Alaina P Vidmar, Ramon Durazo-Arvizu, Marc J Weigensberg, Tanya L Alderete, Michael I Goran
Youth onset type 2 diabetes (T2D) is becoming increasingly prevalent especially among Latinos, and there is limited information on its pathophysiology and causative factors. Here we describe findings from a longitudinal cohort study in 262 Latino children with overweight/obesity at risk of developing T2D with annual measures of oral and intravenous glucose tolerance (IVGTT), body composition and fat distribution. Logistic binomial regression was used to identify significant predictors in those who developed T2D compared to matched controls, and mixed-effects growth models to compare rates of change in metabolic versus adiposity measures between groups...
March 27, 2023: Diabetes
Farhan M Qureshi, Julia K Panzer, Janika Põder, Thomas R Malek, Alejandro Caicedo
Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic period, there is a chronic decline in beta cell function that has long-term implications for disease pathogenesis...
March 20, 2023: Diabetes
Qian Ren, Ping Zhang, Wuyan Pang, Yumin Ma, Siqian Gong, Tianhao Ba, Wei Liu, Fang Zhang, Xiuying Zhang, Rui Zhang, Xiangqing Wang, Xiaomei Zhang, Wenjia Yang, Fang Lv, Leili Gao, Xueyao Han, Linong Ji
Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY) exhibits the unique clinical features of mild fasting hyperglycaemia. However, formal studies of its glucose excursion pattern in daily life in comparison with those with or without other types of diabetes are lacking. We conducted a case-control study including 25 patients with GCK-MODY, 25 A1c-matched, drug naive patients with type 2 diabetes (T2DM) and 25 age-, BMI- and sex-matched subjects with normal glucose tolerance (NGT). All the subjects wore flash glucose monitoring (FGM) sensors for 2 weeks, and glucose readings were masked...
March 20, 2023: Diabetes
Vuong M Pham, Prashanth Komirishetty, Aparna Areti, Trevor Poitras, Nitish Thakor, Douglas W Zochodne
Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. Here we hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells in vitro and chronic Type 1 DPN in mice. IR (insulin receptor) expression was not altered by high glucose conditions in neurons or SCs and insulin promoted survival of neurons and proliferation of SCs in vitro...
March 17, 2023: Diabetes
Finny Monickaraj, Gabriella Acosta, Andrea P Cabrera, Arup Das
Inflammation plays an important role in the pathogenesis of diabetic retinopathy (DR). To precisely define the inflammatory mediators, we examined the transcriptomic profile of human retinal endothelial cells exposed to advanced glycation end products which revealed the neutrophil chemoattractant chemokine, CXCL1 as one of the top genes upregulated. The effect of neutrophils in the alteration of BRB was further assessed in wildtype C57BL/6J mice intravitreally injected with recombinant CXCL1 as well as in streptozotocin-induced diabetic mice...
March 17, 2023: Diabetes
Darling Rojas-Canales, Stacey N Walters, Daniella Penko, Daniele Cultrone, Jacqueline Bailey, Tatyana Chtanova, Jodie Nitschke, Julie Johnston, Svjetlana Kireta, Thomas Loudovaris, Thomas W Kay, Tim R Kuchel, Wayne Hawthorne, Philip J O'Connell, Greg Korbutt, John E Greenwood, Shane T Grey, Chris J Drogemuller, P Toby Coates
Intra-hepatic islet transplantation for type-1 diabetes is limited by the need for multiple infusions and poor islet viability post-transplantation. The development of alternative transplantation sites is necessary to improve islet survival, and facilitate monitoring and retrieval. We tested a clinically proven Biodegradable Temporizing Matrix (BTM), a polyurethane-based scaffold, to generate a well vascularized intracutaneous "neo-dermis" within the skin for islet transplantation. In murine models, BTM did not impair syngeneic islet renal-subcapsular transplant viability or function, and facilitated diabetes cure for over 150 days...
March 16, 2023: Diabetes
Rebecca K Davidson, Sukrati Kanojia, Wenting Wu, Tatsuyoshi Kono, Jerry Xu, Meredith Osmulski, Robert N Bone, Nolan Casey, Carmella Evans-Molina, Emily K Sims, Jason M Spaeth
Pdx1:Chd4 interactions were previously shown to be compromised in β-cells from human donors with type 2 diabetes. β-cell-specific removal of Chd4 impairs insulin secretion and leads to glucose intolerance in mice. Expression of key β-cell functional genes and chromatin accessibility are compromised in Chd4-deficient β-cells. Chromatin remodeling activities enacted by Chd4 are essential for β-cell function under normal physiological conditions.
March 13, 2023: Diabetes
Kim Z Rokamp, Flemming Dela, Niels H Secher, Lars Grønlykke, Birger Thorsteinsson, Ulrik Pedersen-Bjergaard
This study investigates the impact of the β2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Healthy male subjects being homozygous for either Gly16 (GG; n=12) or Arg16 (AA; n=13) participated in the study. Healthy people with the GG genotype have increased metabolic response to epinephrine, compared to the AA genotype, but without difference between genotype groups after repetitive hypoglycemia.
March 13, 2023: Diabetes
Lifang Xie, Wanling Lu, Yanhan Zhang, Lu Deng, Ming Liu, Hong Gao, Chunguang Xie, Gang Wang
We undertake this study to establish a glucose-responsive SIA self-supply system in vivo. Whether ER can serve as a safe and temporary repository to store designed fusion proteins and release SIAs under hyperglycemia condition for efficient blood glucose regulation. Intramuscularly expressed plasmid-encoded CAD-FCS-SIA fusion protein can be temporarily stored in ER and SIA can be released under the stimulation of hyperglycemia, resulting in efficient and long-term regulation of blood glucose stable in T1D mice...
March 13, 2023: Diabetes
Tianjiao Wei, Xiaona Cui, Yafei Jiang, Kangli Wang, Dandan Wang, Fei Li, Xiafang Lin, Liangbiao Gu, Kun Yang, Jin Yang, Tianpei Hong, Rui Wei
Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide-1 (GLP-1) secretion, and notably promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism-induced β-cell regeneration. We showed that in db/db mice and type 1 diabetic wild-type or Flox/cre mice, GCGR monoclonal antibody (mAb) improved glucose control, upregulated plasma insulin level, and increased β-cell area...
February 24, 2023: Diabetes
Stavroula Dionysopoulou, Per Wikstrom, Claudio Bucolo, Giovanni Luca Romano, Vincenzo Micale, Richard Svensson, Dimitris Spyridakos, Niki Mastrodimou, Spiros Georgakis, Panayotis Verginis, Erik Walum, Kyriaki Thermos
NADPH oxidases (NOX) are major players in generating reactive oxygen species (ROS), implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of NOX4 inhibitor (GLX7013114), in two in vivo experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Diabetic-treated animals received GLX7013114 topically (20μl/eye, 10mg/ml, once daily), for 14d (Paradigm A/preventive) and 7d (Paradigm B/treated), 48hr and four wks post STZinjection, respectively...
February 23, 2023: Diabetes
Yuxia Zhou, Lu Liu, Bangming Jin, Yixuan Wu, Lifen Xu, Xuebing Chang, Laying Hu, Guifang Wang, Yali Huang, Lingyu Song, Tian Zhang, Yuanyuan Wang, Ying Xiao, Fan Zhang, Mingjun Shi, Lingling Liu, Tuanlao Wang, Rui Yan, Bing Guo
Ectopic lipid accumulation in renal tubules is closely related to the pathogenesis of diabetic kidney disease (DKD) and mitochondrial dysfunction is thought to play a key role in lipid accumulation. Therefore, maintaining mitochondrial homeostasis holds considerable promise as therapeutic strategies for the treatment of DKD. Here we reported that Meteorin-like (Metrnl) gene product mediates lipid accumulation in the kidney and has therapeutic potential for DKD. We confirmed the reduced expression of Metrnl in renal tubules, which was inversely correlated with DKD pathological changes in patients and mouse models...
February 22, 2023: Diabetes
Heather L Petrick, Leslie M Ogilvie, Henver S Brunetta, Avery Robinson, Aleah J Kirsh, Pierre-Andre Barbeau, Rachel M Handy, Bridget Coyle-Asbil, Connor Gianetto-Hill, Kaitlyn M J H Dennis, Luc J C van Loon, Adrian Chabowski, Jonathan D Schertzer, Emma Allen-Vercoe, Jeremy A Simpson, Graham P Holloway
Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined if dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities...
February 22, 2023: Diabetes
Kenneth E Westerman, Maura E Walker, Sheila M Gaynor, Jennifer Wesse, Daniel DiCorpo, Jiantao Ma, Alvaro Alonso, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Mary L Biggs, Jennifer A Brody, Yii-Der Ida Chen, Joseé Dupuis, Mark O Goodarzi, Xiuqing Guo, Natalie R Hasbani, Adam Heath, Bertha Hidalgo, Marguerite R Irvin, W Craig Johnson, Rita R Kalyani, Leslie Lange, Rozenn N Lemaitre, Ching-Ti Liu, Simin Liu, Jee-Young Moon, Rami Nassir, James S Pankow, Mary Pettinger, Laura Raffield, Laura J Rasmussen-Torvik, Elizabeth Selvin, Mackenzie K Senn, Aladdin H Shadyab, Albert V Smith, Nicholas L Smith, Lyn Steffen, Sameera Talegakwar, Kent D Taylor, Paul S de Vries, James G Wilson, Alexis C Wood, Lisa R Yanek, Jie Yao, Yinan Zheng, Eric Boerwinkle, Alanna C Morrison, Miriam Fornage, Tracy P Russell, Bruce M Psaty, Daniel Levy, Nancy L Heard-Costa, Vasan S Ramachandran, Rasika A Mathias, Donna K Arnett, Robert Kaplan, Kari E North, Adolfo Correa, April Carson, Jerome I Rotter, Stephen S Rich, JoAnn E Manson, Alexander P Reiner, Charles Kooperberg, Jose C Florez, James B Meigs, Jordi Merino, Deirdre K Tobias, Han Chen, Alisa K Manning
Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed N=33,187 diabetes-free participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data...
February 15, 2023: Diabetes
Héléne T Cronjé, Michael Y Mi, Thomas R Austin, Mary L Biggs, David S Siscovick, Rozenn N Lemaitre, Bruce M Psaty, Russell P Tracy, Luc Djoussé, Jorge R Kizer, Joachim H Ix, Prashant Rao, Jeremy M Robbins, Jacob L Barber, Mark A Sarzynski, Clary B Clish, Claude Bouchard, Kenneth J Mukamal, Robert E Gerszten, Majken K Jensen
High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan® proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (CHS, N=2,631), and IVGTT-derived measures in participants from the HERITAGE Family Study (N=752)...
February 7, 2023: Diabetes
Nelly Saber, Cara E Ellis, Diepiriye G Iworima, Robert K Baker, Alireza Rezania, Timothy J Kieffer
Few studies have examined the differentiation of human embryonic stem cell (hESC)-derived pancreatic endoderm cells (PECs) in different implantation sites. Here, we investigate the influence of implantation site and recipient sex on the differentiation of hESC-derived PECs in vivo. Male and female mice were implanted with 5x106 hESC-derived PECs either under the kidney capsule, in the gonadal fat pad, or subcutaneously within macroencapsulation (TheraCyteTM) devices. Mice that received PECs within TheraCyteTM devices developed glucosestimulated human C-peptide secretion faster than cells implanted under the kidney capsule or in the gonadal fat pad...
February 6, 2023: Diabetes
Yiruo Ma, Siyi Shen, Ying Yan, Shengjie Zhang, Shengnan Liu, Zhili Tang, Jing Yu, Mei Ma, Zhoumin Niu, Zhuoyang Li, Yuting Wu, Lin Zhao, Zhiqiang Lu, Chunchun Wei, Weiping J Zhang, Ying Xue, Qiwei Zhai, Yu Li, Cheng Hu, Jingjing Jiang, Yuying Li, Hao Ying
Thyroid hormone (TH) has a profound effect on energy metabolism and systemic homeostasis. Adipose tissues are crucial for maintaining whole-body homeostasis, however, whether TH regulates systemic metabolic homeostasis through its action on the adipose tissues is unclear. Here, we demonstrate that systemic administration of triiodothyronine (T3), the active form of TH, affects both inguinal white adipose tissue (iWAT) and whole-body metabolism. Taking advantage of the mouse model lacking adipocyte TH receptor α (TRα) or β (TRβ) we show that TRβ is the major TR isoform that mediates the T3 action on the expression of genes involved in multiple metabolic pathways in iWAT, including glucose uptake and usage, de novo fatty acid synthesis, and both UCP1-dependent and -independent thermogenesis...
February 1, 2023: Diabetes
Rachel Njeim, Kawthar Braych, Hilda E Ghadieh, Nadim S Azar, William S Azar, Batoul Dia, Angelo Leone, Francesco Cappello, Hala Kfoury, Frederic Harb, Abdo R Jurjus, Assaad A Eid, Fuad N Ziyadeh
Diabetes is associated with decreased epoxyeicosatrienoic acids (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase (sEH) inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the crosstalk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin (STZ)-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of AUDA in drinking water for 6 weeks...
January 20, 2023: Diabetes
Sevda Gheibi, Luis Rodrigo Cataldo, Alexander Hamilton, Mi Huang, Sebastian Kalamajski, Malin Fex, Hindrik Mulder
Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was most markedly downregulated...
January 20, 2023: Diabetes
Mattia Albiero, Stefano Ciciliot, Anna Rodella, Ludovica Migliozzi, Francesco Ivan Amendolagine, Carlotta Boscaro, Gaia Zuccolotto, Antonio Rosato, Gian Paolo Fadini
Innate immune cells infiltrate growing adipose and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by Oncostatin M (OSM) in the metabolic consequences of overfeeding is debated at least in part because prior studies did not distinguish OSM sources and dynamics. Here, we explored the role of OSM in metabolic responses and used bone marrow transplantation to test the hypothesis that hematopoietic cells are major contributors to the metabolic effects of OSM...
January 19, 2023: Diabetes
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