Felix Keller, Stefan Schunk, Sara Denicolò, Samir Sharifli, Stefanie Thöni, Susanne Eder, Johannes Leierer, Hiddo J.L. Heerspink, Patrick B. Mark, László Rosivall, Andrzej Wiecek, Gert Mayer, Danilo Fliser
Accurate prediction of diabetic kidney disease progression is challenging, but mandatory. Urinary Dickkopf-3 (uDKK3), a tubular, epithelial-derived glycoprotein and marker of tubular injury, is a promising biomarker for kidney function decline. We explored the clinical utility of uDKK3 to predict kidney function decline and adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM) in a primary health care setting. In this cohort study, 3,232 patients with T2DM were analyzed. The primary end point was a composite of a sustained estimated glomerular filtration rate (eGFR) decline ≥40%; a sustained increase in albuminuria of at least 30%, including a transition in albuminuria class; progression to end-stage kidney disease; and death from kidney failure. After adjustment for confounding variables, uDKK3 values >200 pg/mg creatinine were associated with a higher risk of the composite kidney end point during a median follow-up of 4.26 years. Furthermore, uDKK3 improved the prediction of the 1-year eGFR decline on top of albuminuria. Individuals with high uDKK3 levels also had an increased risk for adverse cardiovascular events and all-cause mortality. uDKK3 identifies patients with T2DM at high risk for kidney function decline on top of established biomarkers (albuminuria and eGFR). In primary care, uDKK3 may help to identify high-risk patients who might benefit from intensified treatment and/or referrals to specialists. ARTICLE HIGHLIGHTS Prediction of kidney function decline is challenging in patients with type 2 diabetes mellitus (T2DM). Urinary Dickkopf-3 (uDKK3), a profibrotic tubular protein, is a promising biomarker for detecting tubular injury and predicting the progression of chronic kidney disease. This study assessed whether uDKK3 measurements improve risk prediction in patients with T2DM treated at the primary care level. Elevated uDKK3 levels were associated with kidney function decline, on top of established biomarkers (estimated glomerular filtration rate and albuminuria). uDKK3 also identified patients at increased risk for cardiovascular events. uDKK3 may help identify high-risk patients in primary care who could benefit from intensified treatment and/or referrals to specialists.
{"title":"Dickkopf-3 (DKK3) and the Progression of Diabetic Kidney Disease in Primary Health Care","authors":"Felix Keller, Stefan Schunk, Sara Denicolò, Samir Sharifli, Stefanie Thöni, Susanne Eder, Johannes Leierer, Hiddo J.L. Heerspink, Patrick B. Mark, László Rosivall, Andrzej Wiecek, Gert Mayer, Danilo Fliser","doi":"10.2337/db25-0235","DOIUrl":"https://doi.org/10.2337/db25-0235","url":null,"abstract":"Accurate prediction of diabetic kidney disease progression is challenging, but mandatory. Urinary Dickkopf-3 (uDKK3), a tubular, epithelial-derived glycoprotein and marker of tubular injury, is a promising biomarker for kidney function decline. We explored the clinical utility of uDKK3 to predict kidney function decline and adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM) in a primary health care setting. In this cohort study, 3,232 patients with T2DM were analyzed. The primary end point was a composite of a sustained estimated glomerular filtration rate (eGFR) decline ≥40%; a sustained increase in albuminuria of at least 30%, including a transition in albuminuria class; progression to end-stage kidney disease; and death from kidney failure. After adjustment for confounding variables, uDKK3 values >200 pg/mg creatinine were associated with a higher risk of the composite kidney end point during a median follow-up of 4.26 years. Furthermore, uDKK3 improved the prediction of the 1-year eGFR decline on top of albuminuria. Individuals with high uDKK3 levels also had an increased risk for adverse cardiovascular events and all-cause mortality. uDKK3 identifies patients with T2DM at high risk for kidney function decline on top of established biomarkers (albuminuria and eGFR). In primary care, uDKK3 may help to identify high-risk patients who might benefit from intensified treatment and/or referrals to specialists. ARTICLE HIGHLIGHTS Prediction of kidney function decline is challenging in patients with type 2 diabetes mellitus (T2DM). Urinary Dickkopf-3 (uDKK3), a profibrotic tubular protein, is a promising biomarker for detecting tubular injury and predicting the progression of chronic kidney disease. This study assessed whether uDKK3 measurements improve risk prediction in patients with T2DM treated at the primary care level. Elevated uDKK3 levels were associated with kidney function decline, on top of established biomarkers (estimated glomerular filtration rate and albuminuria). uDKK3 also identified patients at increased risk for cardiovascular events. uDKK3 may help identify high-risk patients in primary care who could benefit from intensified treatment and/or referrals to specialists.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"122 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260787","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}
Sevilay Tokgöz, Laura N. Deden, Adrianne Hofboer, Eric J. Hazebroek, Hans de Boer, Arianne C. van Bon, Rick I. Meijer, Bastiaan E. de Galan, Cees J. Tack, Marti Boss, Martin Gotthardt
Postbariatric hypoglycemia (PBH) is a serious complication of Roux-en-Y gastric bypass (RYGB), characterized by severe hypoglycemia that may lead to loss of consciousness and seizures. The exact mechanism of PBH is poorly understood. One potential mechanism is β-cell expansion. To this end, we investigated β-cell mass in individuals with and without PBH after RYGB using [68Ga]Ga-NODAGA–exendin-4 positron emission tomography/computed tomography imaging (PET/CT). Individuals with PBH (n = 10) and without PBH (n = 9) after RYGB were included. PET/CT imaging was performed after infusion with 102.2 ± 6.9 MBq of the [68Ga]Ga-NODAGA–exendin-4 tracer to quantify pancreatic β-cell mass. The two groups did not differ with respect to sex, age, BMI, and total body weight loss after RYGB. Time between RYGB and inclusion was longer for individuals with PBH compared with those without. β-cell mass did not differ between the groups. Individuals with PBH had a smaller pancreas than those without. β-cell mass correlated neither with body weight parameters nor with metabolic parameters. Our data indicating that β-cell mass does not differ between individuals with and without PBH after RYGB argue against expansion of β-cell mass to explain PBH. ARTICLE HIGHLIGHTS The exact mechanism of postbariatric hypoglycemia (PBH) is unclear, but β-cell mass expansion is hypothesized to play a role. We used [68Ga]Ga-NODAGA–exendin-4 positron emission tomography/computed tomography (PET/CT) to determine β-cell mass in individuals with and without PBH after Roux-en-Y gastric bypass surgery. β-Cell mass did not differ between individuals with and without PBH. Pancreas volume was lower in individuals with PBH compared with those without PBH. Our data argue against β-cell mass expansion to explain PBH after Roux-en-Y gastric bypass. Further study is required to understand PBH.
{"title":"β-Cell Mass in Individuals With and Without Postbariatric Hypoglycemia After Roux-en-Y Gastric Bypass","authors":"Sevilay Tokgöz, Laura N. Deden, Adrianne Hofboer, Eric J. Hazebroek, Hans de Boer, Arianne C. van Bon, Rick I. Meijer, Bastiaan E. de Galan, Cees J. Tack, Marti Boss, Martin Gotthardt","doi":"10.2337/db25-0572","DOIUrl":"https://doi.org/10.2337/db25-0572","url":null,"abstract":"Postbariatric hypoglycemia (PBH) is a serious complication of Roux-en-Y gastric bypass (RYGB), characterized by severe hypoglycemia that may lead to loss of consciousness and seizures. The exact mechanism of PBH is poorly understood. One potential mechanism is β-cell expansion. To this end, we investigated β-cell mass in individuals with and without PBH after RYGB using [68Ga]Ga-NODAGA–exendin-4 positron emission tomography/computed tomography imaging (PET/CT). Individuals with PBH (n = 10) and without PBH (n = 9) after RYGB were included. PET/CT imaging was performed after infusion with 102.2 ± 6.9 MBq of the [68Ga]Ga-NODAGA–exendin-4 tracer to quantify pancreatic β-cell mass. The two groups did not differ with respect to sex, age, BMI, and total body weight loss after RYGB. Time between RYGB and inclusion was longer for individuals with PBH compared with those without. β-cell mass did not differ between the groups. Individuals with PBH had a smaller pancreas than those without. β-cell mass correlated neither with body weight parameters nor with metabolic parameters. Our data indicating that β-cell mass does not differ between individuals with and without PBH after RYGB argue against expansion of β-cell mass to explain PBH. ARTICLE HIGHLIGHTS The exact mechanism of postbariatric hypoglycemia (PBH) is unclear, but β-cell mass expansion is hypothesized to play a role. We used [68Ga]Ga-NODAGA–exendin-4 positron emission tomography/computed tomography (PET/CT) to determine β-cell mass in individuals with and without PBH after Roux-en-Y gastric bypass surgery. β-Cell mass did not differ between individuals with and without PBH. Pancreas volume was lower in individuals with PBH compared with those without PBH. Our data argue against β-cell mass expansion to explain PBH after Roux-en-Y gastric bypass. Further study is required to understand PBH.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"121 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255687","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}
Jun Shirakawa, Dario F. De Jesus, Takahiro Tsuno, Giorgio Basile, Ryota Inoue, Tomozumi Takatani, Akira Nishiyama, Erin R. Okawa, Tomohiko Tamura, Yasuo Terauchi, Rohit N. Kulkarni
Insulin-like growth factor−2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysosome and to clear IGF2 from the cell surface by acting as a scavenger receptor. To evaluate the direct role of IGF2R in β-cell biology, we undertook complementary in vitro knockdown and in vivo knockout approaches. A β-cell line with a stable knockdown of IGF2R (IGF2RKD) exhibited decreased glucose-induced insulin secretion and enhanced cell proliferation. Tamoxifen-inducible β-cell–specific IGF2R knockout mice exhibited impaired glucose tolerance and blunted insulin secretion after high-fat-diet loading that was likely secondary to reduced β-cell mass due to attenuated proliferation. β-cells with IGF2RKD had fewer autophagosomes after starvation and reduced expression of p62, LC3B, and ULK1. Aged mice also had impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and N6-methyladenosine (m6A) mRNA methylation were observed in islets from both mouse and human type 2 diabetes. Taken together, these data point to IGF2R as an important regulator of insulin secretion, cell proliferation, and autophagy in mammalian β-cells. Article Highlights The significance of insulin-like growth factor−2 receptor (IGF2R) in β-cells remains unclear. To assess the physiological role of IGF2R in β-cells, the effects of IGF2R deficiency in vivo and in vitro were investigated. IGF2R modulates insulin secretion, cell proliferation, and autophagy in β-cells. IGF2R plays a role in the regulation of β-cell biology.
{"title":"Regulatory Roles of IGF2R in Insulin Secretion and Adaptive β-Cell Proliferation","authors":"Jun Shirakawa, Dario F. De Jesus, Takahiro Tsuno, Giorgio Basile, Ryota Inoue, Tomozumi Takatani, Akira Nishiyama, Erin R. Okawa, Tomohiko Tamura, Yasuo Terauchi, Rohit N. Kulkarni","doi":"10.2337/db25-0215","DOIUrl":"https://doi.org/10.2337/db25-0215","url":null,"abstract":"Insulin-like growth factor−2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysosome and to clear IGF2 from the cell surface by acting as a scavenger receptor. To evaluate the direct role of IGF2R in β-cell biology, we undertook complementary in vitro knockdown and in vivo knockout approaches. A β-cell line with a stable knockdown of IGF2R (IGF2RKD) exhibited decreased glucose-induced insulin secretion and enhanced cell proliferation. Tamoxifen-inducible β-cell–specific IGF2R knockout mice exhibited impaired glucose tolerance and blunted insulin secretion after high-fat-diet loading that was likely secondary to reduced β-cell mass due to attenuated proliferation. β-cells with IGF2RKD had fewer autophagosomes after starvation and reduced expression of p62, LC3B, and ULK1. Aged mice also had impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and N6-methyladenosine (m6A) mRNA methylation were observed in islets from both mouse and human type 2 diabetes. Taken together, these data point to IGF2R as an important regulator of insulin secretion, cell proliferation, and autophagy in mammalian β-cells. Article Highlights The significance of insulin-like growth factor−2 receptor (IGF2R) in β-cells remains unclear. To assess the physiological role of IGF2R in β-cells, the effects of IGF2R deficiency in vivo and in vitro were investigated. IGF2R modulates insulin secretion, cell proliferation, and autophagy in β-cells. IGF2R plays a role in the regulation of β-cell biology.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215583","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}
The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not well understood. Previous studies have revealed a unique subset of macrophages that express triggering receptor expressed on myeloid cells 2 (Trem2) in kidneys of human patients and mice with DN. Here, we explored the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-sequencing of macrophages in kidneys of Trem2 knockout (KO) mice fed a high-fat diet plus streptozotocin (HFD/STZ) revealed functional enrichment of metabolic processes, cytokine production, positive regulation of extracellular signal-regulated kinase (ERK) cascades, and the regulation of phagocytosis. In vivo studies demonstrated that Trem2+ macrophages reduced lipid accumulation and mitigated ferroptosis of TECs in diabetic mice. Mechanistically, Trem2-deficient macrophages amplified the production of interleukin-1β (IL-1β) through activating the ERK signaling pathway. Furthermore, IL-1β triggered CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays showed NF-κB binds the CD36 promoter, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of NF-κB blocked IL-1β–induced CD36 production. This mechanism is exacerbated in Trem2-deficient macrophages, which release excess IL-1β to activate NF-κB in tubular cells, promoting CD36-dependent lipid uptake and ferroptosis. Additionally, we found Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by bone marrow-derived macrophages. Altogether, our results suggest Trem2+ macrophages maintain homeostasis of the renal microenvironment and exert a protective function in DN. Article Highlights Levels of triggering receptor expressed on myeloid cells 2 (Trem2) in macrophages are increased in human patients and in mice with diabetic nephropathy. Trem2 suppresses the extracellular signal-regulated kinase signaling pathways, thereby inhibiting IL-1β production in macrophages. Macrophage Trem2 deficiency exacerbates tubular cell lipid deposition and ferroptosis by increasing CD36 expression in an IL-1β–dependent manner
{"title":"Trem2+ Macrophages Alleviate Renal Tubule Lipid Accumulation and Ferroptosis in Diabetic Nephropathy by Repressing IL-1β–Mediated CD36 Expression","authors":"Xue Wang, Jiayi Wan, Chao Wang, Yan Tong, Yulan Chen, Xu Wang, Jiaona Liu, Qihu Li, Zheyi Dong, Quan Hong, Xuefeng Sun, Guangyan Cai, Qing Ouyang, Xiangmei Chen","doi":"10.2337/db25-0282","DOIUrl":"https://doi.org/10.2337/db25-0282","url":null,"abstract":"The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not well understood. Previous studies have revealed a unique subset of macrophages that express triggering receptor expressed on myeloid cells 2 (Trem2) in kidneys of human patients and mice with DN. Here, we explored the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-sequencing of macrophages in kidneys of Trem2 knockout (KO) mice fed a high-fat diet plus streptozotocin (HFD/STZ) revealed functional enrichment of metabolic processes, cytokine production, positive regulation of extracellular signal-regulated kinase (ERK) cascades, and the regulation of phagocytosis. In vivo studies demonstrated that Trem2+ macrophages reduced lipid accumulation and mitigated ferroptosis of TECs in diabetic mice. Mechanistically, Trem2-deficient macrophages amplified the production of interleukin-1β (IL-1β) through activating the ERK signaling pathway. Furthermore, IL-1β triggered CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays showed NF-κB binds the CD36 promoter, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of NF-κB blocked IL-1β–induced CD36 production. This mechanism is exacerbated in Trem2-deficient macrophages, which release excess IL-1β to activate NF-κB in tubular cells, promoting CD36-dependent lipid uptake and ferroptosis. Additionally, we found Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by bone marrow-derived macrophages. Altogether, our results suggest Trem2+ macrophages maintain homeostasis of the renal microenvironment and exert a protective function in DN. Article Highlights Levels of triggering receptor expressed on myeloid cells 2 (Trem2) in macrophages are increased in human patients and in mice with diabetic nephropathy. Trem2 suppresses the extracellular signal-regulated kinase signaling pathways, thereby inhibiting IL-1β production in macrophages. Macrophage Trem2 deficiency exacerbates tubular cell lipid deposition and ferroptosis by increasing CD36 expression in an IL-1β–dependent manner","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"53 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215919","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}
Shuhui Ji, Hua Shu, Hongqiang Zhao, Hongwei Jiang, Yuanyuan Ye, Xuan Liu, Shanshan Chen, Ying Yang, Wenli Feng, Jingting Qiao, Jinyang Zhen, Xiong Yang, Ziyue Zhang, Yu Fan, Yadi Huang, Qing He, Minxian Wang, Kunling Wang, Ming Liu
Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26L) in two family members exhibiting contrasting diabetic phenotypes. To explore the diabetogenic potential of the GCK-Q26L mutation and investigate the mono- and polygenetic factors contributing to different phenotypes, whole-exome sequencing and polygenic risk score (PRS) assessments were conducted on three family members. We found that the proband inherited the GCK-Q26L mutation from her father (who had mild, stable hyperglycemia) but exhibited more severe diabetic symptoms, including polydipsia, polyuria, weight loss, ketosis, and significant dyslipidemia. Genetic analysis linked the proband’s severe phenotypes to her high PRS for insulin resistance (IR) and type 2 diabetes. A global knock-in mouse model expressing GCK-Q26L presented mild hyperglycemia, impaired glucose tolerance, reduced serum insulin, and impaired glucose-stimulated insulin secretion. Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. This study demonstrates that GCK-Q26L is a pathogenic GCK-MODY mutation, and its associated phenotypes are influenced by PRS for IR and type 2 diabetes. Article Highlights This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.
{"title":"Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance","authors":"Shuhui Ji, Hua Shu, Hongqiang Zhao, Hongwei Jiang, Yuanyuan Ye, Xuan Liu, Shanshan Chen, Ying Yang, Wenli Feng, Jingting Qiao, Jinyang Zhen, Xiong Yang, Ziyue Zhang, Yu Fan, Yadi Huang, Qing He, Minxian Wang, Kunling Wang, Ming Liu","doi":"10.2337/db24-1036","DOIUrl":"https://doi.org/10.2337/db24-1036","url":null,"abstract":"Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26L) in two family members exhibiting contrasting diabetic phenotypes. To explore the diabetogenic potential of the GCK-Q26L mutation and investigate the mono- and polygenetic factors contributing to different phenotypes, whole-exome sequencing and polygenic risk score (PRS) assessments were conducted on three family members. We found that the proband inherited the GCK-Q26L mutation from her father (who had mild, stable hyperglycemia) but exhibited more severe diabetic symptoms, including polydipsia, polyuria, weight loss, ketosis, and significant dyslipidemia. Genetic analysis linked the proband’s severe phenotypes to her high PRS for insulin resistance (IR) and type 2 diabetes. A global knock-in mouse model expressing GCK-Q26L presented mild hyperglycemia, impaired glucose tolerance, reduced serum insulin, and impaired glucose-stimulated insulin secretion. Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. This study demonstrates that GCK-Q26L is a pathogenic GCK-MODY mutation, and its associated phenotypes are influenced by PRS for IR and type 2 diabetes. Article Highlights This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141519","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}
Karin Zemski Berry, Amanda Garfield, Katie L. Whytock, Emily Macias, Simona Zarini, Purevsuren Jambal, Tyler Stepaniak, Sophia Bowen, Leigh Perreault, Chris Johnson, Darcy Kahn, Anna Kerege, Ian J. Tamburini, Christy M. Nguyen, Carlos H. Viesi, Marcus Seldin, Yifei Sun, Martin Walsh, Lauren M. Sparks, Bryan C. Bergman
Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipids and IMAT cellular composition is not known. Twenty-one adults with obesity (18 female and 3 male; 46 ± 2 years; 35.0 ± 0.9 kg/m2) completed a 3-month supervised weight loss and exercise training intervention. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp, and basal and insulin-stimulated vastus lateralis biopsies were collected pre- and postintervention. After the intervention, body weight and body fat decreased (11 ± 1% and 9 ± 1%, respectively), while VO2 peak and insulin sensitivity increased (14 ± 3% and 68 ± 14%, respectively). Lipidomics revealed reduced sarcolemmal and nuclear triglycerides, with unchanged whole-muscle triglycerides. Whole-muscle diacylglycerols increased because of increased nuclear 1,2-diacylglycerols without PKCε, PKCθ, or PKCδ activation. Whole-muscle sphingolipid levels increased because of cytosolic accumulation. Single-nuclei RNA sequencing showed altered IMAT cellular composition, including increased fibro-adipogenic progenitors, vascular cells, and macrophages, and decreased preadipocytes. Bulk muscle RNA sequencing indicated upregulation of genes related to muscle remodeling and cellular respiration, and there were changes in the relationship between nuclear diacylglycerols and gene expression postintervention. These findings dissociate improvements in insulin sensitivity from total muscle diacylglycerol and sphingolipid levels and highlight roles for subcellular lipid redistribution and IMAT remodeling in insulin sensitization. Article Highlights Evaluation of subcellular fractionated muscle revealed decreases in sarcolemmal and nuclear triglycerides and increases in nuclear diacylglycerols and cytosolic sphingolipids postintervention. Weight loss revealed alteration in the cellular composition of intermuscular adipose tissue and upregulation of genes related to muscle remodeling and cellular respiration. These findings dissociate improvements in insulin sensitivity from total muscle 1,2-diacylglycerol and sphingolipid levels and highlight roles of intermuscular adipose tissue remodeling for enhanced insulin sensitivity.
{"title":"Combined Weight Loss and Exercise Training Alters Skeletal Muscle Subcellular Lipid Localization and Intermuscular Adipose Tissue Cellular Composition","authors":"Karin Zemski Berry, Amanda Garfield, Katie L. Whytock, Emily Macias, Simona Zarini, Purevsuren Jambal, Tyler Stepaniak, Sophia Bowen, Leigh Perreault, Chris Johnson, Darcy Kahn, Anna Kerege, Ian J. Tamburini, Christy M. Nguyen, Carlos H. Viesi, Marcus Seldin, Yifei Sun, Martin Walsh, Lauren M. Sparks, Bryan C. Bergman","doi":"10.2337/db25-0492","DOIUrl":"https://doi.org/10.2337/db25-0492","url":null,"abstract":"Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipids and IMAT cellular composition is not known. Twenty-one adults with obesity (18 female and 3 male; 46 ± 2 years; 35.0 ± 0.9 kg/m2) completed a 3-month supervised weight loss and exercise training intervention. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp, and basal and insulin-stimulated vastus lateralis biopsies were collected pre- and postintervention. After the intervention, body weight and body fat decreased (11 ± 1% and 9 ± 1%, respectively), while VO2 peak and insulin sensitivity increased (14 ± 3% and 68 ± 14%, respectively). Lipidomics revealed reduced sarcolemmal and nuclear triglycerides, with unchanged whole-muscle triglycerides. Whole-muscle diacylglycerols increased because of increased nuclear 1,2-diacylglycerols without PKCε, PKCθ, or PKCδ activation. Whole-muscle sphingolipid levels increased because of cytosolic accumulation. Single-nuclei RNA sequencing showed altered IMAT cellular composition, including increased fibro-adipogenic progenitors, vascular cells, and macrophages, and decreased preadipocytes. Bulk muscle RNA sequencing indicated upregulation of genes related to muscle remodeling and cellular respiration, and there were changes in the relationship between nuclear diacylglycerols and gene expression postintervention. These findings dissociate improvements in insulin sensitivity from total muscle diacylglycerol and sphingolipid levels and highlight roles for subcellular lipid redistribution and IMAT remodeling in insulin sensitization. Article Highlights Evaluation of subcellular fractionated muscle revealed decreases in sarcolemmal and nuclear triglycerides and increases in nuclear diacylglycerols and cytosolic sphingolipids postintervention. Weight loss revealed alteration in the cellular composition of intermuscular adipose tissue and upregulation of genes related to muscle remodeling and cellular respiration. These findings dissociate improvements in insulin sensitivity from total muscle 1,2-diacylglycerol and sphingolipid levels and highlight roles of intermuscular adipose tissue remodeling for enhanced insulin sensitivity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116413","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}
Ryan D. Carter, Ujang Purnama, Marcos Castro-Guarda, Claudia N. Montes-Aparicio, Anandhakumar Chandran, Richard Mbasu, Maxwell Ruby, Charlotte Daly, Kirsti Brisk, Helen C. Christian, Jack J.J.J. Miller, Francesca M. Buffa, Lisa C. Heather, Carolyn A. Carr
Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using insulin resistant (IR) two-dimensional (2D) human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and three-dimensional (3D) engineered heart tissue (EHT) provides a comprehensive evaluation of dysregulated pathways and determines suitability as a translationally relevant model of DbCM. Culturing hiPSC-CMs in 2D or 3D EHT in IR media induced insulin resistance and activated multiple pathways implicated in DbCM, including metabolic remodeling, mitochondrial dysfunction, extracellular matrix remodeling, endoplasmic reticulum stress, and blunted response to hypoxia, as assessed using transcriptomics and proteomics. Metabolic flux measurements in both IR 2D and 3D platforms demonstrated increased fatty acid oxidation and lipid storage, whereas glucose metabolism was downregulated. Modeling DbCM in 3D EHTs conferred additional metabolic and functional advantages over the 2D hiPSC-CM, demonstrating impaired contractility and muscle architecture. Metformin treatment improved both contractility and metabolic function, demonstrating the utility of IR EHT for drug assessment. In conclusion, IR 2D and 3D hiPSC-CM models effectively capture key DbCM features. However, 3D EHT provides additional insights into physiological and structural modifications. This highlights the potential of IR EHT for both mechanistic studies and drug screening in DbCM. Article Highlights Human-centric cardiac models are needed that recapitulate mechanistic and functional changes in the type 2 diabetic myocardium for understanding disease pathogenesis and developing new therapies. Using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM) in 2D and 3D as engineered heart tissue (EHT), we aimed to model diabetic cardiomyopathy in cellulo. Taking an unbiased systems biology approach, our cellular models recapitulated the dysregulated pathways and functional derangement of diabetic cardiomyopathy. Three-dimensional EHT models showed contractile dysfunction akin to that seen in patients, with mechanistic and functional changes reversed with metformin. It is possible to generate translationally relevant hiPSC-CM models that mimic diabetic cardiomyopathy.
{"title":"Systems Biology and Functional Assessments of Human iPSC-Cardiomyocyte Models of Insulin Resistance Capture Key Hallmarks of Diabetic Cardiomyopathy","authors":"Ryan D. Carter, Ujang Purnama, Marcos Castro-Guarda, Claudia N. Montes-Aparicio, Anandhakumar Chandran, Richard Mbasu, Maxwell Ruby, Charlotte Daly, Kirsti Brisk, Helen C. Christian, Jack J.J.J. Miller, Francesca M. Buffa, Lisa C. Heather, Carolyn A. Carr","doi":"10.2337/db25-0204","DOIUrl":"https://doi.org/10.2337/db25-0204","url":null,"abstract":"Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using insulin resistant (IR) two-dimensional (2D) human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and three-dimensional (3D) engineered heart tissue (EHT) provides a comprehensive evaluation of dysregulated pathways and determines suitability as a translationally relevant model of DbCM. Culturing hiPSC-CMs in 2D or 3D EHT in IR media induced insulin resistance and activated multiple pathways implicated in DbCM, including metabolic remodeling, mitochondrial dysfunction, extracellular matrix remodeling, endoplasmic reticulum stress, and blunted response to hypoxia, as assessed using transcriptomics and proteomics. Metabolic flux measurements in both IR 2D and 3D platforms demonstrated increased fatty acid oxidation and lipid storage, whereas glucose metabolism was downregulated. Modeling DbCM in 3D EHTs conferred additional metabolic and functional advantages over the 2D hiPSC-CM, demonstrating impaired contractility and muscle architecture. Metformin treatment improved both contractility and metabolic function, demonstrating the utility of IR EHT for drug assessment. In conclusion, IR 2D and 3D hiPSC-CM models effectively capture key DbCM features. However, 3D EHT provides additional insights into physiological and structural modifications. This highlights the potential of IR EHT for both mechanistic studies and drug screening in DbCM. Article Highlights Human-centric cardiac models are needed that recapitulate mechanistic and functional changes in the type 2 diabetic myocardium for understanding disease pathogenesis and developing new therapies. Using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM) in 2D and 3D as engineered heart tissue (EHT), we aimed to model diabetic cardiomyopathy in cellulo. Taking an unbiased systems biology approach, our cellular models recapitulated the dysregulated pathways and functional derangement of diabetic cardiomyopathy. Three-dimensional EHT models showed contractile dysfunction akin to that seen in patients, with mechanistic and functional changes reversed with metformin. It is possible to generate translationally relevant hiPSC-CM models that mimic diabetic cardiomyopathy.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"70 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145072811","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}
Sandra E. Blom, Palin R. Narsian, Riley M. Behan-Bush, James A. Ankrum, Ling Yang, Samuel B. Stephens
Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the β-cell’s Golgi structure and function. The structural modifications include Golgi compaction and loss of the interconnecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell surface glycoprotein composition. Our data demonstrate that inducible nitric oxide synthase (iNOS)–generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi restructuring. Moreover, the unique sensitivity of the β-cell to NO-dependent mitochondrial inhibition results in β-cell–specific Golgi alterations that are absent in other cell types, including α-cells. Examination of human pancreas samples from autoantibody-positive and T1D donors with residual β-cells further revealed alterations in β-cell, but not α-cell, Golgi structure that correlate with T1D progression. Collectively, our studies provide critical clues as to how β-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of β-cell autoantigens relevant to T1D. Article Highlights Proinflammatory cytokines drive disruptions in Golgi structure and function in human, mouse, and rat β-cells. Golgi alterations result from inducible nitric oxide synthase (iNOS)– and nitric oxide (NO)–dependent inhibition of mitochondrial metabolism. α-Cell Golgi structure is insensitive to cytokine- and NO-mediated metabolic inhibition. Analysis of human donor tissue shows early Golgi alteration in β-cells from autoantibody-positive donors, which persists in residual β-cells from T1D donors.
{"title":"Proinflammatory Cytokines Mediate Pancreatic β-Cell–Specific Alterations to Golgi Integrity via iNOS-Dependent Mitochondrial Inhibition","authors":"Sandra E. Blom, Palin R. Narsian, Riley M. Behan-Bush, James A. Ankrum, Ling Yang, Samuel B. Stephens","doi":"10.2337/db25-0132","DOIUrl":"https://doi.org/10.2337/db25-0132","url":null,"abstract":"Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the β-cell’s Golgi structure and function. The structural modifications include Golgi compaction and loss of the interconnecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell surface glycoprotein composition. Our data demonstrate that inducible nitric oxide synthase (iNOS)–generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi restructuring. Moreover, the unique sensitivity of the β-cell to NO-dependent mitochondrial inhibition results in β-cell–specific Golgi alterations that are absent in other cell types, including α-cells. Examination of human pancreas samples from autoantibody-positive and T1D donors with residual β-cells further revealed alterations in β-cell, but not α-cell, Golgi structure that correlate with T1D progression. Collectively, our studies provide critical clues as to how β-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of β-cell autoantigens relevant to T1D. Article Highlights Proinflammatory cytokines drive disruptions in Golgi structure and function in human, mouse, and rat β-cells. Golgi alterations result from inducible nitric oxide synthase (iNOS)– and nitric oxide (NO)–dependent inhibition of mitochondrial metabolism. α-Cell Golgi structure is insensitive to cytokine- and NO-mediated metabolic inhibition. Analysis of human donor tissue shows early Golgi alteration in β-cells from autoantibody-positive donors, which persists in residual β-cells from T1D donors.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995496","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}
Pengcheng Pang, Yonghao Liu, Haicheng Song, Zhifei Ye, Heng Zhou, Rui Zhang, Tushar Kumeria, Wenting She, Chun Xu, Peter L. Mei, Yan He, Qingsong Ye
Diabetic wounds represent a significant clinical and economic burden, affecting both patients and health care systems. While current therapeutic approaches, such as negative pressure wound therapy, offer benefits, their limitations necessitate alternative strategies. Newly discovered dental pulp stem cell–derived intracellular vesicles have emerged as a promising candidate in regenerative medicine due to their therapeutic potential. In vitro assessments using HUVECs, HaCaTs, and RAW264.7 cells revealed that intracellular vesicles enhance cell migration, angiogenesis, and proliferation while suppressing the cGAS-STING pathway. Additionally, intracellular vesicles promoted M2 macrophage polarization and maintained mitochondrial function. In a diabetic mouse wound model, both intracellular vesicles and negative pressure wound therapy individually improved wound healing, but their combination exhibited a synergistic effect, resulting in faster wound closure, enhanced angiogenesis, and reduced inflammation. The combined treatment also exhibited excellent biocompatibility. These findings highlight the therapeutic potential of intracellular vesicles as an adjunct to negative pressure wound therapy for diabetic wound treatment. Article Highlights Chronic diabetic wounds are difficult to heal, and current treatments, such as negative pressure wound therapy, have limited effectiveness. The potential of intracellular vesicles derived from dental pulp stem cell lysate for diabetic wound healing is well worth exploring. Intracellular vesicles promoted angiogenesis, cell proliferation, and M2 macrophage polarization by inhibiting cGAS-STING signaling and restoring mitochondrial function. Combined with negative pressure wound therapy, intracellular vesicles accelerated wound healing in diabetic mice. Intracellular vesicles offer a promising cell-free strategy to enhance negative pressure wound therapy outcomes and improve diabetic wound treatment.
{"title":"Application of Dental Pulp Stem Cell–Derived Intracellular Vesicles for Diabetic Wound Healing","authors":"Pengcheng Pang, Yonghao Liu, Haicheng Song, Zhifei Ye, Heng Zhou, Rui Zhang, Tushar Kumeria, Wenting She, Chun Xu, Peter L. Mei, Yan He, Qingsong Ye","doi":"10.2337/db24-0686","DOIUrl":"https://doi.org/10.2337/db24-0686","url":null,"abstract":"Diabetic wounds represent a significant clinical and economic burden, affecting both patients and health care systems. While current therapeutic approaches, such as negative pressure wound therapy, offer benefits, their limitations necessitate alternative strategies. Newly discovered dental pulp stem cell–derived intracellular vesicles have emerged as a promising candidate in regenerative medicine due to their therapeutic potential. In vitro assessments using HUVECs, HaCaTs, and RAW264.7 cells revealed that intracellular vesicles enhance cell migration, angiogenesis, and proliferation while suppressing the cGAS-STING pathway. Additionally, intracellular vesicles promoted M2 macrophage polarization and maintained mitochondrial function. In a diabetic mouse wound model, both intracellular vesicles and negative pressure wound therapy individually improved wound healing, but their combination exhibited a synergistic effect, resulting in faster wound closure, enhanced angiogenesis, and reduced inflammation. The combined treatment also exhibited excellent biocompatibility. These findings highlight the therapeutic potential of intracellular vesicles as an adjunct to negative pressure wound therapy for diabetic wound treatment. Article Highlights Chronic diabetic wounds are difficult to heal, and current treatments, such as negative pressure wound therapy, have limited effectiveness. The potential of intracellular vesicles derived from dental pulp stem cell lysate for diabetic wound healing is well worth exploring. Intracellular vesicles promoted angiogenesis, cell proliferation, and M2 macrophage polarization by inhibiting cGAS-STING signaling and restoring mitochondrial function. Combined with negative pressure wound therapy, intracellular vesicles accelerated wound healing in diabetic mice. Intracellular vesicles offer a promising cell-free strategy to enhance negative pressure wound therapy outcomes and improve diabetic wound treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995346","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}
Yi Ding, Qi Zhou, Youjin Jiang, Qiuyu Cao, Xianglin Wu, Xiaoran Li, Yu Xu, Jieli Lu, Min Xu, Tiange Wang, Zhiyun Zhao, Yuhong Chen, Yan Liu, Jie Li, Guang Ning, Weiqing Wang, Yufang Bi, Mian Li
Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visualize the difference in lifestyle intervention efficacy in Chinese patients. Based on 17,816 participants with newly diagnosed type 2 diabetes (aged ≥40 years) from a nationwide cohort, 12 key phenotypes were residualized for age and sex to construct a two-dimensional tree structure. The tree demonstrated the continuous type 2 diabetes spectrum and region-specific characteristics, with a mixed phenotypic trunk and three extreme phenotypic branches. When mapping data from 325 participants with type 2 diabetes from a randomized controlled trial onto the original tree, lifestyle intervention induced a migration toward the left part of tree, indicating an overall metabolic improvement. Specifically, diet intervention was more effective for glycemic control in the upper part of the tree and featured moderate diabesity and elevated insulin, whereas exercise intervention was more effective for glycemic control in the left side of the tree and featured less adiposity and better overall metabolic status. In summary, this analysis depicted the tree structure representing the underlying pathophysiological features of patients with newly diagnosed type 2 diabetes and identified tree regions with different sensitivity to diet or exercise intervention. The results have the potential to aid lifestyle intervention selection. Article Highlights Deciphering the heterogeneity of diabetes is essential for prognosis prediction and treatment guidance, but current classifications are flawed because they lose continuous phenotypic information. We wanted to determine if the novel data reduction method, the data dimensionality reduction tree (DDRTree), is applicable to visualizing the phenotypic continuum, comorbid conditions, and lifestyle intervention effects in Chinese patients with type 2 diabetes. The DDRTree structure demonstrated the region-specific characteristics of type 2 diabetes. Diet intervention was more effective for glycemic control in the upper part of the tree, featuring moderate diabesity, whereas exercise intervention was more effective in the left side of the tree, featuring less adiposity and better overall metabolic status. The Chinese type 2 diabetes tree structure indicates individualized pathophysiology and guides the selection of lifestyle intervention.
{"title":"Heterogeneity in Phenotype and Early Metabolic Response to Lifestyle Interventions in Type 2 Diabetes in China Using a Tree-Like Representation","authors":"Yi Ding, Qi Zhou, Youjin Jiang, Qiuyu Cao, Xianglin Wu, Xiaoran Li, Yu Xu, Jieli Lu, Min Xu, Tiange Wang, Zhiyun Zhao, Yuhong Chen, Yan Liu, Jie Li, Guang Ning, Weiqing Wang, Yufang Bi, Mian Li","doi":"10.2337/db25-0197","DOIUrl":"https://doi.org/10.2337/db25-0197","url":null,"abstract":"Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visualize the difference in lifestyle intervention efficacy in Chinese patients. Based on 17,816 participants with newly diagnosed type 2 diabetes (aged ≥40 years) from a nationwide cohort, 12 key phenotypes were residualized for age and sex to construct a two-dimensional tree structure. The tree demonstrated the continuous type 2 diabetes spectrum and region-specific characteristics, with a mixed phenotypic trunk and three extreme phenotypic branches. When mapping data from 325 participants with type 2 diabetes from a randomized controlled trial onto the original tree, lifestyle intervention induced a migration toward the left part of tree, indicating an overall metabolic improvement. Specifically, diet intervention was more effective for glycemic control in the upper part of the tree and featured moderate diabesity and elevated insulin, whereas exercise intervention was more effective for glycemic control in the left side of the tree and featured less adiposity and better overall metabolic status. In summary, this analysis depicted the tree structure representing the underlying pathophysiological features of patients with newly diagnosed type 2 diabetes and identified tree regions with different sensitivity to diet or exercise intervention. The results have the potential to aid lifestyle intervention selection. Article Highlights Deciphering the heterogeneity of diabetes is essential for prognosis prediction and treatment guidance, but current classifications are flawed because they lose continuous phenotypic information. We wanted to determine if the novel data reduction method, the data dimensionality reduction tree (DDRTree), is applicable to visualizing the phenotypic continuum, comorbid conditions, and lifestyle intervention effects in Chinese patients with type 2 diabetes. The DDRTree structure demonstrated the region-specific characteristics of type 2 diabetes. Diet intervention was more effective for glycemic control in the upper part of the tree, featuring moderate diabesity, whereas exercise intervention was more effective in the left side of the tree, featuring less adiposity and better overall metabolic status. The Chinese type 2 diabetes tree structure indicates individualized pathophysiology and guides the selection of lifestyle intervention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995500","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}
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