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 f...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.
UNLABELLED: 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...UNLABELLED: 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. ARTICLE HIGHLIGHTS: This study highlights how bioabsorbable functionalized scaffolds (BAFS) create a subcutaneous vascularized niche that supports islet graft function. BAFS exhibit sustained release of vascular endothelial growth factor and laminin, which promoted enhanced vascularization in the subcutaneous space. Additionally, these vessels are mature and patent as evidenced by intraluminal cells positive for lectin and smooth muscle actin. BAFS transplanted with neonatal porcine islets achieved normoglycemia faster and exhibited higher serum porcine insulin levels than all other groups. Overall, BAFS transplanted with neonatal porcine islets facilitates long-term islet graft function and corrects diabetes in mice, suggesting a clinically relevant and tunable alternative site for β-cell replacement therapies.
In the article cited above, the first affiliation for author Chieh-Kai Chan was incomplete as published. The complete affiliation is Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, H...In the article cited above, the first affiliation for author Chieh-Kai Chan was incomplete as published. The complete affiliation is Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan. The editors apologize for the error. The online version of the article (https://doi.org/10.2337/db23-0273) has been updated with the correct affiliation information.
Retinol-binding protein 4 (RBP4) levels are elevated in the vitreous humor of patients with diabetic retinopathy (DR) and in RBP4 transgenic mice. Elevated vitreous RBP4 exacerbates both vascular and neuronal deficits as...Retinol-binding protein 4 (RBP4) levels are elevated in the vitreous humor of patients with diabetic retinopathy (DR) and in RBP4 transgenic mice. Elevated vitreous RBP4 exacerbates both vascular and neuronal deficits associated with DR in streptozotocin-induced diabetic mice. Hyperglycemia augments the RBP4-induced inflammatory response in retinal microvascular endothelial cells to exacerbate DR-related vascular pathologies. RBP4 triggers retinal microglial activation and phagocytosis via TLR4/nuclear factor-κB/mitogen-activated protein kinase pathway, and microglial depletion or inhibition alleviates RBP4-induced retinal neurodegeneration.
Lipolysis is stimulated by glucose and supports glucose-stimulated insulin secretion in pancreatic β-cells. However, the mechanism by which glucose increases lipolysis in β-cells is unknown. We aimed to identify a glucos...Lipolysis is stimulated by glucose and supports glucose-stimulated insulin secretion in pancreatic β-cells. However, the mechanism by which glucose increases lipolysis in β-cells is unknown. We aimed to identify a glucose-responsive regulator of lipolysis in β-cells. Glucose promotes α/β-hydrolase domain containing 5 (ABHD5) recruitment to lipid droplets where lipolysis occurs, which is at least partially mediated by cAMP-dependent kinase A. ABHD5 is required for glucose-stimulated lipolysis and insulin secretion. ABHD5 is a potential target to restore glucose-stimulated lipolysis in β-cells affected by type 2 diabetes.
UNLABELLED: 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...UNLABELLED: 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. ARTICLE HIGHLIGHTS: Myeloid cell PTP1B is required to induce retinal neurodegeneration in diabetes. Both local (microglia) and systemic (bone marrow-derived) myeloid cells are implicated. Inhibition of myeloid cell PTP1B prevents development of acellular retinal capillaries in diabetic mice. PTP1B mediates superoxide production, decreases mitochondrial membrane potential, and, in female mice, increases macrophage cell death in chronic conditions associated with abnormally high glucose levels. Protective effects of PTP1B deletion on diabetic retinopathy were also observed in mice treated with the small molecular PTP1B inhibitor MSI-1436; both retinal neurodegeneration and local glial cell activation were decreased.
UNLABELLED: We investigated whether lowering dietary carbohydrate content and glycemic index (GI) levels altered deep lipidomic profiles and whether these changes were associated with improved diurnal postprandial glucos...UNLABELLED: We investigated whether lowering dietary carbohydrate content and glycemic index (GI) levels altered deep lipidomic profiles and whether these changes were associated with improved diurnal postprandial glucose response (PPGR). In the OmniCarb trial, 59 adults completed 5-week controlled feeding interventions (low carbohydrate/low GI vs. high carbohydrate/high GI) and 12-h meal tests. Comprehensive lipidomic profiling was performed to measure lipid species and lipid class-specific fatty acids (FAs) at the end of each intervention. We found that lowering carbohydrate content and GI levels significantly decreased triacylglycerols (TAGs) and phosphatidylcholines, while increasing lactosylceramides and phosphatidylethanolamines (PEs). Of 731 lipid species analyzed, 521 (71%) were significantly modified, including TAGs (n = 398), PEs (n = 45), and ceramides. Of 199 FAs analyzed across and within lipid classes, 89 showed significant changes (false discovery rate-adjusted P < 0.05), including decreases in saturated FAs (total and TAG FA12:0 and FA14:0) and palmitoleic acid and increases in very-long-chain saturated FAs, when lowering carbohydrate and GI levels. Between-diet changes in six total FAs and 17 lipid class-specific FAs were associated with half-day PPGR changes; greater decreases in joint FA score changes were linked to improved PPGRs. Our study suggests the potential importance of dietary carbohydrate-responsive lipidomic signatures in explaining individual variability in half-day PPGRs and may encourage future intervention studies to target these signatures. ARTICLE HIGHLIGHTS: Carbohydrate diets with high glycemic index (GI) increase postprandial glucose response (PPGR) and diabetes risk; however, the pathways underlying individual variability in diurnal PPGRs to diets differing in carbohydrate content and GI remain unclear. We examined the effect of lowering dietary carbohydrate content and GI levels on comprehensive lipidomic pathways and tested whether these changes were associated with improved half-day PPGRs. Five-week controlled feeding interventions altered multiple lipid species and lipid class-specific fatty acids toward more favorable profiles, and composite fasting blood fatty acid scores derived from comprehensive targeted lipidomic profiling were associated with improved 12-h PPGRs. These lipidomic signatures explain individual variability in PPGRs and provide targets for future intervention studies.
UNLABELLED: The second-meal phenomenon refers to the improved glycemic response to a subsequent identical meal. We previously showed that morning hyperinsulinemia is a key mediator, priming the liver for enhanced net hep...UNLABELLED: The second-meal phenomenon refers to the improved glycemic response to a subsequent identical meal. We previously showed that morning hyperinsulinemia is a key mediator, priming the liver for enhanced net hepatic glucose uptake (NHGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic clamp. Postprandial NHGU is regulated by three primary mechanisms: insulin action, initiated by hyperinsulinemia; glucose effectiveness (GE), driven by hyperglycemia; and the portal glucose signal (PGS), a neurally mediated signal activated by glucose delivery into the hepatoportal circulation. It remains unclear, however, which of these mechanisms govern the increase in afternoon NHGU following morning insulin exposure. To address this, dogs underwent a morning clamp with either a 4-h hyperinsulinemic prime (prime group) (n = 8) or basal insulin delivery (no-prime group) (n = 8). After a 1.5-h rest, both groups underwent an afternoon hyperglycemic clamp with portal glucose delivery under basal insulin conditions to isolate the effects of a morning insulin prime on afternoon glucose-mediated hepatic signals (GE and the PGS). Mean afternoon NHGU was significantly greater in the prime group (2.2 ± 0.3 mg/kg/min) compared with the no-prime group (0.1 ± 0.3 mg/kg/min; P = 0.005), accompanied by augmented net glycolytic and glycogen flux. These findings indicate that morning insulin can enhance glucose-mediated afternoon NHGU independently of a rise in afternoon insulin. However, maximal second-meal NHGU also requires elevated afternoon insulin. Together, these findings suggest that strategically timed early-day insulin or insulinotropic interventions could potentially improve hepatic responsiveness in settings of impaired postprandial glycemic control, such as insulin resistance or diabetes. ARTICLE HIGHLIGHTS: Elevated morning insulin primes the liver for enhanced afternoon net hepatic glucose uptake (NHGU), but it is unclear whether augmentation of insulin action, glucose effectiveness, or the portal glucose signal mediates this effect. Dogs underwent a morning euglycemic clamp with either elevated or basal insulin delivery, followed by an afternoon euinsulinemic-hyperglycemic clamp to isolate the effect of morning insulin priming on afternoon glucose effectiveness and the portal glucose signal. Morning insulin priming enhanced afternoon NHGU via increased glucose-mediated mechanisms, though maximal afternoon NHGU also required elevated afternoon insulin. These findings identify mechanisms underlying insulin-induced hepatic metabolic memory, providing a framework to inform strategies improving postprandial glucose handling in diabetes.
Koprivica I, Jonić N, Dimitrijević M
… +13 more, Jevtić B, Mićanović D, Stegnjaić G, Lazarević M, Stanisavljević S, Pilipović I, Radulović N, Saksida T, Mišić D, Zdravković V, Fraser G, Miljković Đ, Stojanović I
UNLABELLED: Reduction in intestinal type 3 innate lymphoid cells (ILC3) frequency is associated with type 1 diabetes (T1D) pathogenesis in humans and in animal models. The current study showed that, after T1D induction b...UNLABELLED: Reduction in intestinal type 3 innate lymphoid cells (ILC3) frequency is associated with type 1 diabetes (T1D) pathogenesis in humans and in animal models. The current study showed that, after T1D induction by multiple-low-dose streptozotocin in male C57BL/6 mice, ILC3 were reduced in both blood and pancreas and produced less IL-22 and IL-2, and a decreased proportion expressed the gut-homing α4β7 integrin in the pancreas. Additionally, T1D induction in ILC3-impaired mice produced exacerbated hyperglycemia. To activate ILC3, Compound 1 (Cpd1), a synthetic selective free fatty acid receptor 2 (FFAR2) agonist, was administered orally in a prophylactic regimen, at early therapeutic stages, or during established disease, resulting in significant amelioration of T1D symptoms. Cpd1 upregulated ILC3 and activated regulatory T cells (Treg) within the small intestine lamina propria and the pancreas, enhanced intestinal barrier integrity, and increased microbial diversity. Cpd1 also reduced α4β7-expressing inflammatory cells in the pancreas while promoting the accumulation of gut-imprinted ILC3. IL-22 was important for this anti-inflammatory response, as treatment efficacy was inhibited when mice were additionally given neutralizing anti-IL-22 antibodies. Of note, NOD mice receiving Cpd1 exhibited postponed disease initiation, but the incidence of disease was similar to that of the control group. Overall, activation of intestinal ILC3 and Treg via FFAR2 engagement, and translation of these anti-inflammatory effects to the pancreas, provided significant benefit in a mouse T1D model. ARTICLE HIGHLIGHTS: Modulating the adaptive immune response alone is insufficient for effective type 1 diabetes treatment. This study investigates targeting intestinal type 3 innate lymphoid cells as a novel therapeutic approach for type 1 diabetes. A synthetic free fatty acid receptor 2 agonist, Compound 1, activates intestinal IL-2+ and IL-22+ type 3 innate lymphoid cells and thereby reduces pancreatic inflammation, stabilizes intestinal barrier, and improves clinical outcomes in a type 1 diabetes mouse model. Compound 1 demonstrates therapeutic potential and may serve as a candidate for future clinical trials in type 1 diabetes.
UNLABELLED: Diabetic kidney disease (DKD) and diabetic cardiomyopathy continue to drive excess morbidity and mortality in diabetes, underscoring a critical gap between mechanistic insight and clinical translation. Growth...UNLABELLED: Diabetic kidney disease (DKD) and diabetic cardiomyopathy continue to drive excess morbidity and mortality in diabetes, underscoring a critical gap between mechanistic insight and clinical translation. Growth differentiation factor-15 (GDF-15), a stress-inducible cytokine of the transforming growth factor-β superfamily, has emerged as a critical biomarker and putative modulator of metabolic inflammation. Yet the field remains divided on a fundamental question: is GDF-15 simply reporting tissue distress, or does it shape disease trajectories? In this article, we explore how GDF-15 may both signal and shape DKD and cardiovascular disease. Drawing on evidence from experimental models, longitudinal clinical studies, and multi-omics analyses, we highlight the context-dependent biology of GDF-15, protective during acute metabolic or inflammatory stress but potentially pathogenic when chronically elevated in diabetes. We examine its regulation via the GFRAL-RET signaling axis, its segment-specific expression across renal tubular compartments, and its emerging role in cardiac remodeling and metabolic inflammation. Recent clinical data position circulating GDF-15 as an early and sensitive indicator of DKD progression and cardiovascular events. At the same time, mechanistic studies increasingly implicate sustained GDF-15 signaling in mitochondrial dysfunction, inflammatory amplification, and maladaptive tissue remodeling. Together, these observations place GDF-15 at a critical inflection point between risk stratification and disease mechanism. A key unresolved challenge is defining when, where, and how GDF-15 signaling exerts adaptive versus maladaptive effects-knowledge that will be essential for determining whether GDF-15 should be targeted, harnessed, or restrained in diabetes. ARTICLE HIGHLIGHTS: GDF-15 is a stress-responsive cytokine of the TGF-β superfamily regulated by p53, mitochondrial dysfunction, and inflammatory signaling. Circulating GDF-15 levels are low under physiological conditions but rise markedly in response to cellular and metabolic stress. Elevated GDF-15 predicts incident diabetes and reflects hyperglycemia-induced oxidative and cellular stress. GDF-15 correlates with albuminuria, estimated glomerular filtration rate decline, and progression risk in diabetic kidney disease. Increased levels predict heart failure, myocardial infarction, and cardiovascular mortality in diabetes. Targeting the GDF-15-GFRAL axis and leveraging GDF-15 as a biomarker offer emerging translational potential.
UNLABELLED: Diabetic retinopathy (DR) is a predominant cause of vision impairment among working-age individuals, with a subset of patients responding poorly to current treatments. This study investigated alterations in d...UNLABELLED: Diabetic retinopathy (DR) is a predominant cause of vision impairment among working-age individuals, with a subset of patients responding poorly to current treatments. This study investigated alterations in double-stranded DNA (dsDNA) levels in the aqueous humor and retinal pigment epithelium (RPE) dysfunction in DR patients, exploring the potential role of the cyclic GMP-AMP synthase (cGAS)-STING pathway in DR progression. We found that DR patients showed significantly elevated dsDNA levels in the aqueous humor compared with control individuals. Fundus autofluorescence imaging revealed an increase in high-autofluorescence spots in DR patients, indicating early RPE dysfunction. In vivo and in vitro models of DR demonstrated mitochondrial damage and dsDNA leakage in RPE cells, along with cGAS-STING pathway activation in the retina. Pharmacological inhibition of STING reduced cytoplasmic dsDNA accumulation and damaged mitochondria, alleviating inflammation in vitro. In vivo, STING inhibition ameliorated RPE dysfunction and vascular changes. These findings highlight the critical role of the cGAS-STING pathway in DR pathogenesis and suggest that STING inhibition may serve as a promising therapeutic strategy to reduce retinal inflammation and slow the progression of DR. ARTICLE HIGHLIGHTS: The retinal pigment epithelium (RPE) serves as the outer blood-retinal barrier, protecting the neural retina from systemic changes. We aimed to preserve RPE integrity through early intervention and inhibit DR progression. Our study focused on determining whether the involvement of the cyclic GMP-AMP synthase-STING pathway and mitochondrial damage drive RPE dysfunction. We found that mitochondrial dysfunction in the RPE under diabetic conditions triggers activation of the cyclic GMP-AMP synthase-STING pathway, leading to disruption of RPE and retinal vascular instability. Targeting this pathway restored RPE function and limited retinal deterioration. These findings highlight a promising therapeutic approach for preventing disease progression.