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.

Abdominal obesity with hyperinsulinemia reflects a prediabetic risk state signified by metabolic inflexibility and an overreliance on glucose as a metabolic fuel in skeletal muscle. There is limited information on net metabolic substrate flux across human skeletal muscle under physiological and pathophysiological conditions. Using arteriovenous difference sampling across the forearm in overweight (n = 9) compared with lean men (n = 7), we characterized net metabolic substrate fluxes over three consecutive meals and after an overnight fast during a 24-h cycle. Normoglycemic overweight men had significantly higher fasting and postprandial insulin levels compared with lean men. Overweight men had 3.6-fold higher forearm glucose uptake in the fasted and preprandial state compared with lean men (1.7 ± 0.3 vs. 0.5 ± 0.07 µmol/min/100 mL; P = 0.02), challenging the concept of decreased glucose uptake in skeletal muscle as a consequence of insulin resistance. The dominance of glucose uptake over the 24-h period in overweight men occurred in the context of lower fatty acid uptake. Forearm lactate flux fluctuated from positive to negative in lean men, whereas overweight men displayed lactate uptake across the meal cycles. In contrast, overweight men had 44% higher diurnal mass-adjusted alanine output compared with lean men (312 ± 25 vs. 216 ± 30 nmol/min; P = 0.048). In this cohort, elevated fasting insulin in overweight men was observed alongside greater reliance on glucose relative to fatty acids and increased alanine output from the forearm. These patterns may represent early metabolic adaptations associated with moderate obesity with likely impact on gluconeogenic substrates.

Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations.

One-third of patients with diabetes will develop end-stage kidney disease, and approximately one-half of the patients requiring kidney transplantation in the U.S. suffer from diabetes. In 2002, Yamada, Sachs, and their colleagues explored the renal subcapsular site for islet implantation in a partially inbred miniature swine model. All pancreatectomized pigs that received autologous islets under the renal capsule maintained normoglycemia. The transplantation of a composite islets-kidney (i.e., the kidney with the revascularized autologous islets) into another pancreatectomized, bilaterally nephrectomized pig provided successful renal and islet function. In 2011, this model was extended successfully to nonhuman primates (NHPs). There are several hurdles to be overcome if this model is to be successfully translated into clinical practice, and xenotransplantation might resolve this problem. Pancreases harvested from gene-edited pigs could be sources of islets that could be isografted beneath the renal capsule of an identical cloned littermate. After allowing the islets to become vascularized over a period of 6-12 weeks, during which no immunosuppressive therapy would be required, the composite islets-kidney would then be transplanted into an immunosuppressed NHP or human recipient. On reperfusion of the graft, both renal and islet function should rapidly return. If sufficient islets have been transplanted with the kidney and the immunosuppressive regimen is successful, normoglycemia and normal renal function should be quickly achieved. However, a large number of genetically engineered neonatal donor piglets will be required to manufacture one therapeutic patient dose of islets, which may prove to be a logistical problem. Alternative approaches are discussed.

Thickening of the glomerular basement membrane (GBM) is one of the most common pathological changes in diabetic nephropathy (DN), but its underlying mechanisms remain unclear. Collagen α1(IV) is predominantly expressed by endothelial cells and upregulated in the glomeruli in DN. Glucose transporter type 1 (GLUT1) serves as the primary transporter for glucose uptake in endothelial cells. This study demonstrates that GLUT1 and collagen α1(IV) expression are both upregulated and positively correlated in glomerular endothelial cells (GECs) in DN. Inhibition of GLUT1 improved renal dysfunction and morphological abnormalities associated with DN progression in db/db mice and streptozotocin-induced diabetic rat models. Mechanistically, GLUT1 promotes collagen α1(IV) overexpression through activation of the Rheb/mTORC1 pathway in GECs. In vitro studies revealed that O-GlcNAcylation of Rheb seems to mediate GLUT1-driven Rheb upregulation and subsequent mTORC1 activation. Collectively, these data establish the GLUT1-Rheb/mTORC1-collagen α1(IV) axis in GECs, highlighting the pivotal role of GECs in mediating GBM thickening during DN pathogenesis.

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 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 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.

Diabetic cardiomyopathy (DbCM) is commonly defined as ventricular dysfunction in a person living with diabetes in the absence of hypertension and/or coronary artery disease (CAD). There is increasing recognition in the field that this is a poor definition to reflect the pathology of DbCM, as many individuals with diabetes (both type 1 and type 2) are often at risk of or have coexisting hypertension or CAD. On the contrary, there is increasing evidence that people living with diabetes, particularly in the early stages of disease progression, often have asymptomatic and subclinical diastolic dysfunction. Herein, we will interrogate the clinical evidence supporting the presence of diastolic dysfunction in people living with either type 1 or type 2 diabetes in the absence of hypertension and/or CAD, and whether diastolic dysfunction should be a central feature in how we clinically define DbCM. Clinical agreement on how we define and interpret the pathology of DbCM is necessary should the field aim to develop specific pharmacotherapies for this disorder. DbCM should not be confused with heart failure with preserved ejection fraction (HFpEF), despite the latter also being characterized by diastolic dysfunction. Nonetheless, it will be imperative to understand whether DbCM can be a precursor toward the progression of HFpEF in people living with diabetes, as that may further reinforce the clinical importance of managing diastolic dysfunction in the population with diabetes.

The subcutaneous (SQ) space is a promising site for islet transplantation to treat type 1 diabetes. We hypothesize that nanofibrous bioabsorbable functionalized scaffolds (BAFS) implanted in the SQ space will create a highly vascularized niche that will support islet engraftment. Electrospun poly(lactic-co-glycolic acid) (PLGA) and gelatin (G) (PLGA + G) scaffolds functionalized with vascular endothelial growth factor (V) and laminin (L) were wrapped around a nylon catheter and implanted into the SQ space of immunodeficient mice. Experimental groups included PLGA, PLGA + G, PLGA + G + V + L, and the device-less catheter alone. The degree of vascularization in these sites was assessed 4 weeks after implantation, and in a separate cohort of mice, neonatal porcine islets (NPIs) were transplanted subcutaneously into diabetic mice. NPIs transplanted under the kidney capsule served as controls. PLGA + G + V + L recipients showed enhanced vascularization, with a higher number of cells positive for lectin, smooth muscle actin, and CD31 compared with other groups (P < 0.05). Recipients of PLGA + G + V + L scaffolds and NPIs achieved normoglycemia faster (P < 0.05) and exhibited higher serum porcine insulin levels (P < 0.05) compared with all other groups. Our nanofibrous BAFS (PLGA + G + V + L) significantly vascularized the SQ space and supported long-term islet graft survival, suggesting a clinically relevant and tunable alternative site for β-cell replacement therapies.

Diabetic retinopathy (DR) is recognized as an inflammatory neurovascular complication, with neuronal deficits preceding vascular symptoms. This study identified elevated serum retinol-binding protein 4 (RBP4) as a risk factor for DR, because it induces retinal neuronal injuries and exacerbates vascular defects. Vitreous RBP4 levels were significantly elevated in patients with DR compared with those with macular disease. Elevated vitreous and serum RBP4 levels exacerbated hyperglycemia-induced endothelial inflammation, retinal vascular leakage, pericyte loss, and acellular capillaries in streptozotocin-induced diabetic mice. Progressive retinal degeneration and impaired electroretinography function were exhibited with RBP4 overexpression, likely through inducing retinal microglial activation and phagocytosis. Microglial depletion via PLX3397 (CSF-1R inhibitor) or inhibition using minocycline (anti-inflammatory tetracycline) significantly mitigated retinal degeneration in RBP4 transgenic (RBP4-Tg) mice. Furthermore, minocycline abolished the enhanced phagocytosis of zymosan in murine microglial BV2 cells induced by RBP4. The application of TAK242 or use of microglia-specific TLR4 knockout markedly reduced retinal neuroinflammation and degeneration in RBP4-Tg mice. Overall, these results suggest that elevated serum and vitreous RBP4 levels may be a risk factor for DR by exacerbating retinal neuronal and vascular injuries.

Adipose triglyceride (TG) lipase (ATGL) is the rate-limiting enzyme of TG catabolism at the surface of lipid droplets (LDs). In pancreatic β-cells, lipolysis by ATGL increases with glucose and produces metabolites that support glucose-stimulated insulin secretion (GSIS). Upregulation of lipolysis by glucose is blunted in human islets affected by type 2 diabetes. However, how glucose regulates lipolysis in β-cells is unknown. We found that glucose recruits ATGL coactivator α/β-hydrolase domain containing 5 (ABHD5) to LDs in INS-1 cells and human β-cells. ABHD5 recruitment to LDs was reduced by inhibitors of cAMP-dependent protein kinase (PKA) or the expression of PKA-resistant mutant ABHD5, indicating that PKA phosphorylation contributes to ABHD5 recruitment to LDs. Importantly, ABHD5 was indispensable for glucose-stimulated lipolysis in INS-1 cells and human β-cells. ABHD5 knockdown increased LDs and TG content in INS-1 cells and human islets, indicating that ABHD5 is a critical regulator of ATGL activity in β-cells. Additionally, GSIS was impaired in ABHD5-downregulated INS-1 cells and human pseudoislets, which agrees with a role of ATGL in supporting GSIS in β-cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness in lipolysis and supporting insulin secretion in β-cells.

Diabetic retinopathy (DR) is the leading cause of vision loss in the working-age population, with public health economic implications worldwide. Systemic inflammation and leukocyte activation are early events in diabetes, whereas microglial activation, neuroinflammation, and retinal neurodegeneration are early events in DR. Protein tyrosine phosphatase 1B (PTP1B) plays a complex role in monocyte and macrophage activation, which may affect DR. We investigated the role of myeloid cell-specific PTP1B using LysMcre-PTP1B fl/fl (LysM-PTP1B) transgenic mice, as well as pharmacological inhibition with a PTP1B inhibitor, MSI-1436, in the early stages of DR. Mice were rendered diabetic for 6 weeks using anomer-equilibrated streptozotocin (STZ). Retinal changes were evaluated by histology and immunohistochemistry, and systemic leukocyte activation by flow cytometry. Mitochondrial function in high-glucose-concentration-challenged, cultured bone marrow-derived macrophages (BMDMs) from LysM-PTP1B- and MSI-I436-treated mice was determined in vitro. Both myeloid cell-specific depletion and pharmacological inhibition of PTP1B prevented STZ-induced retinal neurodegeneration, development of acellular retinal capillaries, as well as microglial and systemic leukocyte activation without altering the development of diabetes. In vitro, inhibition of PTP1B prevented high-glucose-level-induced mitochondrial dysfunction in BMDMs. We conclude that inhibition of PTP1B prevents DR by decreasing myeloid cell-driven inflammation, and PTP1B represents a therapeutic target for prevention DR.