Diabetes

Maternal (m) consumption of a Western-style diet (WD) during pregnancy alters fatty-acid metabolism and reduces insulin sensitivity in fetal skeletal muscle. The long-term impact of these fetal adaptations and the pathways underlying disordered lipid metabolism are incompletely understood. Therefore, we tested whether a mWD chronically fed to lean, insulin sensitive adult Japanese macaques throughout pregnancy and lactation would impact skeletal muscle oxidative capacity and lipid metabolism in adolescent offspring fed a postweaning (pw)WD or control diet (CD)...

Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis upon insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly...

Type 2 diabetes is associated with cognitive impairment and a twofold increased risk of dementia compared to age-matched individuals without diabetes. Given that the eye and the brain share similar embryologic origin and anatomical features the retina offers a unique "window" to the brain. In this study we wanted to determine whether there was a difference in retinal imaging-based neuronal and vascular markers in individuals with type 2 diabetes with or without minimal cognitive impairment (MCI). We included 134 persons with type 2 diabetes...

Both long- and short-term glycemic variability have been associated with incident diabetes complications. We evaluated their relative and potential additive effects on incident renal complications in the Action to Control Cardiovascular Risk in Diabetes trial. A marker of shortterm glycemic variability 1,5-anhydroglucitol (1,5-AG) was measured in 4,000 random 12-months post-randomization plasma samples (when hemoglobin A1C (HbA1c) was stable). Visit-to-visit fasting plasma glucose coefficient of variation (CV-FPG) was determined from 4 months postrandomization until the endpoints of (1) microalbuminuria or (2) macroalbuminuria...

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 cases of congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth to 24 years and severity of the phenotype was also variable...

There is clinical evidence that increased urinary serine proteases are associated with the disease severity in the setting of diabetic nephropathy (DN). Elevation of serine proteases may mediate [Ca2+]i dynamics in podocytes through the protease-activated receptors (PARs) pathway, including associated activation of non-specific cation channels. Cultured human podocytes and freshly isolated glomeruli were used for fluorescence and immunohistochemistry stainings, calcium imaging, Western blot analysis, scanning ionconductance microscopy, and patch-clamp analysis...

Hemopexin (HPX) is overexpressed in the retina of diabetic patients, and induces the breakdown of the blood-retinal barrier (BRB) in vitro. The present study was aimed at evaluating whether HPX blockade by specific antibodies (aHPX) could avoid vascular leakage in vivo and microvascular angiogenesis in vitro and ex vivo. For this purpose, the effect of intravitreal injections (IVT) of aHPX on vascular leakage was evaluated in db/db mice and rats with streptozotocin-induced diabetes (D-STZ) using the Evans Blue method...

Prediabetes is a metabolic condition associated with gut microbiome composition, though mechanisms remain elusive. We searched for faecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1105 healthy individuals from TwinsUK. We used the KORA cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined 8 IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios for IFG (TwinsUK: OR[95%CI]=3...

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional non-apoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance...

Nerve conduction velocity (NCV) abnormalities are the forerunners of diabetic peripheral neuropathy (DPN). As such, the study aimed to analyze the effect of glucose profile quality on NCV in children and young adults with type 1 diabetes. Fifty-three children aged 5 to 23 years with type 1 diabetes were recruited to participate in this study, which was conducted prospectively at the Children's Hospital of Eastern Switzerland from 2016 to 2022. Glycemic targets were recorded, and a cross-sectional nerve conduction study analyzing the peroneal, tibial, median motor and median sensory nerves was performed...

The ability of metabolically active tissues to increase glucose uptake in response to insulin is critical to whole-body glucose homeostasis. This report describes the Dual Tracer Test, a robust method involving sequential retro-orbital injection of 14C-2-deoxyglucose (14C-2DG) alone, followed 40 min later by injection of 3H-2DG with a maximal dose of insulin to quantify both basal and insulin-stimulated 2DG uptake in the same mouse. The collection of both basal and insulin-stimulated measures from a single animal is imperative for generating high-quality data since differences in insulin action may be misinterpreted mechanistically if basal glucose uptake is not accounted for...

In the article cited above, a National Institutes of Health funding source was inadvertently omitted. This work was also funded by National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK133504 to author Senta K. Georgia. The authors apologize for the omission. The online version of the article (https://doi.org/10.2337/db22-0506) has been updated to correct the error.

In the article cited above, a mistake during the assembly of Fig. 5C in preparation for manuscript submission resulted in an overlap between the images for untreated (panel a) and treated (panel b) cells (CHOP and DAPI staining overlay). The images in Fig. 5C were intended only as an illustration of the data, and the mistake does not impact the quality of the data presented in the article. A corrected Fig. 5C (below) has been assembled using the original data files. The authors apologize for the error. The online version of the article https://doi...

Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like, Metrnl) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing...

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA-sequencing (RNA-seq) using a reference single nuclear RNA-seq dataset. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower body mass index (BMI), respectively...

ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and beta-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in 2 subjects and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY and Type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank...

Co-stimulation serves as a critical checkpoint for T cell activation, and several genetic variants affecting co-stimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a co-stimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected non-obese diabetic (NOD) mice from disease, but the impact of CD226 on individual immune subsets remained unclear...

Obesity increases the risk of myocardial fibrosis, a pathological change in most heart diseases, but the mechanism has not been fully elucidated. Here, we found that mice with high-fat diet (HFD)-induced obesity had more severe myocardial fibrosis than control mice under normal and ischemia/reperfusion (I/R) conditions, which could be alleviated by neutralizing antibodies against interleukin (IL)-1β and IL-18, downstream products of the nucleotide-binding oligomerization-like receptor protein 3 (NLRP3) inflammasome, and the NLRP3 inhibitor MCC950...

Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at the site of inflammation and it is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes, we then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NODs as compared to pre-diabetic NODs...

The Cre-loxP system provides valuable resources to analyze the importance of tissue-specific gene knockout, including pancreatic beta cells associated with the pathogenesis of diabetes mellitus. However, it is expensive and time-consuming to generate transgenic mice harboring floxed genes of interest and cross them with cell-specific Cre-expression mice. We establish a βCas9 system with mice expressing Cas9 in pancreatic beta cells and adeno-associated virus 8 (AAV8) -mediated gRNA delivery based on CRISPR-Cas9 technology to overcome those shortcomings...