UNLABELLED: Refractory chronic diabetic wounds severely threaten patient survival; however, current treatments do not adequately promote healing. Cathepsin K (CTSK), a collagen-degrading protease upregulated in early dia...UNLABELLED: Refractory chronic diabetic wounds severely threaten patient survival; however, current treatments do not adequately promote healing. Cathepsin K (CTSK), a collagen-degrading protease upregulated in early diabetic wounds, presents a potential therapeutic target, and human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUMSC-EVs) show promise in regeneration but are associated with challenges related to production yield and stability. This study hypothesized that combining a stable CTSK inhibitor with hUMSC-EVs could enhance therapeutic efficacy and overcome these challenges. The hypothesis was tested using diabetic wound models in db/db mice with high glucose-exposed human dermal fibroblasts and human umbilical vein endothelial cells. The combination of a CTSK inhibitor and hUMSC-EVs at half doses outperformed full-dose monotherapies, accelerating wound healing through superior effects on collagen synthesis, cell proliferation, migration, and angiogenesis. Mechanistically, the combined treatment promoted wound healing by inhibiting ferroptosis. This strategy demonstrates accelerated wound healing with a lower hUMSC-EV dosage, suggesting promising clinical application potential. ARTICLE HIGHLIGHTS: A half-dose combination of a cathepsin K and human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUMSC-EVs) achieved superior diabetic wound healing compared with full-dose monotherapies. The combined therapy more potently suppressed ferroptosis in diabetic wound tissue as well as in high glucose-exposed fibroblasts and endothelial cells. Ferroptosis inhibition enhanced cell survival, migration, angiogenesis, and mitochondrial function in high glucose-exposed fibroblasts and endothelial cells. This dual-target strategy has the potential to reduce the hUMSC-EV dosage while improving wound healing outcomes, thus enhancing clinical potential.
Meier CZ, Wagner R, Ganslmeier M
… +10 more, Kantartzis K, Heni M, Peter A, Jumpertz-von Schwartzenberg R, Machann J, Schick F, Birkenfeld AL, Häring HU, Fritsche A, Stefan N
UNLABELLED: We previously identified six clusters of people at different risks of type 2 diabetes and/or comorbidities, of which cluster 3 (β-cell deficient) and 5 (older age, higher BMI, severe insulin resistance) had a...UNLABELLED: We previously identified six clusters of people at different risks of type 2 diabetes and/or comorbidities, of which cluster 3 (β-cell deficient) and 5 (older age, higher BMI, severe insulin resistance) had a high risk of progression to diabetes. We have now investigated whether cluster 3 and 5 individuals differed from those of the other clusters in changes in insulin sensitivity, insulin secretion, and the development of type 2 diabetes during a long-term reduction of body weight. A total of 190 participants completed a 24-month lifestyle intervention in the Tübingen Lifestyle Intervention Program (TULIP) and were followed up for 8.7 ± 1.6 years. Sixty participants had a weight loss ≥3% (mean reduction of 8%) at the long-term follow-up. Of them, cluster 5 participants (n = 17) had a larger increase of adjusted fasting glycemia compared with the cluster group 1,2,4,6 (n = 33) and cluster 3 (n = 10) and a larger increase of adjusted 2-h glucose levels compared with cluster 3 (all P < 0.05). In cluster 5, a larger decrease of adjusted insulin secretion compared with cluster 3 (P = 0.01) and cluster group 1,2,4,6 (P = 0.05) was observed. Forty-one percent of cluster 5 participants (0% in cluster group 1,2,4,6 and 10% in cluster 3) developed type 2 diabetes. In conclusion, despite a sustained and large amount of weight loss, diabetes risk cluster 5 participants had deterioration of glycemia and insulin secretion and a high risk of type 2 diabetes. If this result can be replicated in a prospective study, people of this cluster would need targeted prevention strategies. ARTICLE HIGHLIGHTS: There may be heterogeneity in the response to a lifestyle intervention to prevent type 2 diabetes. This study investigated whether participants of Tübingen Lifestyle Intervention Program (TULIP) type 2 diabetes risk clusters 3 and 5, who have a very high risk of diabetes, benefit from long-term weight loss following a 2-year lifestyle intervention. Diabetes risk cluster 5 participants had an impaired response regarding improvement of glycemia and insulin secretion and a high risk of developing type 2 diabetes, despite a long-term (9-year) mean weight loss of 8%. Alternative or intensified interventions should be considered for people in Tübingen type 2 diabetes risk cluster 5.
UNLABELLED: The strongest type 2 diabetes signal in Indigenous Americans from Arizona is in intron 15 of KCNQ1. We previously identified a functional region in this intron that contained four type 2 diabetes-associated s...UNLABELLED: The strongest type 2 diabetes signal in Indigenous Americans from Arizona is in intron 15 of KCNQ1. We previously identified a functional region in this intron that contained four type 2 diabetes-associated single nucleotide polymorphisms (SNPs) (rs2299620, rs2237896, rs2237897, and rs74046911) and demonstrated functionality of this fragment using Indigenous American induced pluripotent stem cell (iPSC)-derived pancreatic islets (SC-islets). In the current study, we used isogenic iPSCs with targeted edits at these four SNPs, and three additional SNPs (rs2237895, rs60808706, and rs234864), to generate SC-islets and study the effect of these variants during different developmental stages. We identify an 11% reduction in stem cell-derived β-cells (SC-β-cells) in SC-islets with the risk alleles, suggesting an effect of these variants on β-cell mass. We further show premature endocrine commitment in cells with the risk allele and lower rate of β-cell commitment during the endocrine progenitor stages, likely due to differences in H19 and INS gene expression dynamics. We also show that the differential expression may be attributable to lower CpG methylation and higher chromatin accessibility in cells with the risk alleles. In summary, the type 2 diabetes SNPs at KCNQ1 affect SC-β-cell generation, and this effect is manifested early during development, likely via an epigenomic effect on gene regulation. ARTICLE HIGHLIGHTS: We previously developed an induced pluripotent stem cell-based model to study an intronic region of KCNQ1 that represents the strongest association signal with type 2 diabetes in Indigenous Americans from Arizona. The current study builds on this model by using CRISPR/Cas9-edited isogenic cells that differ only by targeted type 2 diabetes single nucleotide polymorphisms in this intronic region. The effect of KCNQ1 type 2 diabetes single nucleotide polymorphisms on pancreatic β-cell development and the probable mechanism of this effect were previously unknown. The current study shows an effect on INS and H19 gene expression dynamics specifically during the endocrine progenitor stage of pancreatic islet development likely via an epigenomic effect on gene regulation resulting in generation of lower β-like cells. Individuals carrying KCNQ1 risk alleles for type 2 diabetes will likely benefit from therapeutics that increase pancreatic β-cell mass.
UNLABELLED: Diabetic kidney disease (DKD) is a major cause of end-stage renal failure, driven by tubulointerstitial fibrosis. While persistent Wnt/β-catenin signaling promotes fibrosis, its sustained activation mechanism...UNLABELLED: Diabetic kidney disease (DKD) is a major cause of end-stage renal failure, driven by tubulointerstitial fibrosis. While persistent Wnt/β-catenin signaling promotes fibrosis, its sustained activation mechanism was unclear. This study, using DKD patient samples, db/db mice, and Nedd4L knockout models combined with molecular techniques, identified a key pathogenic circuit. LGR5, upregulated in diabetic kidneys, amplifies Wnt signaling by stabilizing Wnt receptors. The E3 ligase Nedd4L counteracts this by targeting LGR5 for degradation. Crucially, in DKD, the activated β-catenin/TCF4 complex transcriptionally represses Nedd4L, creating a self-reinforcing feedback loop that maintains high LGR5 levels and perpetual Wnt/β-catenin activation. This loop promotes nuclear translocation of β-catenin and expression of fibrotic mediators like Snail and fibronectin. Disrupting this circuit by restoring Nedd4L or knocking down LGR5 attenuated renal fibrosis in experimental models. Thus, the LGR5-Wnt-Nedd4L feed-forward circuit is a key driver of fibrosis in DKD, suggesting Nedd4L restoration or LGR5 inhibition as potential therapeutic strategies. ARTICLE HIGHLIGHTS: This study was undertaken to explain why Wnt/β-catenin signaling stays persistently active in diabetic kidney disease tubules. This study aimed to determine whether LGR5 amplifies Wnt signaling and whether Nedd4L controls LGR5 stability via ubiquitination. This study found a feed-forward loop: Wnt induces LGR5, LGR5 limits RNF43-receptor interactions to stabilize Wnt receptors, and β-catenin/TCF4 represses Nedd4L to reduce LGR5 ubiquitination. This LGR5-Wnt-Nedd4L circuit represents a targetable mechanism to dampen Wnt signaling and renal fibrosis in diabetic kidney disease.
UNLABELLED: Dietary, surgical, and pharmacological methods can effectively reduce body weight; however, rapid weight loss can also be accompanied by a loss of lean mass. Previously, we found that intestinal fibroblast gr...UNLABELLED: Dietary, surgical, and pharmacological methods can effectively reduce body weight; however, rapid weight loss can also be accompanied by a loss of lean mass. Previously, we found that intestinal fibroblast growth factor 15 (FGF15; mouse ortholog of human FGF19) protects against lean mass loss after sleeve gastrectomy in mice and that circulating FGF19 predicts lean mass retention after very-low-energy diets in humans. We investigated the regulatory functions of intestine-derived FGF15 in lean and bone mass, glucose tolerance, and changes in bile acid and lipid parameters after weight loss in mice. Rapid weight loss was induced either by transitioning high-fat diet-fed intestine-specific FGF15-knockout and control mice to standard chow for 25 days or by administering daily semaglutide. Semaglutide decreased body weight, fat mass, and lean mass, all of which returned to baseline levels after treatment cessation. Lean mass was not preserved during dietary intervention in mice lacking FGF15, whereas semaglutide decreased lean mass irrespective of FGF15. Dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance was observed with semaglutide. Semaglutide modulated shifts in bile acid composition, with particularly pronounced changes seen in the absence of FGF15. These data indicate that multiple factors, including intervention strategy and dietary context, modulate gut-liver and muscle communication and preservation of lean mass. ARTICLE HIGHLIGHTS: We evaluated the role of intestinal fibroblast growth factor 15 (FGF15) in regulating lean mass, glucose tolerance, bile acid, and lipid profiles after diet-induced compared with semaglutide-induced weight loss in mice. Mice lacking FGF15 lost more lean mass during dietary intervention, whereas semaglutide decreased lean mass irrespective of FGF15; dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance and elevated cecal bile acid levels were observed with semaglutide; and loss of FGF15 altered bile acid levels, whereas semaglutide treatment further regulated these levels in both genotypes, with particularly pronounced changes observed in the absence of FGF15. Weight-loss intervention strategy and dietary context modulate gut-liver and muscle communication and preservation of lean mass.
UNLABELLED: Diabetes-related vascular complications are characterized by impaired ischemia-driven angiogenesis and delayed wound healing. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases. We...UNLABELLED: Diabetes-related vascular complications are characterized by impaired ischemia-driven angiogenesis and delayed wound healing. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases. We previously identified that miRNA-181c-5p has anti-angiogenic properties, but its role in diabetes is unknown. In a hindlimb ischemia model, streptozotocin-rendered diabetic mice treated with an miRNA-181c-5p inhibitor (anti-miR-181c-5p) exhibited improved blood flow reperfusion and increased arteriolar density compared with diabetic anti-miR-negative (anti-miR-Neg) control mice. Diabetic anti-miR-Neg mice had reduced perfusion relative to nondiabetic control mice. In a murine wound-healing model, inhibition of miRNA-181c-5p rescued diabetes-impaired wound closure rate and increased capillary density, whereas diabetic anti-miR-Neg wounds healed more slowly than nondiabetic anti-miR-Neg wounds. In vitro, inhibition of miRNA-181c-5p increased endothelial tubule formation and cell migration under high-glucose conditions. Mechanistically, anti-miR-181c-5p elevated VEGFA and VEGFR2 protein expression, ERK2 phosphorylation, and Bcl2 mRNA levels. Whole-transcriptome sequencing identified two genes (Elmo3 and Trib1) that were upregulated in anti-miR-181c-5p-treated hindlimbs and wounds. Luciferase assays confirmed VEGFA as a likely direct target of miR-181c-5p, whereas ERK2, ELMO3, and TRIB1 are indirectly regulated. These findings demonstrate that miRNA-181c-5p inhibition promotes angiogenesis and improves vascular repair in diabetes, identifying miRNA-181c-5p as a potential therapeutic target for preventing diabetic vascular complications. ARTICLE HIGHLIGHTS: We found that patients with diabetic vascular complications have elevated circulating levels of miR-181c-5p, an antiangiogenic microRNA. We tested whether inhibition of miR-181c-5p increases angiogenesis in diabetic hindlimb ischemia and wound-healing models and elucidated its mechanisms of action. miR-181c-5p inhibition rescues diabetes-impaired ischemia-driven angiogenesis and wound healing and increases endothelial angiogenic capacity. This was concomitant with increases in VEGFA, VEGFR2, ERK2 phosphorylation, Bcl2, Elmo3, and Trib1. VEGFA is a likely direct target of miR-181c-5p, whereas ERK2, ELMO3, and TRIB1, although upregulated after miR-181c-5p inhibition, are indirectly regulated downstream. miR-181c-5p inhibition represents a promising therapeutic strategy for diabetic vascular complications.
UNLABELLED: Phosphoglucomutase 1 (PGM1) is a type 1 diabetes susceptibility gene that potentially plays a key role in regulating central carbon metabolism in β-cells. Previous work suggested that β-cell PGM1 transcriptio...UNLABELLED: Phosphoglucomutase 1 (PGM1) is a type 1 diabetes susceptibility gene that potentially plays a key role in regulating central carbon metabolism in β-cells. Previous work suggested that β-cell PGM1 transcription is lowered after coxsackievirus B4 infection. Thus, we hypothesized that decreased PGM1 levels disrupt β-cell metabolic homeostasis and result in β-cell fragility and type 1 diabetes. First, we showed that the synthetic double-stranded RNA polyinosinic:polycytidylic acid, or Poly(I:C) attenuated PGM1 transcription both in human islets and EndoC-βH1 cell line. At 5.5 mmol/L glucose, PGM1 deficiency enhanced the rate of glycolysis, tricarboxylic acid cycle, hexosamine, and pentose phosphate pathway. However, at 20 mmol/L glucose, PGM1-deficient cells showed impaired mitochondrial respiration. Moreover, truncated N-glycans were enriched in PGM1-deficient cells, suggesting aberrant protein glycosylation. Autophagic flux, which was dependent on the lysosomal glycosylated protein function, was impaired in PGM1-deficient cells. Increased endoplasmic reticulum stress was evident in PGM1-deficient cells. Our results suggest that PGM1 is a metabolic regulator of pancreatic β-cells. Its deficiency leads to metabolic imbalance and cellular stress, potentially augmenting type 1 diabetes development. ARTICLE HIGHLIGHTS: In the β-cell, the expression of phosphoglucomutase 1 (PGM1), a type 1 diabetes risk gene, is reduced by double-stranded RNA exposure, modeled by polyinosinic:polycytidylic acid transfection. Deficient PGM1 expression disrupts central carbon metabolism, protein glycosylation, and autophagic flux. These changes precipitate endoplasmic reticulum stress and mitochondrial dysfunction, potentially augmenting type 1 diabetes development.
UNLABELLED: The naturally occurring peptide, liver-expressed antimicrobial peptide 2 (LEAP2), has gained interest as a ghrelin receptor antagonist. We previously reported reduced food intake and plasma glucose-lowering e...UNLABELLED: The naturally occurring peptide, liver-expressed antimicrobial peptide 2 (LEAP2), has gained interest as a ghrelin receptor antagonist. We previously reported reduced food intake and plasma glucose-lowering effects of LEAP2 infusion in lean healthy men; however, the effects of this competitive antagonist and inverse agonist of the ghrelin receptor in men with obesity have not been investigated. In the current study, 20 men with obesity were enrolled in a randomized, double-blind, placebo-controlled, crossover study comprising two experimental visits, each involving a ∼5-h intravenous infusion of LEAP2 (infusion rate 40 pmol/kg/min) or placebo during which a liquid mixed meal test and a subsequent ad libitum meal test were performed. The LEAP2 infusion resulted in a fivefold increase in plasma concentrations of LEAP2 compared with placebo. The infusion lowered postprandial plasma glucose levels and reduced ad libitum food intake by ∼12%. We conclude that a continuous intravenous LEAP2 infusion reduces glycemia and food intake in men with obesity, supporting further exploration of LEAP2's therapeutic potential in obesity and related metabolic conditions. ARTICLE HIGHLIGHTS: Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist and inverse agonist, reduces food intake and improves markers of dysmetabolism in preclinical studies and in lean men; however, the effects of LEAP2 in obesity are unknown. We investigated the effects of exogenous LEAP2 on ad libitum food intake and metabolic parameters in men with obesity. We found that LEAP2 reduces ad libitum food intake and reduces postprandial plasma glucose concentration, revitalizing the ghrelin receptor as a potential target in the treatment of obesity and its related conditions.
Eid SA, Jaisil P, Guo K
… +18 more, Hayes JM, Pacut C, Rigan DM, Carter A, Teener SJ, Kim B, Kiriluk C, Lentz W, Miller CM, Webber-Davis I, McQuown H, Jang DG, Patterson A, Koubek EJ, Bridges D, Hur J, Meyer JD, Feldman EL
UNLABELLED: Metabolic syndrome (MetS) is a growing health concern that increases risk for peripheral neuropathy (PN), defined by nerve degeneration and sensory dysfunction. Although lifestyle strategies, like ketogenic d...UNLABELLED: Metabolic syndrome (MetS) is a growing health concern that increases risk for peripheral neuropathy (PN), defined by nerve degeneration and sensory dysfunction. Although lifestyle strategies, like ketogenic diet (KD) and exercise, are known to mitigate MetS, their efficacy in maintaining nerve health or reversing established PN is less clear. First, in a maintenance paradigm, we tested whether long-term KD could maintain nerve health in mice, as opposed to a Western-style high-fat diet (HFD) that induces MetS PN. Second, in an intervention paradigm of mice with established MetS PN, we compared the efficacy of low-fat standard diet, KD, exercise, and combined KD-exercise interventions in reversing MetS PN. Long-term KD maintained body composition, nerve function, and neuromuscular innervation. In mice with established MetS PN, all interventions improved metabolic parameters and nerve function, albeit to varying extents. Transcriptomic profiling revealed that HFD dysregulated genes related to cytoskeletal dynamics and inflammation in sciatic nerve, with interventions partially reversing these changes. In muscle, dietary interventions modulated fatty acid and amino acid metabolism. Notably, exercise generated a unique gene expression signature in nerve and muscle. These findings support KD and exercise as promising approaches for treating MetS PN and offer mechanistic insights into their therapeutic benefits. ARTICLE HIGHLIGHTS: Metabolic syndrome (MetS) increases risk for peripheral neuropathy (PN), a progressive nerve disorder with limited treatment options. We examined whether long-term ketogenic diet (KD) could maintain nerve health, and whether KD, exercise, or both could reverse established MetS PN. Maintenance KD preserved body composition, liver health, and nerve function, while all interventions improved metabolic and nerve outcomes to varying degrees. Transcriptomic profiling of sciatic nerve and gastrocnemius muscle revealed partial reversal of MetS-induced inflammatory, cytoskeletal, and metabolic gene alterations. These findings highlight KD and exercise for treating MetS PN.
UNLABELLED: An inflection point (IP) marking accelerated β-cell decline occurs ∼1-2 years before type 1 diabetes diagnosis. Precisely determining this timing could optimize clinical intervention. We developed machine lea...UNLABELLED: An inflection point (IP) marking accelerated β-cell decline occurs ∼1-2 years before type 1 diabetes diagnosis. Precisely determining this timing could optimize clinical intervention. We developed machine learning models to predict proximity to the inferred metabolic IP using oral glucose tolerance test (OGTT) data from islet autoantibody-positive individuals in the TrialNet Pathway to Prevention study. OGTTs were retrospectively labeled by estimating time to the IP using thresholds from 1.2 to 1.6 years. Models were trained on engineered glucose and C-peptide dynamics, slopes, and composite indices, with feature selection by recursive feature elimination (RFE). Classifiers included support vector machines (SVM), random forests, and gradient boosting; a Cox proportional hazards model was also applied to estimate visit-level time to diagnosis and derive time-to-IP predictions. External validation was performed in the independent Diabetes Prevention Trial-Type 1 cohort. The best-performing model-SVM with RFE at the 1.4-year threshold-achieved an area under the curve of 0.77 (95% CI 0.72-0.82). The Cox model provided complementary numeric estimates of time to diagnosis and time to IP, sensitive to the cohort-level lead time offset (Δ). These findings show that machine learning and survival analysis can support early metabolic shift detection, enabling timely risk stratification and personalized monitoring in at-risk individuals. ARTICLE HIGHLIGHTS: We undertook this study to improve early identification of the metabolic inflection point (IP) preceding clinical type 1 diabetes in autoantibody-positive individuals. We aimed to develop and validate machine learning models using oral glucose tolerance test-derived dynamic features to detect proximity to the IP. A support vector machine trained on TrialNet Pathway to Prevention and tested on Diabetes Prevention Trial-Type 1 achieved an area under the curve of 0.77 at 1.4 years prior to diagnosis, with strong calibration and interpretability. Additionally, a Cox proportional hazards model provided numeric estimates of time to IP, offering complementary predictions. These results can support earlier intervention and timely monitoring through personalized oral glucose tolerance test-based risk stratification.
We previously reported that transgenic overexpression of Nfkbid in NOD mice led to robust type 1 diabetes protection associated with enhanced negative selection of autoreactive T cells and expansion of regulatory T cells...We previously reported that transgenic overexpression of Nfkbid in NOD mice led to robust type 1 diabetes protection associated with enhanced negative selection of autoreactive T cells and expansion of regulatory T cells (Tregs) with increased suppressive capacity. The goal of this study was to further identify cellular and molecular mechanisms underlying strong protection from type 1 diabetes imbued by overexpressing Nfkbid. Transcript analysis of Tregs from Nfkbid-overexpressing NOD mice show enrichment of cellular replication pathways. Effector T cells from Nfkbid-overexpressing NOD mice have increased indicators of activation-induced exhaustion in pancreatic lymph nodes and islets. This trait is intrinsic to Nfkbid-overexpressing T cells, as ex vivo anti-CD3 stimulation of splenic-derived T cells can reproduce this phenotype. Anti-PD-1 administration breaks the diabetes protective effect. Furthermore, we found that Nfkbid-overexpressing dendritic cells, but not B cells, have an enhanced capacity to stimulate proliferation of diabetogenic AI4 CD8+ T cells (with wild-type levels of Nfkbid). Conversely, B cells, but not dendritic cells, drive enhanced de novo conversion of regulatory T cells from effector T cells. Together, this study documents additional mechanisms that likely synergize to contribute to the diabetes-protective effects of Nfkbid overexpression. Understanding the mechanisms underlying protection from Nfkbid overexpression may lead to novel therapeutic avenues.
UNLABELLED: The pentose phosphate pathway (PPP) furnishes NADPH for hepatic de novo lipogenesis, driving intrahepatic lipid (IHL) accumulation. The aim of the current study was to examine the association between the PPP,...UNLABELLED: The pentose phosphate pathway (PPP) furnishes NADPH for hepatic de novo lipogenesis, driving intrahepatic lipid (IHL) accumulation. The aim of the current study was to examine the association between the PPP, proxied by 24-h urinary erythritol, and IHL content at the population level. We used cross-sectional data from the Maastricht Study, a population-based cohort study (N = 1,494; mean ± SD age 59 ± 8 years; 49% women). We first assessed the relationship between 24-h urinary erythritol and IHL content (quantified with 3T Dixon MRI), with adjustment for age, sex, type 2 diabetes, proxies of socioeconomic status/lifestyle, MRI lag time, BMI, and intake of erythritol-containing food items. Second, we performed a genome-wide association study (GWAS) for 24-h urinary erythritol (N = 2,000) and Mendelian randomization (MR) study using common variants in genes associated with erythritol in relation to IHL content. In the fully adjusted model, 24-h urinary erythritol levels were associated with higher (10log) IHL content. The GWAS identified one genome-wide significant locus (rs72686491; TESK2) and replicated two previously reported genetic variants at nominal significance. MR analysis, using these three genetic instruments, did not reveal a statistically significant association between genetically predicted erythritol levels and IHL content. The findings of this population-based study show that higher PPP flux is associated with higher IHL content, a well-established risk factor for type 2 diabetes. An active role for erythritol per se was excluded by MR analysis. ARTICLE HIGHLIGHTS: The role of the pentose phosphate pathway (PPP) in the pathogenesis of intrahepatic lipid (IHL) accumulation has not been studied before in humans. Is the PPP, proxied by 24-h urinary erythritol, associated with IHL content at the population level? In the fully adjusted model, 24-h urinary erythritol levels were associated with higher IHL content. Furthermore, genetically predicted erythritol levels were not associated with liver fat, suggesting that erythritol per se is not responsible for the former observation. Findings of the current study suggest that 1) the PPP is associated with IHL content at the population level, and 2) erythritol could potentially serve as a urinary biomarker for IHL content.
UNLABELLED: GRP78/BiP/HSPA5 is a widely expressed endoplasmic reticulum (ER) chaperone that also performs the critical role of regulating the unfolded protein response, an adaptive mechanism that maintains ER homeostasis...UNLABELLED: GRP78/BiP/HSPA5 is a widely expressed endoplasmic reticulum (ER) chaperone that also performs the critical role of regulating the unfolded protein response, an adaptive mechanism that maintains ER homeostasis. As the exclusive source of circulating insulin, pancreatic β-cells are prone to ER stress due to proinsulin synthesis workload. GRP78 is important for the ER stress response, but it is unknown whether β-cells require GRP78 in the absence of metabolic stress. Here, we report the impact of genetic deletion of GRP78 in β-cells of healthy adult mice during normal metabolic conditions. Glucose intolerance occurred in both sexes, mildly in females but profoundly in males, concomitant with weight loss. Islet size and β-cell mass were reduced only in males. Both sexes showed similar increases in β-cell death and residual α-cell proportion, but females more robustly showed increased β-cell proliferation. Intriguingly, dedifferentiation was prominent in males, both in vivo and ex vivo, and male islet cells showed hyperactive induction of ATF6 target genes during ex vivo Grp78 deletion compared with female. We conclude that GRP78 is essential for β-cell health, even in resting conditions, and that sex differences exist in the β-cell ER stress response. ARTICLE HIGHLIGHTS: We investigated the consequence of reducing GRP78 abundance in pancreatic β-cells of adult mice in normal physiological conditions. Genetic Grp78 reduction caused β-cell failure and diabetes in male mice, with weight loss, hyperglycemia, glucose intolerance, β-cell mass reduction, and β-cell dedifferentiation. Male and female mice showed similar increases in β-cell death, but proliferation was more profoundly increased in females. Ex vivo Grp78 deletion led to hyperactivation of ATF6 target genes in male islet cells compared with female. Preserving β-cell GRP78 abundance may reduce the likelihood of diabetes, especially in males.
UNLABELLED: Noninvasive measurement of pancreatic β-cell mass remains an important unmet need in type 1 diabetes because conventional surrogate markers, such as C-peptide, often lack sensitivity in advanced disease. This...UNLABELLED: Noninvasive measurement of pancreatic β-cell mass remains an important unmet need in type 1 diabetes because conventional surrogate markers, such as C-peptide, often lack sensitivity in advanced disease. This study evaluated the glucagon-like peptide 1 receptor-targeted positron emission tomography tracer, 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), to determine its ability to visualize pancreatic β-cell mass. Positron emission tomography/computed tomography performed at 60 and 120 min after tracer injection in individuals with type 1 diabetes was compared with data from healthy control participants. No serious adverse events occurred. Pancreatic uptake was consistently lower in individuals with type 1 diabetes and showed clear separation between individuals with insulin-dependent diabetes and healthy control participants at 120 min. Pancreatic uptake at 120 min correlated with fasting C-peptide index and inversely with hemoglobin A1c and daily insulin dose per body weight. These findings support [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography as a noninvasive approach for assessing β-cell mass and disease status. ARTICLE HIGHLIGHTS: We undertook this study to address the persistent need for noninvasive assessment of β-cell mass in type 1 diabetes. We aimed to determine whether 18F-exendin positron emission tomography/computed tomography can reliably visualize residual β-cell mass and distinguish stages of disease. We found that pancreatic tracer uptake was consistently reduced in type 1 diabetes, differentiated insulin-dependent patients from control participants, and aligned with markers of β-cell function and glycemic status. Our findings suggest that 18F-exendin imaging may offer fundamental platform for disease staging, therapeutic monitoring, and individualized care.