. Here the authors report that IBI362 (LY3305677), a balanced once-weekly GLP-1 and glucagon receptor dual agonist, showed favourable safety and tolerability in Chinese patients with type 2 diabetes in a randomized controlled phase 1b clinical trial.
- Hongwei Jiang
- , Shuguang Pang
- & Wenying Yang
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Article
| Open AccessIslet autoantibody seroconversion in type-1 diabetes is associated with metagenome-assembled genomes in infant gut microbiomes
Here, by characterizing gut metagenomes of at-risk children in the TEDDY project, the authors associate onset of autoimmunity leading to Type-1 diabetes with certain sets of microorganisms in the gut microbiota, and identify metabolic capabilities encoded in the genomes of these microorganisms that provide functional insights to the association.
- Li Zhang
- , Karen R. Jonscher
- & Chongle Pan
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Article
| Open AccessMicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake
The microRNA miR-21 is induced in the islets of patients with glucose intolerance and diabetic mice. Here the authors report that deletion of miR-21 in pancreatic β-cells impairs glucose-stimulated insulin secretion via reduced glucose uptake, while a miR-21 agomir reduces blood glucose leves in diabetic male mice.
- Ruiling Liu
- , Cuilian Liu
- & Qingguo Ruan
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Article
| Open AccessA randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes
Evidence from preclinical models suggest that lowering levels of branched chain amino acids (BCAA) improves glucose metabolism. Here the authors report that NaPB, an accelerator of BCAA catabolism, improves peripheral insulin sensitivity in patients with type 2 diabetes in a randomized placebo-controlled crossover clinical trial.
- Froukje Vanweert
- , Michael Neinast
- & Esther Phielix
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Article
| Open AccessAdipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling
Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.
- Teng Huang
- , Jia Song
- & Cong-Yi Wang
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Article
| Open AccessMultiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice
Adipose immune cells contribute to obesity-related disease, but less is known about weight cycling. Here, authors show that weight loss reduces diabetes risk, but inflammatory adipose immune cell populations persist and may contribute to worsened diabetes risk upon weight regain.
- Matthew A. Cottam
- , Heather L. Caslin
- & Alyssa H. Hasty
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Article
| Open AccessStructural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.
- Mengmeng Wang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessMitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis
Sidarala et al. examine the importance of the mitochondrial structural proteins, Mitofusins 1 and 2 (Mfn1/2), in diabetes. They find that Mfn1/2 control blood glucose by preserving mitochondrial DNA content, rather than mitochondrial structure.
- Vaibhav Sidarala
- , Jie Zhu
- & Scott A. Soleimanpour
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Article
| Open AccessA parallel randomised controlled trial of the Hypoglycaemia Awareness Restoration Programme for adults with type 1 diabetes and problematic hypoglycaemia despite optimised self-care (HARPdoc)
Impaired awareness of hypoglycaemia (IAH) is a risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). Here the authors report that a group programme focussing on changing cognitive barriers to avoiding hypoglycaemia (HARPdoc) does not reduce severe hypoglycaemia more than a programme focussing on behaviours (BGAT) in a randomized control trial in adults with T1D and treatment-resistant IAH and severe hypoglycaemia.
- Stephanie A. Amiel
- , Laura Potts
- & Nicole de Zoysa
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Article
| Open AccessGlycaemic control is associated with SARS-CoV-2 breakthrough infections in vaccinated patients with type 2 diabetes
In this study, Marfella et al. show that patients with diabetes and poor glycaemic control have a blunted response to COVID-19 vaccine and are more prone to develop breakthrough infections, with further analysis suggesting smoking and male sex as potential risk factors to get COVID-19 despite vaccination.
- Raffaele Marfella
- , Celestino Sardu
- & Giuseppe Paolisso
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Article
| Open AccessGeneration of human islet cell type-specific identity genesets
Cell therapy to replace β-cells is a potential therapeutic avenue to treat diabetes, but the production of insulin-secreting replacement cells requires reliable tools to assess islet cellular identity. Here the authors use single-cell transcriptomics meta-analysis to construct gene sets that describe the identity of human α-, β-, γ- and δ-cells.
- Léon van Gurp
- , Leon Fodoulian
- & Pedro L. Herrera
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Article
| Open AccessInsulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis
The downstream mechanisms involved in insulin signaling and resistance remain incompletely understood. Here the authors report that insulin-dependent dephosphorylation stabilizes ERRα via the GSK3β/FBXW7 axis, and disruption of this post-translational mechanism results in insulin resistance in mice.
- Hui Xia
- , Charlotte Scholtes
- & Vincent Giguère
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Article
| Open AccessCitrullination of glucokinase is linked to autoimmune diabetes
Post translational modifications are involved in the regulation of a number of proteins and can be themselves modified by the cellular environment. Here the authors implicate citrullination of glucokinase in autoimmune diabetes
- Mei-Ling Yang
- , Sheryl Horstman
- & Mark J. Mamula