Vossen LE, Van Netten JJ, Hulshof CM
… +4 more, Jelsma N, Slootman A, Merkx MJM, Bus SA
Diabetes Care
· 2026 Jun · PMID 42247281
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OBJECTIVE: Diabetes-related foot ulcers impose a large burden on patients and society. To prevent foot ulcers, adherence to wearing custom-made footwear is essential. However, adherence is often low in people at high ulc...OBJECTIVE: Diabetes-related foot ulcers impose a large burden on patients and society. To prevent foot ulcers, adherence to wearing custom-made footwear is essential. However, adherence is often low in people at high ulcer risk, while evidence for interventions that improve adherence is scarce. We assessed the effectiveness of an integrated personalized multimodal intervention on footwear adherence in people with diabetes at high risk of ulceration. RESEARCH DESIGN AND METHODS: In a multicenter randomized controlled trial, 126 participants with diabetes, peripheral neuropathy, ulcer history, and custom-made footwear were randomized to usual care or enhanced treatment. Usual care was guideline-based; that is, custom-made footwear, nonstructured education, and podiatric foot care and screening. Enhanced treatment consisted of usual care plus pressure-optimized custom-made footwear, provision of indoor-specific custom-made footwear, structured education, and motivational interviewing that included personalized feedback. The primary outcome was footwear adherence (i.e., percentage of steps taken wearing prescribed footwear) objectively measured at 6 and 12 months of follow-up. A secondary outcome was shoe-wearing time in hours per day, assessed 2 weeks before and after study visits. RESULTS: Footwear adherence was significantly higher for enhanced treatment compared with usual care: 75% (SD 10) vs 56% (SD 22) at 6 months (i.e., relative increase 34%, P < 0.001), and 58% (SD 18) vs 49% (SD 20) at 12 months (P = 0.013). Shoe-wearing time significantly increased after the randomization visit in which structured education was provided (7.8-8.3 h/day, P = 0.049) and after the provision of indoor-specific footwear (7.7-9.4 h/day, P < 0.001). CONCLUSIONS: Footwear adherence can be significantly increased through an integrated personalized multimodal intervention.
Phee AAT, Foo RX, Guivarch C
… +9 more, Liu P, Gneezy R, Shanmugan S, Zhang C, Shen J, Wong WCW, Cheung KW, Chan KKL, Li LJ
Diabetes Care
· 2026 Jun · PMID 42247277
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BACKGROUND: Gestational diabetes mellitus (GDM) confers substantial long-term cardiometabolic risk. The postpartum period represents a critical window for intervention, but the benefits of dietary interventions on cardio...BACKGROUND: Gestational diabetes mellitus (GDM) confers substantial long-term cardiometabolic risk. The postpartum period represents a critical window for intervention, but the benefits of dietary interventions on cardiometabolic profiles in women with prior GDM remain unclear. PURPOSE: To evaluate whether postpartum dietary interventions improved cardiometabolic profiles in women with GDM. DATA SOURCES: Six databases were searched from 1 January 1980-31 December 2025. STUDY SELECTION: Twenty-one randomized controlled trials (RCTs) met inclusion criteria. DATA EXTRACTION: Data extraction and risk-of-bias assessment followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SYNTHESIS: Meta-analyses pooled mean differences (MDs) with 95% CIs using a random-effects model. Intermediate cardiometabolic surrogate markers, such as BMI, waist circumference, weight, fasting and 2-h blood glucose, HOMA of insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), systolic and diastolic blood pressure, lipids, and inflammatory biomarkers were evaluated. The meta-analysis included 19 RCTs (participants were aged 18-45 years; sample size: 23 to 1,639; follow-up: 12 weeks-3 years). Compared with standard care, postnatal dietary interventions significantly reduced BMI (MD -0.46 kg/m2; 95% CI -0.71, -0.20), waist circumference (-1.47 cm; -2.39, -0.55), weight (-0.73 kg; -1.19, -0.27), HOMA-IR (-0.55; -1.04, -0.06), and HbA1c (-0.24%; -0.46, -0.02). No improvements were found for other markers. LIMITATIONS: Heterogeneity across studies, variable adherence to counseling-based interventions, and comprehensive standard postpartum care may have limited observed effects. CONCLUSIONS: Postpartum dietary interventions yield modest but statistically significant improvements in key cardiometabolic indicators among women with prior GDM without overt disease, highlighting the postpartum period as an important window to optimize intermediate cardiometabolic markers.
Bisno DI, Turner LV, Gallop RJ
… +5 more, Jo Kamimoto JL, Reddy S, Gal RL, Riddell MC, Rickels MR
Diabetes Care
· 2026 Jun · PMID 42247270
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OBJECTIVE: To identify modifiable factors associated with postexercise nocturnal hypoglycemia in the Type 1 Diabetes and Exercise Initiative (T1DEXI) study. RESEARCH DESIGN AND METHODS: In this real-world prospective coh...OBJECTIVE: To identify modifiable factors associated with postexercise nocturnal hypoglycemia in the Type 1 Diabetes and Exercise Initiative (T1DEXI) study. RESEARCH DESIGN AND METHODS: In this real-world prospective cohort study, overnight continuous glucose monitoring data following exercise days versus sedentary days were assessed in adults with type 1 diabetes. Nocturnal hypoglycemia was defined as a continuous glucose monitoring level of 54-69 mg/dL (level 1) or <54 mg/dL (level 2) for ≥15 min between midnight and 6:00 a.m. RESULTS: Among 496 adults across 12,340 nights, exercise days were associated with more frequent level 1 nocturnal hypoglycemia relative to sedentary days (15.6% vs. 13.1%, P = 0.001). Factors associated with reduced risk included lower preexercise time below range, higher preexercise and bedtime glucose, absence of hypoglycemia during or within 4 h after exercise, and hybrid closed-loop delivery. Time below range ≥4% in the 24 h preceding exercise was associated with substantially higher nocturnal hypoglycemia risk relative to <4% for level 1 (22.9% vs. 11.7%) and level 2 (10.2% vs. 3.3%) (both P < 0.001). Hybrid closed-loop users experienced approximately half the rate of nocturnal hypoglycemia compared with participants using standard pumps or multiple daily injections (level 1: 9.7% vs. 20.3% vs. 17.3%, respectively; level 2: 3.2% vs. 7.2% vs. 5.8%, respectively) (both P < 0.001). CONCLUSIONS: In the T1DEXI study, exercise was associated with increased nocturnal hypoglycemia risk in adults with type 1 diabetes. Targeting modifiable factors may reduce risk and address a critical barrier to safe physical activity in type 1 diabetes.
Miller RG, Costacou T, El Khoudary SR
… +1 more, Orchard TJ
Diabetes Care
· 2026 Jun · PMID 42240440
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OBJECTIVE: Data on sex-specific risk factors for type 1 diabetes microvascular complications are limited. We assessed sex-specific associations of longitudinal clinical risk factors and 30-year retinopathy and kidney end...OBJECTIVE: Data on sex-specific risk factors for type 1 diabetes microvascular complications are limited. We assessed sex-specific associations of longitudinal clinical risk factors and 30-year retinopathy and kidney end point incidence in the Pittsburgh Epidemiology of Diabetes Complications type 1 diabetes cohort. RESEARCH DESIGN AND METHODS: The cohort (n = 325 women and 333 men; mean baseline age 27 years; diabetes duration 19 years) was followed from 1986-1988 to 2016-2018 for the following: incident proliferative diabetic retinopathy (PDR) (Early Treatment of Diabetic Retinopathy Study grade ≥60 or laser photocoagulation); severely increased albuminuria (SIA) (albumin excretion rate ≥200 µg/min); and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (chronic kidney disease [CKD] G3). Associations between longitudinal risk factors and time to each event were assessed by sex in multivariable joint models in those who were complication-free at baseline. RESULTS: PDR incidence was similar by sex (57% in women vs. 59% in men; P = 0.54). SIA incidence was lower in women (18% vs. 25% in men; P = 0.10); and CKD G3 was higher in women (28% vs. 21% in men; P = 0.11). In both sexes, independent risk factors for PDR included HbA1c and blood pressure (BP) (women's systolic BP: hazard ratio [HR] 1.27 [95% CI 1.12, 1.45]; men's diastolic BP: HR 1.40 [95% CI 1.15, 1.70]). For SIA, HbA1c was associated in both sexes, but other factors differed, including triglyceride levels (HR 1.38 per log1.2; 95% CI 1.06, 1.78) and BMI (HR 0.87; 95% CI 0.76, 1.00) in women and smoking (HR 3.46; 95% CI 1.07, 11.24) in men. For CKD G3, HbA1c was a risk factor in both sexes; smoking was also associated in men. CONCLUSIONS: Although HbA1c and BP are important risk factors for retinopathy regardless of sex, sex-specific clinical targets warrant further research to optimize kidney protection in type 1 diabetes.
Petrelli A, Thomas NJ, Hope SV
… +2 more, Bucciarelli L, Fiorina P
Diabetes Care
· 2026 Jun · PMID 42237872
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This article highlights how age and type 1 diabetes interact to shape clinical onset and treatment, emphasizing the need for tailored strategies in classifying and managing type 1 diabetes across the lifespan, particular...This article highlights how age and type 1 diabetes interact to shape clinical onset and treatment, emphasizing the need for tailored strategies in classifying and managing type 1 diabetes across the lifespan, particularly in later life. This article represents an expert perspective based on selected literature. In considering type 1 diabetes in adults, distinction is needed between incident cases, where biological age influences underlying pathophysiology, and prevalent cases, capturing both adult-onset type 1 diabetes and long-standing childhood-onset type 1 diabetes in individuals reaching older age. Type 1 diabetes diagnosed after age 30 years presents diagnostic and management challenges. Diagnosis remains difficult due to high prevalence of type 2 diabetes and frequent misclassification. When adult-onset type 1 diabetes is rigorously defined, key clinical features, including progression from dysglycemia and early β-cell decline, more resemble those in younger individuals. Differences across ages are best interpreted as an age-related phenotype arising from the biological context in which autoimmunity occurs, immune remodeling, insulin resistance, and pancreatic changes, rather than distinct pathogenic mechanisms. While incidence of adult-onset type 1 diabetes is largely static, prevalence is increasing, especially among those ages ≥65 years, largely due to improved outcomes with declining mortality and disability-adjusted life-years. While type 1 diabetes management should not intrinsically alter with age, older adults face elevated risks of comorbidities, including frailty and cognitive and visual impairment, which can complicate management and impact glucose levels, particularly hypoglycemia risk; individualized glycemic targets are needed with a focus on safety and quality of life. Moving forward integrating adults into pre-type 1 diabetes screening and prevention efforts will be essential to refine prediction, reduce misclassification, and guide disease-modifying interventions.
Chorniy A, Owen AL, Kang RH
… +6 more, Cherupally M, Liss DT, French DD, Aikman C, Harris SA, Ackermann RT
Diabetes Care
· 2026 Jun · PMID 42227951
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OBJECTIVE: The U.S. National Diabetes Prevention Program (NDPP) is an intensive lifestyle intervention to prevent type 2 diabetes, but its real-world effectiveness is unclear. We estimated NDPP's effectiveness to prevent...OBJECTIVE: The U.S. National Diabetes Prevention Program (NDPP) is an intensive lifestyle intervention to prevent type 2 diabetes, but its real-world effectiveness is unclear. We estimated NDPP's effectiveness to prevent diabetes among insured, high-risk adults. RESEARCH DESIGN AND METHODS: This comparative cohort study included privately insured adults enrolled in 5,714 health plans spanning all 50 states who had medical claims between 2015 and 2019 indicating diagnosed prediabetes, followed by at least one procedure code indicating engagement in some form of lifestyle treatment. Each patient was classified as NDPP treated (at least one NDPP claim) or NDPP untreated (at least one claim for lower intensity services only). In the same quarter when each patient became eligible, we calculated the proportion of others in the same health plan who participated in NDPP. We used this variable, reflecting the intensity of external encouragement to start NDPP, as an instrumental variable (IV) to estimate differences in diabetes progression after NDPP treatment, while adjusting for individual risk factors. RESULTS: Among 3.73 million adults with diagnosed prediabetes, 245,896 had at least one claim for lifestyle treatment, of whom 27,703 (11.3%) were NDPP treated. NDPP-treated patients were more often women, aged <55 years, and less likely to live in low-poverty zip codes. With IV estimation, for every 100 adults participating in NDPP rather than in lower intensity services, there were 1.94 (95% CI 1.44-2.44) and 1.58 (95% CI 0.76-2.39) fewer cases of diabetes at 12 and 24 months, respectively. CONCLUSIONS: For privately insured adults with prediabetes, using NDPP was associated with lower progression to diabetes over 1-2 years.
Narasaki Y, Kalantar-Zadeh K, Zisman-Ilani Y
… +14 more, Klonoff DC, Kovesdy CP, Li Z, Jin A, Crowley S, M Belcher J, Gee P, Gin GE, Jordan M, You AS, Daza AC, Hanna R, Nguyen DV, Rhee CM
Diabetes Care
· 2026 Jul · PMID 42224118
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OBJECTIVE: Patients receiving dialysis who have diabetes have a high burden of dysglycemia. Whereas traditional glycemic markers have limited accuracy and convenience in dialysis, continuous glucose monitoring (CGM) prov...OBJECTIVE: Patients receiving dialysis who have diabetes have a high burden of dysglycemia. Whereas traditional glycemic markers have limited accuracy and convenience in dialysis, continuous glucose monitoring (CGM) provides automated, less invasive, and more comprehensive glycemic data than do conventional measures. However, it remains unclear whether CGM is associated with improved clinical outcomes in patients undergoing dialysis. RESEARCH DESIGN AND METHODS: We examined the association between CGM use versus non-CGM use and survival among U.S. veterans receiving dialysis who also have diabetes, using linked national Veterans Affairs, U.S. Renal Data System, and Medicare data. We examined data from veterans undergoing dialysis and with diabetes with incident CGM use (newly prescribed CGM) versus non-CGM use over the period January 2012 to December 2023 matched by propensity score (PS) to address confounding by indication and who were followed for all-cause mortality events through February 2025. Associations of CGM use versus non-CGM use with death were evaluated using complete case analysis and multiple imputation. RESULTS: Among 2,008 patients in the complete case analysis cohort, CGM use was associated with a lower mortality risk in PS-matched unadjusted and doubly adjusted Cox models (reference: non-CGM use; hazard ratio [HR] 0.86 [95% CI 0.76, 0.98]; and 0.83 [95% CI 0.75, 0.92], respectively). Among 3,088 patients in the multiple imputation cohort, CGM use was also associated with greater survival in PS-matched unadjusted and doubly adjusted Cox models (HR 0.88 [95% CI 0.77, 0.99]; and 0.84 [95% CI 0.73, 0.96], respectively). CONCLUSIONS: In veterans receiving dialysis who also had diabetes, incident CGM use was associated with better survival versus non-CGM use. Further studies are needed to determine underlying mechanisms and the impact of CGM on other dialysis outcomes.
OBJECTIVE: To determine outcomes from early versus later age of transfer from pediatric to adult type 1 diabetes (T1D) services, and factors associated with adult service HbA1c. RESEARCH DESIGN AND METHODS: We used a lon...OBJECTIVE: To determine outcomes from early versus later age of transfer from pediatric to adult type 1 diabetes (T1D) services, and factors associated with adult service HbA1c. RESEARCH DESIGN AND METHODS: We used a longitudinal design from the Australasian Diabetes Data Network (ADDN) registry. Transferred youth (2013-2022) were compared by age group at last pediatric visit (<18 vs. ≥18 years). Multivariable generalized estimated equations (GEEs) were used to model factors associated with adult-service HbA1c. Explanatory variables included transfer age, sex, socioeconomic status, and mean HbA1c in the 36 months before transfer. RESULTS: There were 784 youth (n = 342 early and 442 late transferers; 49.7% male). The mean ± SD transfer age was 18.1 ± 1.4 years with median [interquartile range] 18.2 [5.5; 38.9] months of adult-service follow-up. The gap between the last pediatric and first adult visit was longer in early transferers (13.5 [5.5; 28.0] vs. 8.1 [3.7; 23.8] months; P < 0.001). At first adult visit, early transferers had higher HbA1c (9.3 ± 1.9 vs. 8.8 ± 1.9% [78.2 ± 20.6 vs. 72.9 ± 20.4 mmol/mol]; P = 0.01) and socioeconomic disadvantage (score 976.8 ± 101.7 vs. 992.8 ± 81.1; P = 0.03). In multivariable GEEs, higher adult-service HbA1c was associated with younger transfer age (β = -0.15; 95% CI -0.30 to -0.002; P = 0.047), socioeconomic disadvantage (β = 0.58; 95% CI 0.10-1.06; P = 0.02), and higher mean HbA1c in the 36 months before transfer (β = 0.06; 95% CI 0.04-0.07; P < 0.001). CONCLUSIONS: Early transfer from pediatric to adult T1D services was associated with higher HbA1c in real-world settings. There is a need for caution with early transfer. Findings should be interpreted in the context of other international models to understand optimal transfer timing.
Crites K, Pape K, Sherman K
… +5 more, Mai M, Kabele C, Altavilla A, Cleary EM, Scifres CM
Diabetes Care
· 2026 May · PMID 42207920
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OBJECTIVE: To assess the relationship between restricted weight gain or weight loss (defined as weight gain <5 kg) and perinatal outcomes in pregnant individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: This wa...OBJECTIVE: To assess the relationship between restricted weight gain or weight loss (defined as weight gain <5 kg) and perinatal outcomes in pregnant individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study of 954 pregnant individuals with type 2 diabetes from two academic health centers. Maternal demographics, health care utilization, glycemia, and diabetes therapies were compared between groups. Weight gain <5 kg occurred in 327 (34.3%) of all pregnancies. Logistic regression analyses were used to compare perinatal outcomes between those with <5 kg weight gain and ≥5 kg weight gain, adjusted for covariates. RESULTS: Weight gain <5 kg was associated with a significant reduction in the risk for multiple perinatal outcomes, including large-for-gestational-age birth weight (adjusted odds ratio [aOR] 0.42, 95% CI 0.29-0.59), neonatal intensive care unit admission (aOR 0.74, 95% CI 0.55-0.98), hypertensive disorders of pregnancy (aOR 0.56, 95%C CI 0.42-0.75), and cesarean delivery (aOR 0.66, 95% CI 0.48-0.91). We did not detect a significant increase in small-for-gestational-age birth weight (aOR 1.61, 95% CI 0.96-2.71) or preterm birth (aOR 0.92, 95% CI 0.67-1.25) in pregnancies with maternal weight gain <5 kg. CONCLUSIONS: Weight gain <5 kg was associated with significantly lower rates of several adverse perinatal outcomes. Future interventional studies are needed to assess whether lifestyle or pharmacologic interventions can limit weight gain and improve both short- and long-term maternal and child outcomes in pregnant individuals with type 2 diabetes.
Donovan LE, Lemieux P, Yamamoto JM
… +16 more, Dunlop AD, Murphy HR, Liu SL, Chaput KH, Simmons D, Bell RC, Benham JL, Ross GP, Nerenberg KA, Booth JE, Mohammad K, Perkins BA, Crawford S, Tomlinson G, Feig DS, CIRCUIT Collaborative Group:
Diabetes Care
· 2026 May · PMID 42201836
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OBJECTIVE: Following the demonstrated improvement in pregnancy glycemia with Control-IQ closed loop in the Closed loop Insulin delivery by glucose Responsive Computer algorithms In Type 1 diabetes pregnancies (CIRCUIT) t...OBJECTIVE: Following the demonstrated improvement in pregnancy glycemia with Control-IQ closed loop in the Closed loop Insulin delivery by glucose Responsive Computer algorithms In Type 1 diabetes pregnancies (CIRCUIT) trial, we compared intrapartum and early postpartum glycemic effectiveness and safety with standard care in type 1 diabetes. RESEARCH DESIGN AND METHODS: The primary outcome of this prespecified analysis was percentage of time in pregnancy-specific glucose range (63-140 mg/dL) during the 24 h prior to childbirth, measured by continuous glucose monitoring. A key secondary outcome was percentage of time at <70 mg/dL in the first postpartum week, with additional secondary outcomes including continuous glucose monitoring metrics through 6 weeks postpartum. Analyses were adjusted for baseline measure, insulin delivery mode, and site. RESULTS: In the intrapartum period (24 h before delivery), 39 of 44 (89%) participants continued closed loop. Intravenous insulin was used intrapartum by one (2%) closed loop participant and 20 (45%) standard care participants (P < 0.001). Intrapartum closed loop users spent more time in pregnancy-specific glucose range (79.6% vs. 64.8%) than the standard-care group (mean adjusted difference 13.2 percentage points; 95% CI 5.2, 21.2). In the first postpartum week, the closed loop group spent less time <70 mg/dL (1.7% vs. 3.2%; mean adjusted difference -1.8 percentage points; 95% CI -0.9 to -2.7) compared with the standard care group. No maternal severe hypoglycemia occurred in the closed loop group, while one episode occurred in the standard care group postpartum. No diabetic ketoacidosis occurred in either group. CONCLUSIONS: Use of this closed loop system resulted in superior intrapartum and early postpartum glycemia compared with standard care, without safety concerns. Together with previous results, this supports use of this closed loop system throughout pregnancy, labor, and the early postpartum period.
Hilliard ME, Minard CG, Carreon SA
… +7 more, Levy WL, Lyons SK, Streisand R, Tang TS, McKay SV, Devaraj S, Anderson BJ
Diabetes Care
· 2026 May · PMID 42201336
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OBJECTIVE: Transition between pediatric and adult health care is complex, with high risk for loss to follow-up and suboptimal health outcomes for young adults with type 1 diabetes. This trial evaluated the efficacy of Di...OBJECTIVE: Transition between pediatric and adult health care is complex, with high risk for loss to follow-up and suboptimal health outcomes for young adults with type 1 diabetes. This trial evaluated the efficacy of DiaBetter Together, a 12-month strengths-based behavioral intervention delivered by trained peer mentors. The intervention aimed to help young adults navigate the transfer process to promote optimal glycemic outcomes, shorten time to adult care follow-up, and improve psychosocial outcomes. RESEARCH DESIGN AND METHODS: Using a single-site randomized clinical trial design, we compared the 12-month intervention to usual care among n = 100 young adults aged 17-25 years with type 1 diabetes following completion of pediatric diabetes care. Outcomes were measured at baseline and 6 and 12 months. The primary outcome was HbA1c, and secondary outcomes included person-reported psychosocial outcomes, self-management behaviors, and time to adult care. RESULTS: There were no statistically significant differences between study arms in HbA1c, self-management behaviors, or transfer to adult care. Significant differences in diabetes-specific health-related quality of life and diabetes distress between groups at 12 months favored the intervention arm. Intervention satisfaction was high. CONCLUSIONS: DiaBetter Together produced modest benefits for psychosocial outcomes during the challenging transfer period, although glycemic, behavioral, and transfer improvements remain difficult to achieve. Reduced sample size due to the coronavirus disease 2019 pandemic may have limited power to detect significant outcomes between groups and impacted outcomes. Peer mentor-based support may be useful to support young adults during transition to adult care, although additional intervention components are likely warranted to improve clinical outcomes.
Diabetes Care
· 2026 May · PMID 42201316
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OBJECTIVE: To investigate the impact of diabetes on incidence rates (IRs), incidence rate ratios (IRRs), and site-specific fracture susceptibility of subtrochanteric/femoral shaft (ST/FS) and hip fractures. RESEARCH DESI...OBJECTIVE: To investigate the impact of diabetes on incidence rates (IRs), incidence rate ratios (IRRs), and site-specific fracture susceptibility of subtrochanteric/femoral shaft (ST/FS) and hip fractures. RESEARCH DESIGN AND METHODS: Using Danish registries, we estimated IRs, IRRs, and fracture site associations of ST/FS and hip fracture (1997-2021) in adults ≥65 years old with type 1 diabetes, with type 2 diabetes, and without diabetes. RESULTS: IRRs were significantly higher in those with type 1 diabetes (ST/FS 2.53, P < 0.001; hip 2.17, P < 0.001) and type 2 diabetes (ST/FS 1.08, P = 0.002; hip 1.06, P = 0.008) compared with no diabetes. After age adjustment, only type 1 diabetes remained significantly increased. Adjusted analysis found both type 1 (OR = 1.14, P = 0.002) and type 2 (OR = 1.05, P = 0.008) diabetes to be significantly associated with higher odds of ST/FS compared with hip fractures. CONCLUSIONS: Type 1 diabetes was associated with increased incidence of femoral fractures and slightly higher odds of ST/FS than hip fractures after adjustment.
Zaitoon H, Feigin E, Abdul-Ghani M
… +3 more, Clarke GD, Tuttle KR, DeFronzo RA
Diabetes Care
· 2026 May · PMID 42201307
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Renal lipotoxicity, the maladaptive accumulation of lipid species in nonadipose kidney cells, is a key driver of chronic kidney disease (CKD), especially in individuals with diabetes. Insulin resistance, hyperinsulinemia...Renal lipotoxicity, the maladaptive accumulation of lipid species in nonadipose kidney cells, is a key driver of chronic kidney disease (CKD), especially in individuals with diabetes. Insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, and inflammation converge to disrupt renal lipid metabolism, resulting in toxic lipid deposition, mitochondrial dysfunction, and fibrosis, linking renal injury to the broader cardiovascular-kidney-metabolic (CKM) syndrome. This article synthesizes current evidence on the molecular and cellular mechanisms of renal lipotoxicity, its contribution to diabetic kidney disease (DKD) and CKM syndrome, and emerging therapeutic strategies targeting lipid dysregulation. In the kidney dysregulated lipid transporters, including CD36, FATPs, and FABPs, increase lipid uptake, while SREBPs and ChREBP drive de novo lipogenesis. Impaired fatty acid oxidation due to PPARα downregulation and defective cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) further exacerbate lipid accumulation. Podocytes, mesangial cells, endothelial cells, macrophages, and tubular epithelial cells undergo cell-specific injuries that trigger oxidative stress, endoplasmic reticulum stress, inflammation, and fibrotic remodeling. Mitochondrial dysfunction emerges as a unifying mechanism linking lipid overload to progressive nephron loss. Therapeutic interventions-including lifestyle modification, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, thiazolidinediones, statins, fibrates, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ABCA1 inducers-show potential to restore lipid homeostasis and preserve renal function. By connecting systemic metabolic dysfunction to CKD progression and cardiovascular risk, targeting renal lipotoxicity represents a promising therapeutic frontier in DKD and CKM syndrome, emphasizing the need for integrated metabolic and renal management strategies.