Female C57BL/6 J mice are relatively resistant to weight gain, which complicates the study of sex-specific metabolic responses. So, we used ob/ob mice to examine semaglutide-induced weight loss in both sexes. We wanted t...Female C57BL/6 J mice are relatively resistant to weight gain, which complicates the study of sex-specific metabolic responses. So, we used ob/ob mice to examine semaglutide-induced weight loss in both sexes. We wanted to determine whether semaglutide-induced weight loss produces sex-specific effects on skeletal muscle mass and function in ob/ob mice. Semaglutide had minimal effects on skeletal muscle mass and strength in ob/ob mice. In particular, females were completely resistant to loss of muscle mass. These findings reveal that semaglutide exerts sex-specific effects, highlighting a need for further research into the molecular mechanisms driving these distinct protective outcomes.
UNLABELLED: Impaired cognitive function caused by insulin-induced hypoglycemia is a complication of type 1 diabetes mellitus (T1DM) for which no protective strategies are currently available. In this first-in-human mecha...UNLABELLED: Impaired cognitive function caused by insulin-induced hypoglycemia is a complication of type 1 diabetes mellitus (T1DM) for which no protective strategies are currently available. In this first-in-human mechanistic study using magnetic resonance spectroscopy, the direct contribution of the infused ketone β-hydroxybutyrate (BHB) to brain metabolism during clamped hypoglycemia was greater in participants with T1DM than healthy participants. In a randomized dietary intervention trial of participants with T1DM and recurrent hypoglycemia, receiving medium-chain triglycerides (MCTs) as a dietary ketone precursor was associated with higher working memory performance and greater regional brain activation during clamped hypoglycemia compared with an isocaloric standard diet. Counterregulatory hormone responses to hypoglycemia were not affected by MCT supplementation. We conclude that ketone bodies are well suited to support brain metabolism in persons with T1DM experiencing insulin-induced hypoglycemia. Dietary MCT supplementation raising BHB may represent a novel strategy to prevent hypoglycemia-induced brain injury in this vulnerable patient population. ARTICLE HIGHLIGHTS: There are currently no strategies to prevent cognitive impairment caused by insulin-induced hypoglycemia in type 1 diabetes mellitus (T1DM). We examined whether β-hydroxybutyrate (BHB) supports brain metabolism during clamped hypoglycemia and whether dietary medium-chain triglycerides (MCTs), by raising BHB availability, elicit this protective effect. BHB contributed more to brain metabolism in participants with T1DM than in healthy control participants, and long-term MCT supplementation improved working memory and brain activation during hypoglycemia. Dietary MCT supplementation may protect against hypoglycemia-related cognitive deficits in T1DM.
Challenging the view that elevated circulating adenosine deaminase (ADA) is merely a secondary phenomenon, this study defines its pathogenic role in linking dyslipidemia to β-cell failure and establishes adenosine (ADO)...Challenging the view that elevated circulating adenosine deaminase (ADA) is merely a secondary phenomenon, this study defines its pathogenic role in linking dyslipidemia to β-cell failure and establishes adenosine (ADO) homeostasis restoration as a disease-remitting therapy. We identify tissue-specific compensatory ADA upregulation that paradoxically fails to prevent systemic ADO accumulation, with elevated adenosine selectively inducing apoptosis in immune and pancreatic β-cells. We establish a novel systemic clearance-local decompression therapeutic mechanism in which exogenous ADA reduces circulating ADO, normalizes compensatory tissue ADA hyperactivity, and rescues islet function. This work redefines plasma ADA from a diagnostic marker to a therapeutic target, providing the rationale for an ADA-based therapy that uniquely combines immune modulation with metabolic correction to halt β-cell failure progression.
This study identifies the carbohydrate-responsive element-binding protein as the direct transcriptional activator of TXNIP in vascular smooth muscle cells under conditions of hyperglycemia. Aorta-specific TXNIP knockdown...This study identifies the carbohydrate-responsive element-binding protein as the direct transcriptional activator of TXNIP in vascular smooth muscle cells under conditions of hyperglycemia. Aorta-specific TXNIP knockdown demonstrates therapeutic potential by alleviating arterial stiffness and attenuating atherosclerotic plaque in diabetic mice. Pharmacologic inhibition of TXNIP or activation of AKT ameliorates the senescent phenotype, highlighting a druggable pathway in diabetic vasculopathy.
UNLABELLED: Diabetic retinopathy (DR) is a major cause of irreversible vision loss driven primarily by retinal vascular damage, yet its mechanisms remain incompletely understood. Here, we identify calnexin (Canx) as a cr...UNLABELLED: Diabetic retinopathy (DR) is a major cause of irreversible vision loss driven primarily by retinal vascular damage, yet its mechanisms remain incompletely understood. Here, we identify calnexin (Canx) as a critical suppressor of pathological angiogenesis in DR. We demonstrate that hyperglycemia synergizes with TNF-α to downregulate Canx in mouse retinal microvascular endothelial cells. This loss of Canx activates Nox4, leading to hyperactivation of the Ire1α/Xbp1s branch of the unfolded protein response. Consequently, endoplasmic reticulum stress is amplified, pathological Vegfa transcription is upregulated, and the inner blood-retinal barrier is disrupted. In streptozotocin-induced diabetic mouse models, Canx deficiency exacerbated endothelial dysfunction and retinal vascular pathology. Conversely, both adalimumab treatment and adeno-associated virus-mediated Canx overexpression in vivo suppressed the Nox4/Ire1α/Xbp1s/Vegfa cascade, significantly reduced vascular leakage and acellular capillary formation, attenuated retinal thinning, and normalized endothelial cell functions (proliferation, migration, tube formation). Collectively, our findings establish Canx as a key upstream regulator of Vegfa-mediated vascular injury in DR. Our study suggests that targeting Canx, either genetically or via repurposing adalimumab, represents a source-specific strategy to halt DR progression by blocking pathological Vegfa production at its origin. ARTICLE HIGHLIGHTS: Diabetic retinopathy (DR) remains a leading cause of blindness, with current interventions often failing to halt progression. In mouse retinal microvascular endothelial cells (mRMVECs), hyperglycemia/tumor necrosis factor-α suppress calnexin (Canx). Canx downregulation drove vascular pathology in mRMVECs via the Nox4/Ire1α/Xbp1s pathway, amplifying endoplasmic reticulum stress and pathological Vegfa production. In streptozotocin-induced diabetic mouse models, Canx overexpression or adalimumab intervention attenuated DR in vivo by blocking this cascade. Our findings establish Canx as a critical upstream regulator, proposing Canx-targeted strategies as source-specific therapeutics for DR.
Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabe...Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.
UNLABELLED: Type 2 diabetes partitioned polygenic risk scores (pPRS) are related to their physiological impact on insulin secretion and sensitivity. We investigated associations of two pPRS sets obtained from multiancest...UNLABELLED: Type 2 diabetes partitioned polygenic risk scores (pPRS) are related to their physiological impact on insulin secretion and sensitivity. We investigated associations of two pPRS sets obtained from multiancestry cohorts with the relationship between insulin secretion and sensitivity and diabetes incidence in the Diabetes Prevention Program (DPP). We generated 12 and 8 pPRS from soft- and hard-clustering approaches, respectively, in 2,052 DPP participants randomized to intensive lifestyle intervention, metformin, or placebo. Baseline insulin secretion demand and compensation were estimated through the relationship between secretion and sensitivity. Most expected associations of pPRS with insulin secretion and sensitivity were replicated. Some pPRS associated with lower secretion compensation. Global PRS associations with diabetes incidence were stronger than those of any pPRS in both sets. When insulin secretion compensation and demand modified pPRS associations with diabetes incidence, modification occurred only for demand: higher compensation associated with decreased diabetes incidence regardless of pPRS level. A β-cell dysfunction pPRS interacted with DPP treatments in a way that suggested that these treatments may be less effective in those genetically predisposed to diabetes due to insulin deficiency. Regardless of genetic risk as measured by pPRS, inadequate compensatory insulin secretion contributes to progression to diabetes in people with prediabetes. ARTICLE HIGHLIGHTS: The extent to which partitioned polygenic risk scores (pPRS) for type 2 diabetes influence the relationship between insulin secretion and sensitivity has not been examined in people with prediabetes. We investigated whether insulin secretion compensation and demand, estimated through the relationship between insulin secretion and sensitivity, mediated or modified the associations of two sets of pPRS with diabetes incidence in Diabetes Prevention Program participants. Several pPRS modified the effects of insulin demand on diabetes incidence, but none modified the effect of compensation. In people with prediabetes, inadequate compensatory insulin secretion contributes to progression to diabetes regardless of genetic risk as measured by pPRS.
Li C, Gu K, Huang Y
… +16 more, Wei L, Qiu Q, Feng L, Zhang B, Wang S, Yang J, Zhang X, Zheng J, Sun P, Li J, Liu M, Zhang GL, Liao DJ, Liu M, Cheng J, Zhang G
Ribosomal S6 kinase 4 (Rsk4) is predominantly expressed in hypothalamic neurons. Rsk4 is negligible for maintaining energy homeostasis in mice. Loss of Rsk4 promotes diet-induced obesity and related metabolic disorders i...Ribosomal S6 kinase 4 (Rsk4) is predominantly expressed in hypothalamic neurons. Rsk4 is negligible for maintaining energy homeostasis in mice. Loss of Rsk4 promotes diet-induced obesity and related metabolic disorders in mice. Rsk4 is required for central fibroblast growth factor-19 to reduce body weight in obese mice.
UNLABELLED: Type 2 diabetes (T2D) impairs antiviral immunity; however, the causal link between T2D and interferon-α2 (IFN-α2) deficiency remains unclear. This study used genome-wide association study-based Mendelian rand...UNLABELLED: Type 2 diabetes (T2D) impairs antiviral immunity; however, the causal link between T2D and interferon-α2 (IFN-α2) deficiency remains unclear. This study used genome-wide association study-based Mendelian randomization (MR) to investigate this relationship and validated the findings in an H1N1-infected diabetic mouse model. MR analysis of 26 single nucleotide polymorphisms showed a significant negative association between T2D and IFN-α2 levels (inverse variance weighted odds ratio 0.667; P = 0.000116) without heterogeneity or pleiotropy. In vivo experiments confirmed that db/db mice exhibited more severe H1N1-induced lung injury, higher viral loads, and lower survival rates compared with nondiabetic controls. However, exogenous IFN-α2 treatment significantly reversed these pathologic outcomes. Inflammatory cytokine profiling showed that IFN-α2 downregulated 21 elevated cytokines and restored Fas ligand levels in lung tissue. Mechanistically, Western blotting demonstrated that IFN-α2 inhibited the phosphorylation of JAK1/2 and STAT3, thereby suppressing excessive inflammation. In conclusion, our findings indicate that T2D leads to IFN-α2 deficiency, contributing to susceptibility to viral infection. Supplementation with IFN-α2 effectively attenuated virus-induced lung injury by inhibiting JAK/STAT3 signaling and cytokine storms, positioning IFN-α2 supplementation as a promising therapeutic strategy for managing influenza complications in patients with diabetes. ARTICLE HIGHLIGHTS: Type 2 diabetes (T2D) is linked to impaired antiviral immunity, but whether it drives interferon-α2 (IFN-α2) deficiency remains unknown. We asked whether T2D causally suppresses IFN-α2 levels and whether exogenous supplementation could rescue host defense mechanisms against influenza infection. By integrating genetic analysis with an H1N1-infected diabetic mouse model, we show that T2D genetically lowers IFN-α2 and that treatment reverses lung injury by inhibiting JAK/STAT3-mediated hyperinflammation. Our study positions IFN-α2 supplementation as a promising therapeutic strategy to prevent severe viral pneumonia in patients with T2D.
This study investigated glucose metabolism in the forearm during fasting and postprandial states, comparing overweight men with lean men. We sought to understand how glucose is metabolized to prevent hyperglycemia in ins...This study investigated glucose metabolism in the forearm during fasting and postprandial states, comparing overweight men with lean men. We sought to understand how glucose is metabolized to prevent hyperglycemia in insulin-resistant obese men and the implications of increased basal glucose uptake in this population. Our findings reveal that overweight men exhibit elevated basal glucose uptake in the face of increased insulin concentrations and, unlike lean men, very limited basal lactate output. The overweight group demonstrated increased alanine release, suggesting a pathway toward enhanced hepatic gluconeogenesis.
We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loc...We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.
Autologous islet implantation in the kidney subcapsular space of pigs and baboons and subsequent allotransplantation of the composite islet-kidney graft have been demonstrated to be successful, but the limited availabili...Autologous islet implantation in the kidney subcapsular space of pigs and baboons and subsequent allotransplantation of the composite islet-kidney graft have been demonstrated to be successful, but the limited availability of human islets limits this approach in clinical practice. The implantation of neonatal pig islets under the kidney capsule of an identical cloned piglet and subsequent transplantation into a human patient with diabetic nephropathy could potentially correct both diabetes and renal failure. Neonatal pig islets can become revascularized in cloned littermates in the absence of immunosuppressive therapy, but a very large number of donors may be required.
The role of glomerular endothelial cells in basement membrane collagen α1(IV) accumulation in diabetic nephropathy was previously unclear. Glucose transporter type 1 (GLUT1) expression drives collagen α1(IV) production v...The role of glomerular endothelial cells in basement membrane collagen α1(IV) accumulation in diabetic nephropathy was previously unclear. Glucose transporter type 1 (GLUT1) expression drives collagen α1(IV) production via Rheb upregulation and mTORC1 activation. Rheb O-GlcNAcylation serves as a key modification that activates mTORC1 signaling, leading to increased collagen α1(IV) production. Pharmacological inhibition of GLUT1 mitigates diabetic nephropathy progression, highlighting its therapeutic potential.
Infections represent major but underrecognized complications of type 1 diabetes (T1D), type 2 diabetes (T2D), and prediabetes. This recent overview includes use of linked U.K. primary care, hospitalization, and mortality...Infections represent major but underrecognized complications of type 1 diabetes (T1D), type 2 diabetes (T2D), and prediabetes. This recent overview includes use of linked U.K. primary care, hospitalization, and mortality data to examine infection risk for >800,000 individuals with diabetes or prediabetes, compared with an age-, sex-, and ethnicity-matched group without diabetes. We assessed 1) infections in primary care and requiring a prescription, 2) infections leading to hospitalization, and 3) infection-related mortality, over 5 years (2015-2019). Infection risks were consistently elevated across all forms of diabetes, compared with risk for those without diabetes. The highest relative risks were observed in T1D and lowest in prediabetes. While relative risks were similar across different ethnicities, the population burden of infections attributable to diabetes was highest among South Asians. There were independently strong graded associations for average HbA1c level and visit-to-visit HbA1c variability with infection risk, particularly for hospitalization infections. Among individuals with T1D, the strongest associations with infection risk were seen for elevated HbA1c levels, whereas for T2D, variability contributed more to the excess burden of infections. Infection-related mortality across all ICD-10 chapters was substantial, representing the third leading cause of death in T2D after cardiovascular disease and cancer. Further, it might be underreported, as sepsis is rarely coded as the underlying cause of death. These findings highlight the importance of improved glycemic control, earlier recognition and treatment of infections, and stronger emphasis on infection management in clinical guidelines. Incorporation of HbA1c variability into diabetes risk algorithms, and evaluation of interventions that might stabilize control, such as continuous glucose monitoring, may enhance infection prevention and reduce complications.
Accumulating evidence indicates that diabetes is associated with increased risk of several cancers. The strongest evidence has been reported for cancers of the breast, colorectum, endometrium, liver, pancreas, and gallbl...Accumulating evidence indicates that diabetes is associated with increased risk of several cancers. The strongest evidence has been reported for cancers of the breast, colorectum, endometrium, liver, pancreas, and gallbladder. However, distinguishing causal relationships from associations driven by shared risk factors such as obesity, aging, and lifestyle behaviors remains challenging. Several biological mechanisms have been proposed to explain these associations. Key pathways include the effects of insulin resistance and compensatory hyperinsulinemia on mitogenic signaling pathways, including PI3K/AKT/mTOR and MAPK, as well as the influence of adiposity, chronic inflammation, and altered metabolic substrates on tumor initiation and progression. Hyperglycemia may also contribute by promoting tumor metabolism and cellular proliferation, although its independent contribution remains debated. These mechanisms likely interact to create a protumorigenic metabolic environment in individuals with diabetes. Obesity, which frequently co-occurs with diabetes, further amplifies these risks through altered adipokine secretion and increased estrogen production, highlighting the interrelated contributions of metabolic and hormonal factors. The relationship between diabetes and cancer has important clinical implications. Diabetes has been associated with worse cancer prognosis and higher cancer-related mortality, highlighting the importance of integrated management strategies. The impact of antihyperglycemic therapy on cancer risk and progression has been extensively studied, and ongoing research continues to evaluate potential protective or tumor-modifying effects. In this article, we summarize the epidemiologic and pathophysiologic evidence describing the relationship between diabetes and cancer and discuss strategies for risk mitigation, screening, and management.
Worldwide metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease. Despite high global prevalence, MASLD is not yet recognized as a noncommunicable disease, although...Worldwide metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease. Despite high global prevalence, MASLD is not yet recognized as a noncommunicable disease, although all of the criteria are fulfilled for such a classification. MASLD is strongly associated with type 2 diabetes, cardiovascular disease, chronic kidney disease, and certain extrahepatic cancers. At 65% and 37% the prevalence of MASLD is extremely high in adults and children with type 2 diabetes, respectively. The pathogenesis of MASLD is closely related to that of type 2 diabetes, and diabetes-associated hyperglycemia, hyperinsulinemia, and hyperlipidemia promote progression from simple steatosis to hepatic inflammation and fibrosis. Thus, MASLD is now considered a complication of diabetes. However, there is still a great deal of work to be done to implement screening for and treatment of MASLD in everyday clinical diabetes management. In this article, the major mechanisms involved in the pathogenesis of MASLD and type 2 diabetes are discussed. Furthermore, the heterogeneity in the pathophysiology of MASLD and clusters in MASLD that may be relevant for future stratification of MASLD-associated risk of diseases are addressed. Finally, because of their strong hepato-, cardio-, and nephroprotective effects this article provides support as to why sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor (co)agonists should be used as first-line pharmacotherapies in people with MASLD and type 2 diabetes.