Diabetes最新文献_第3页

Brain Defense of Glycemia in Health and Diabetes 健康和糖尿病患者大脑对血糖的防御能力

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-14 DOI: 10.2337/dbi24-0001

Zaman Mirzadeh, Chelsea Faber

引用次数: 0

Role of Sec61α2 translocon in insulin biosynthesis Sec61α2 转座子在胰岛素生物合成中的作用

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-26 DOI: 10.2337/db24-0115

Xiaoxi Xu, Thomas W. Bell, Truc Le, Ivy Zhao, Emily Walker, Yiqing Wang, Ning Xu, Scott A. Soleimanpour, Holger A. Russ, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan

{"title":"Role of Sec61α2 translocon in insulin biosynthesis","authors":"Xiaoxi Xu, Thomas W. Bell, Truc Le, Ivy Zhao, Emily Walker, Yiqing Wang, Ning Xu, Scott A. Soleimanpour, Holger A. Russ, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan","doi":"10.2337/db24-0115","DOIUrl":"https://doi.org/10.2337/db24-0115","url":null,"abstract":"Translocational regulation of proinsulin biosynthesis in pancreatic β-cells is unknown, although several studies have reported an important accessory role for the Translocon-Associated Protein complex to assist preproinsulin delivery into the endoplasmic reticulum via the heterotrimeric Sec61 translocon (comprised of α, β, and γ subunits). The actual protein-conducting channel is the α–subunit encoded either by Sec61A1 or its paralog Sec61A2. Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61α to date have focused on Sec61α1. There is currently no evidence to suggest that this gene product plays a major role in proinsulin production, whereas genome-wide association studies indicate linkage of Sec61A2 with diabetes. Here, we report that evolutionary differences in mouse preproinsulin signal peptides affect proinsulin biosynthesis. Moreover, we find that although some preproinsulin translocation can proceed through Sec61α1, Sec61α2 has a greater impact on proinsulin biosynthesis in pancreatic β-cells. Remarkably, Sec61α2-translocon deficiency exerts a significant inhibitory effect on the biosynthesis of preproinsulin itself, including a disproportionate increase of full-length nacent chain unreleased from ribosomes. This study not only reveals novel translocational regulation of proinsulin biosynthesis, but also provides a rationale for genetic evidence suggesting an important role of Sec61α2 in maintaining blood glucose homeostasis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"39 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in obese male mice 血红蛋白-aptoglobin 受体 CD163 的缺失会降低肥胖雄性小鼠对胰岛素的敏感性

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-26 DOI: 10.2337/db24-0405

Michael W. Schleh, Magdalene Ameka, Alec Rodriguez, Hasty Alyssa H.

{"title":"Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in obese male mice","authors":"Michael W. Schleh, Magdalene Ameka, Alec Rodriguez, Hasty Alyssa H.","doi":"10.2337/db24-0405","DOIUrl":"https://doi.org/10.2337/db24-0405","url":null,"abstract":"Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles including managing inflammatory tone and regulating parachymal iron homeostasis; thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages, and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Further, CD163 deficiency mediated a pro-inflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+CD11B− non-myeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimised proteomic analysis of insulin granules from MIN6 cells identifies Scamp3, a novel regulator of insulin secretion and content. 对 MIN6 细胞胰岛素颗粒的优化蛋白质组分析发现了胰岛素分泌和含量的新型调节因子 Scamp3。

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0355

Nicholas Norris, Belinda Yau, Carlo Famularo, Hayley Webster, Thomas Loudovaris, Helen E. Thomas, Mark Larance, Alistair M. Senior, Melkam A. Kebede

{"title":"Optimised proteomic analysis of insulin granules from MIN6 cells identifies Scamp3, a novel regulator of insulin secretion and content.","authors":"Nicholas Norris, Belinda Yau, Carlo Famularo, Hayley Webster, Thomas Loudovaris, Helen E. Thomas, Mark Larance, Alistair M. Senior, Melkam A. Kebede","doi":"10.2337/db24-0355","DOIUrl":"https://doi.org/10.2337/db24-0355","url":null,"abstract":"Pancreatic β-cells in the Islets of Langerhans are key to maintaining glucose homeostasis, by secreting the peptide hormone insulin. Insulin is packaged within vesicles named insulin secretory granules (ISGs), that have recently been considered to have intrinsic structures and proteins that regulate insulin granule maturation, trafficking, and secretion. Previously, studies have identified a handful of novel ISG-associated proteins using different separation techniques. Here, this study combines an optimized ISG isolation technique and mass spectrometry-based proteomics, with an unbiased protein correlation profiling and targeted machine learning approach to uncover 211 ISG-associated proteins with confidence. Four of these proteins: Syntaxin-7, Synaptophysin, Synaptotagmin-13 and Scamp3 have not been previously ISG-associated. Through colocalization analysis of confocal imaging we validate the association of these proteins to the ISG in MIN6 and human β-cells. We further validate the role for one (Scamp3) in regulating insulin content and secretion from β-cells for the first time. Scamp3 knock-down INS-1 cells show a reduction in insulin content and dysfunctional insulin secretion. These data provide the basis for future investigation of Scamp3 in β-cell biology and the regulation of insulin secretion.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microglia Mediate Metabolic Dysfunction from Common Air Pollutants through NF-κB Signaling 小胶质细胞通过 NF-κB 信号介导常见空气污染物造成的代谢功能障碍

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0110

Lucas K. Debarba, Hashan S.M. Jayarathne, Lukas Stilgenbauer, Ana L.Terra dos Santos, Lisa Koshko, Sydney Scofield, Ryan Sullivan, Abhijit Mandal, Ulrike Klueh, Marianna Sadagurski

{"title":"Microglia Mediate Metabolic Dysfunction from Common Air Pollutants through NF-κB Signaling","authors":"Lucas K. Debarba, Hashan S.M. Jayarathne, Lukas Stilgenbauer, Ana L.Terra dos Santos, Lisa Koshko, Sydney Scofield, Ryan Sullivan, Abhijit Mandal, Ulrike Klueh, Marianna Sadagurski","doi":"10.2337/db24-0110","DOIUrl":"https://doi.org/10.2337/db24-0110","url":null,"abstract":"The prevalence of Type 2 Diabetes (T2D) poses a significant health challenge yet the contribution of air pollutants to T2D epidemics remains understudied. Several studies demonstrated a correlation between exposure to volatile organic compounds (VOCs) in indoor/outdoor environments, and T2D. Here, we conducted the first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages. We utilized a controlled benzene exposure system, continuous glucose monitoring (CGM) approach and indirect calorimetry in mice, to investigate the underlying mechanisms. Following exposure, disruptions in energy homeostasis, accompanied by modifications in the hypothalamic transcriptome and alterations in insulin and immune signaling, were observed exclusively in males, leading to a surge in blood glucose levels. In agreement, RNA-sequencing of microglia reveals increased expression of genes associated with immune response and NF-κB signaling. Selective ablation of IKKβ in immune cells (Cx3cr1GFPΔIKK) or exclusively in microglia (Tmem119ERΔIKK) in adult mice alleviated benzene-induced gliosis, restored energy homeostasis, hypothalamic gene expression, and protected against hyperglycemia. We conclude that the microglial NF-κB pathway plays a critical role in chemical-induced metabolic disturbances, revealing a vital pathophysiological mechanism linking exposure to airborne toxicants and the onset of metabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Podocyte-Specific Expression of the Stress Response Protein REDD1 is Necessary for Diabetes-induced Podocytopenia 应激反应蛋白 REDD1 在荚膜细胞中的特异性表达是糖尿病诱导的荚膜细胞减少症的必要条件

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0533

Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, Han Chen, Yandong Zhou, Donald L. Gill, Scot R. Kimball, Michael D. Dennis

{"title":"Podocyte-Specific Expression of the Stress Response Protein REDD1 is Necessary for Diabetes-induced Podocytopenia","authors":"Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, Han Chen, Yandong Zhou, Donald L. Gill, Scot R. Kimball, Michael D. Dennis","doi":"10.2337/db24-0533","DOIUrl":"https://doi.org/10.2337/db24-0533","url":null,"abstract":"Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (Regulated in Development and DNA Damage 1) contributes to the development of diabetic complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted NF-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity 小胶质细胞衍生的原粒细胞蛋白胞外裂解促进饮食诱导的肥胖症

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-20 DOI: 10.2337/db24-0097

Chae Beom Park, Chan Hee Lee, Kae Won Cho, Sunghun Shin, Won Hee Jang, Junyeong Byeon, Yu Rim Oh, Sung Jun Kim, Jae Woo Park, Gil Myoung Kang, Se Hee Min, Seyun Kim, Rina Yu, Min-Seon Kim

{"title":"Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity","authors":"Chae Beom Park, Chan Hee Lee, Kae Won Cho, Sunghun Shin, Won Hee Jang, Junyeong Byeon, Yu Rim Oh, Sung Jun Kim, Jae Woo Park, Gil Myoung Kang, Se Hee Min, Seyun Kim, Rina Yu, Min-Seon Kim","doi":"10.2337/db24-0097","DOIUrl":"https://doi.org/10.2337/db24-0097","url":null,"abstract":"Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily -conserved secretory protein containing seven-and-a-half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, that encodes PGRN. Mice with microglia-specific Grn gene depletion displayed dietdependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn gene depletion produced adverse outcomes like fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appear linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating dietinduced obesity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CRTC1 in Mc4r-expressing cells is required for peripheral metabolism and systemic energy homeostasis Mc4r表达细胞中的CRTC1是外周代谢和全身能量平衡所必需的

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-12 DOI: 10.2337/db24-0014

Haruka Miyamori, Takumi Yokokawa, Motoki Miyakita, Kazuki Ozaki, Tsuyoshi Goto, Kazuo Inoue, Shigenobu Matsumura

{"title":"CRTC1 in Mc4r-expressing cells is required for peripheral metabolism and systemic energy homeostasis","authors":"Haruka Miyamori, Takumi Yokokawa, Motoki Miyakita, Kazuki Ozaki, Tsuyoshi Goto, Kazuo Inoue, Shigenobu Matsumura","doi":"10.2337/db24-0014","DOIUrl":"https://doi.org/10.2337/db24-0014","url":null,"abstract":"Melanocortin-4-receptor (Mc4r) is a G protein-coupled receptor (GPCR) that controls systemic energy balance by regulating food intake and energy expenditure. Although the detailed molecular mechanism remains unclear, the activation of cAMP signaling in Mc4r-expressing cells reportedly suppresses food intake and increases energy expenditure. cAMP-responsive element-binding protein-regulated transcriptional co-activator-1 (CRTC1) is selectively expressed in neuronal cells and participates in transcriptional control, thereby contributing to neuronal plasticity and energy homeostasis. Considering the cAMP-dependent regulation of CRTC1 activity, CRTC1 in Mc4r- expressing cells may contribute to energy balance regulation through the melanocortin pathway. In this context, we examined the physiological contribution of CRTC1 in Mc4r-expressing cells to energy metabolism. In this study, mice with CRTC1 deficiency in Mc4r-expressing cells exhibited 1) modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia; 2) decreased systemic energy expenditure and thermogenesis; 3) suppression of melanocortin agonist-induced adaptation of energy expenditure and food intake; 4) impaired thermogenic programs and oxidative pathway in brown adipose tissue and skeletal muscle; and 5) enhanced lipogenic programs in the liver and white adipose tissue. These results provide novel insights into the molecular mechanisms underlying the regulation of energy balance by the melanocortin system.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of Weight Loss on Skeletal Muscle Bioactive Lipids in People with Obesity and Type 2 Diabetes 减肥对肥胖症和 2 型糖尿病患者骨骼肌生物活性脂质的影响

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-12 DOI: 10.2337/db24-0083

Max C. Petersen, Mihoko Yoshino, Gordon I. Smith, Rafael C. Gaspar, Mario Kahn, Dmitri Samovski, Gerald I. Shulman, Samuel Klein

{"title":"Effect of Weight Loss on Skeletal Muscle Bioactive Lipids in People with Obesity and Type 2 Diabetes","authors":"Max C. Petersen, Mihoko Yoshino, Gordon I. Smith, Rafael C. Gaspar, Mario Kahn, Dmitri Samovski, Gerald I. Shulman, Samuel Klein","doi":"10.2337/db24-0083","DOIUrl":"https://doi.org/10.2337/db24-0083","url":null,"abstract":"Muscle sn-1,2-diacylglycerol (DAG) and C18:0 ceramide accumulation in sarcolemmal and mitochondrial compartments have been proposed to regulate muscle insulin sensitivity. Here, we evaluated whether weight loss-induced improvements in insulin sensitivity were associated with changes in muscle sn-1,2-DAG and ceramide content in people with obesity and type 2 diabetes. We measured skeletal muscle insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion, and skeletal muscle sn-1,2-DAG and ceramide contents by using liquid chromatography-tandem mass spectrometry after subcellular fractionation and DAG isomer separation in 14 adults with obesity and type 2 diabetes before and after marked (18.6 ± 2.1%) weight loss. Whole-body insulin sensitivity doubled after weight loss. Sarcolemmal sn-1,2-DAG and C18:0 ceramide contents after weight loss were not different than values before weight loss. In contrast, mitochondrial/ER C18:0 ceramide content decreased by ∼20% after weight loss (from 2.16 ± 0.08 to 1.71 ± 0.13 nmol/g, P&lt;0.005). These results suggest a decrease in muscle mitochondrial/ER C18:0 ceramide content could contribute to the beneficial effect of weight loss on skeletal muscle insulin sensitivity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"73 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study 单剂量磷脂酰肌醇-3-激酶抑制剂 Alpelisib 可诱导健康成人的胰岛素抵抗：随机可行性研究

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-12 DOI: 10.2337/db24-0402

Joshua R. Cook, Nur Bedeir, Zachary D. Sone, Julia Wattacheril, Henry N. Ginsberg, Blandine Laferrère

{"title":"A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study","authors":"Joshua R. Cook, Nur Bedeir, Zachary D. Sone, Julia Wattacheril, Henry N. Ginsberg, Blandine Laferrère","doi":"10.2337/db24-0402","DOIUrl":"https://doi.org/10.2337/db24-0402","url":null,"abstract":"Our objective is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center, double-blind, phase 1 clinical trial randomized healthy adults to take a single oral dose of alpelisib 300 mg (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans. (ClinicalTrials.gov registration: NCT05733455)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"33 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0