Alterations in adipose tissue composition and function are associated with obesity and contribute to the development of type 2 diabetes. While the significance of this relationship has been cemented, our understanding of the multifaceted role of adipose tissue in metabolic heath and disease continues to evolve and expand. Heterogenous populations of cells that make up adipose tissue throughout the body generate diverse secretomes containing a mosaic of bioactive compounds with vast structural and signaling capabilities. While there are many reports highlighting the important role of adipose tissue endocrine signaling in insulin resistance and type 2 diabetes, the direct, local, paracrine effect of adipose tissue has received less attention. Recent studies have begun to underscore the importance of considering anatomically discrete adipose depots for their specific impact on local microenvironments and metabolic function in neighboring tissues as well as regulation of whole-body physiology. This article highlights the important role of adipose tissue paracrine signaling on metabolic function and insulin sensitivity in nearby tissues and organs, specifically focusing on visceral, pancreatic, subcutaneous, intermuscular, and perivascular adipose tissue depots.

β-Cell failure and loss of β-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in β-cell exhaustion/failure, loss of β-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased β-cell metabolism is responsible for β-cell failure and that reducing glucose metabolism will prevent loss of β-cell mass. To test this, KATP-GOF mice were crossed with mice carrying β-cell-specific glucokinase haploinsufficiency (GCK+/-), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/- mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/- mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/- mice. Strikingly, KATP-GOF/GCK+/- mice demonstrated preserved β-cell mass and identity compared with the marked decrease in β-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/- mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing β-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and β-cell failure independently of compensatory insulin hypersecretion and β-cell exhaustion.

Metabolomic signatures of incident diabetes remain largely unclear for the U.S. Hispanic/Latino population, a group with high diabetes burden. We evaluated the associations of 624 known serum metabolites (measured by a global, untargeted approach) with incident diabetes in a subsample (n = 2,010) of the Hispanic Community Health Study/Study of Latinos without diabetes and cardiovascular disease at baseline (2008-2011). Based on the significant metabolites associated with incident diabetes, metabolite modules were detected using topological network analysis, and their associations with incident diabetes and longitudinal changes in cardiometabolic traits were further examined. There were 224 incident cases of diabetes after an average 6 years of follow-up. After adjustment for sociodemographic, behavioral, and clinical factors, 134 metabolites were associated with incident diabetes (false discovery rate-adjusted P < 0.05). We identified 10 metabolite modules, including modules comprising previously reported diabetes-related metabolites (e.g., sphingolipids, phospholipids, branched-chain and aromatic amino acids, glycine), and 2 reflecting potentially novel metabolite groups (e.g., threonate, N-methylproline, oxalate, and tartarate in a plant food metabolite module and androstenediol sulfates in an androgenic steroid metabolite module). The plant food metabolite module and its components were associated with higher diet quality (especially higher intakes of healthy plant-based foods), lower risk of diabetes, and favorable longitudinal changes in HOMA for insulin resistance. The androgenic steroid module and its component metabolites decreased with increasing age and were associated with a higher risk of diabetes and greater increases in 2-h glucose over time. We replicated the associations of both modules with incident diabetes in a U.S. cohort of non-Hispanic Black and White adults (n = 1,754). Among U.S. Hispanic/Latino adults, we identified metabolites across various biological pathways, including those reflecting androgenic steroids and plant-derived foods, associated with incident diabetes and changes in glycemic traits, highlighting the importance of hormones and dietary intake in the pathogenesis of diabetes.

Childhood obesity is a growing worldwide problem. In adults, lower cold-induced brown adipose tissue (BAT) activity is linked to obesity and metabolic dysfunction; this relationship remains uncertain in children. In this cross-sectional study, we compared cold-induced supraclavicular (SCV) BAT activity (percent change in proton density fat fraction [PDFF]) within the SCV region after 1 h of whole-body cold exposure (18°C), using MRI in 26 boys aged 8-10 years: 13 with normal BMI and 13 with overweight/obesity. Anthropometry, body composition, hepatic fat, visceral adipose tissue (VAT), and pre- and postcold PDFF of the subcutaneous adipose tissue (SAT) in the posterior neck region and the abdomen were measured. Boys with overweight/obesity had lower cold-induced percent decline in SCV PDFF compared with those with normal BMI (1.6 ± 0.8 vs. 4.7 ± 1.2%, P = 0.044). SCV PDFF declined significantly in boys with normal BMI (2.7 ± 0.7%, P = 0.003) but not in boys with overweight/obesity (1.1 ± 0.5%, P = 0.053). No cold-induced changes in the PDFF of either neck SAT (-0.89 ± 0.7%, P = 0.250, vs. 0.37 ± 0.3%, P = 0.230) or abdominal SAT (-0.39 ± 0.5%, P = 0.409, and 0.25 ± 0.2%, P = 0.139, for normal BMI and overweight/obesity groups, respectively) were seen. The cold-induced percent decline in SCV PDFF was inversely related to BMI (r = -0.39, P = 0.047), waist circumference (r = -0.48, P = 0.014), and VAT (r = -0.47, P = 0.014). Thus, in young boys, as in adults, BAT activity is lower in those with overweight/obesity, suggesting that restoring activity may be important for improving metabolic health.

Pancreatic ACE2 receptor expression, together with increased prevalence of insulin-requiring hyperglycemia in patients with coronavirus disease 2019 (COVID-19), suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pancreatic infection might trigger a β-cell-selective inflammation precipitating autoimmune type 1 diabetes (T1D). We examined T1D incidence in patients with COVID-19 inside a large, global population using a "big data" approach. The incidence in 0-30-year-old patients with confirmed COVID-19 over an ∼15-month period from the beginning of the COVID-19 pandemic was compared with an age-matched population without COVID-19 inside the TriNetX COVID-19 Research Network (>80 million deidentified patient electronic medical records globally). The cohorts were used to generate outcomes of T1D postindex. In those up to 18 years of age, the incidence of insulin-requiring diabetes that could represent T1D in patients with already diagnosed, confirmed COVID-19 was statistically indistinguishable from the control population without COVID-19. In contrast, in those aged 19-30 years, the incidence was statistically greater. These data suggest that the incidence of T1D among patients with COVID-19 <30 years of age, at least up to this time since the beginning of the pandemic, is not greater when compared with an age-, sex-, and BMI-matched population without COVID-19. Nevertheless, we caution that patients with COVID-19 could be asymptomatic of a diabetic/prediabetic state and therefore would not be expected to come to medical attention, remaining undiagnosed. Hence, it is still possible that asymptomatic virus-infected individuals could acquire β-cell autoimmunity, eventually progressing to dysglycemia and clinical T1D at higher rates.

Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high-fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (H3K4) methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression, and glucose metabolism. Maternal exercise regulates a multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

There is accumulating evidence that mitochondrial dysfunction is associated with the contribution of diabetes to Alzheimer disease (AD) progression. Neuronal mitochondrial proteins are found in plasma neuronal-derived exosomes (NDEs) at levels that reflect those in brain neurons. Here, we tested the performance of mitochondrial proteins in plasma NDEs to predict cognitive decline and brain injury in participants with diabetes. The study participants with type 2 diabetes mellitus (T2DM) included 41 cognitively normal control subjects, 97 individuals with mild cognitive impairment (MCI) (68 individuals with stable MCI; 29 individuals with progressive MCI), and 36 patients with AD dementia. Plasma neuroexosomal proteins were measured by ELISA kits. Spearman correlation was used to test associations between plasma neuroexosomal mitochondrial proteins and other core biomarkers of AD. Diagnostic accuracy for progressive MCI and AD was obtained for mitochondrial proteins using receiver operating characteristic curve analyses. The associations of mitochondrial proteins with the conversion from MCI to AD were assessed by Cox proportional hazard regression analysis. Plasma levels of neuroexosomal NADH ubiquinone oxidoreductase core subunit S3 (NDUFS3) and succinate dehydrogenase complex subunit B (SDHB) were significantly lower in patients with T2DM with AD dementia and progressive MCI than in cognitively normal subjects (P < 0.001 for both groups). We also found that plasma neuroexosomal NDUFS3 and SDHB levels were lower in progressive MCI subjects than in stable MCI subjects. Both plasma neuroexosomal NDUFS3 and SDHB offer diagnostic utility for AD. Low plasma neuroexosomal SDHB levels significantly predicted conversion from MCI to AD. In addition, low mitochondrial protein levels were associated with the rate of hippocampal and gray matter atrophy and reduced AD signature cortical thickness in progressive MCI over the follow-up period. These data suggest that both plasma neuroexosomal NDUFS3 and SDHB are already increased at the early clinical stage of AD, and indicate the promise of plasma neuroexosomal mitochondrial proteins as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD in participants with diabetes.

Fatty acid (FA) signaling contributes to β-cell mass expansion in response to nutrient excess, but the underlying mechanisms are poorly understood. In the presence of elevated glucose, FA metabolism is shifted toward synthesis of complex lipids, including sphingolipids. Here, we tested the hypothesis that sphingolipids are involved in the β-cell proliferative response to FA. Isolated rat islets were exposed to FA and 16.7 mmol/L glucose for 48-72 h, and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or knockdown of SphK, fatty acid elongase 1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Rats were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. β-Cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipids were analyzed by liquid chromatography-tandem mass spectrometry. Among the FAs tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very-long-chain sphingolipids produced from the available C24:1 acyl-CoA pool mediate oleate-induced β-cell proliferation in rats.

Diabetic polyneuropathy (DPN) is the most common complication of diabetes, yet its pathophysiology has not been established. Accumulating evidence suggests that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays pivotal roles in the regulation of cell growth and survival during diabetic complications. This study aimed to investigate the impact of MALAT1 silencing in dorsal root ganglion (DRG) sensory neurons, using an α-tocopherol-conjugated DNA/RNA heteroduplex oligonucleotide (Toc-HDO), on the peripheral nervous system of diabetic mice. We identified MALAT1 upregulation in the DRG of chronic diabetic mice that suggested either a pathological change or one that might be protective, and systemic intravenous injection of Toc-HDO effectively inhibited its gene expression. However, we unexpectedly noted that this intervention paradoxically exacerbated disease with increased thermal and mechanical nociceptive thresholds, indicating further sensory loss, greater sciatic-tibial nerve conduction slowing, and additional declines of intraepidermal nerve fiber density in the hind paw footpads. Serine/arginine-rich splicing factors, which are involved in pre-mRNA splicing by interacting with MALAT1, reside in nuclear speckles in wild-type and diabetic DRG neurons; MALAT1 silencing was associated with their disruption. The findings provide evidence for an important role that MALAT1 plays in DPN, suggesting neuroprotection and regulation of pre-mRNA splicing in nuclear speckles. This is also the first example in which a systemically delivered nucleotide therapy had a direct impact on DRG diabetic neurons and their axons.

Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP). In preclinical models of DKD, overexpression of NOX5 in Nox4-deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. In addition, the only first-in-class NOX inhibitor, GKT137831, appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated upregulation of EGR1, PKC-α, and TXNIP induced by high glucose levels, as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared with other NOX isoforms such as NOX4, which may have been overinterpreted in previous rodent studies.

Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit β2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1β (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and α1-3-N-acetylgalactosaminyltransferase and α1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets.

A growing body of evidence suggests that intrapancreatic fat is associated with diabetes, but whether distribution of intrapancreatic fat across the regions of the pancreas has a pathophysiologic role is unknown. The aim of this study was to investigate the differences in intrapancreatic fat deposition between the head, body, and tail of the pancreas, as well as the relationship between regional intrapancreatic fat deposition and diabetes status and insulin traits. A total of 368 adults from the general population underwent MRI on a 3 Tesla scanner, and intrapancreatic fat was manually quantified in duplicate. Statistical models included adjustment for age, sex, ethnicity, BMI, and liver fat. Intrapancreatic fat deposition in the head, body, and tail of the pancreas did not differ significantly in adjusted models in either the overall cohort or the three subgroups based on diabetes status. HOMA of insulin resistance and fasting insulin were significantly positively associated with fat in the tail and body of the pancreas. There was no significant association between regional intrapancreatic fat and HOMA of β-cell function. The association of increased intrapancreatic fat deposition in the tail and body regions with increased insulin resistance may have an important role in the early identification of patients at risk for developing insulin resistance and diseases that stem from it.

We investigated the application of rate-dependent depression (RDD) of the Hoffmann (H) wave as a predictor of treatment efficacy in patients with painful diabetic peripheral neuropathy (DPN). General medical information, scales, and nerve conduction data were collected from 73 healthy subjects, 50 subjects with type 2 diabetes and painless DPN, and 71 subjects with type 2 diabetes and painful DPN. The left tibial nerve was stimulated, and RDD was calculated by the decline in amplitude of the third H wave relative to the first one. Gabapentin treatment was initiated after baseline evaluation, and the RDD and visual analog scale (VAS) score were both evaluated regularly during the 2-week study period. At baseline, the painful DPN group exhibited significant RDD impairment across all stimulation frequencies. Gabapentin treatment significantly reduced the VAS score and restored RDD during the 2-week observation period. RDD was found to be an independent factor of minimal VAS score improvement, such that the benefit increased by 1.27 times per 1% decrease in the RDD value. In conclusion, this study demonstrates that diabetes-induced loss of RDD can be modified by gabapentin and suggests that RDD may be valuable for predicting the initial efficacy of gabapentin therapy in patients with painful DPN.

Growing evidence indicates an important link between gut microbiota, obesity, and metabolic syndrome. Alterations in exocrine pancreatic function are also widely present in patients with diabetes and obesity. To examine this interaction, C57BL/6J mice were fed a chow diet, a high-fat diet (HFD), or an HFD plus oral vancomycin or metronidazole to modify the gut microbiome. HFD alone leads to a 40% increase in pancreas weight, decreased glucagon-like peptide 1 and peptide YY levels, and increased glucose-dependent insulinotropic peptide in the plasma. Quantitative proteomics identified 138 host proteins in fecal samples of these mice, of which 32 were significantly changed by the HFD. The most significant of these were the pancreatic enzymes. These changes in amylase and elastase were reversed by antibiotic treatment. These alterations could be reproduced by transferring gut microbiota from donor C57BL/6J mice to germ-free mice. By contrast, antibiotics had no effect on pancreatic size or exocrine function in C57BL/6J mice fed the chow diet. Further, 1 week vancomycin administration significantly increased amylase and elastase levels in obese men with prediabetes. Thus, the alterations in gut microbiota in obesity can alter pancreatic growth, exocrine function, and gut endocrine function and may contribute to the alterations observed in patients with obesity and diabetes.

To examine associations between sleep disturbance and changes in weight and body composition and the mediating role of changes of appetite and food cravings in the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) 2-year weight-loss diet intervention trial, this study included 810 overweight or obese individuals with baseline sleep disturbance assessment who were randomly assigned one of four diets varying in macronutrient composition. Changes in body weight and fat distribution were assessed by DEXA and computed tomography during the 2-year intervention. Participants were asked to provide sleep disturbance levels (no, slight, moderate, or great) at baseline and to recall their sleep disturbances since last visit at 6, 12, 18, and 24 months. Weight loss during the first 6 months was followed by 1.5 years of steady weight regain. Participants with greater sleep disturbance from baseline to 6 months showed significant losses of body weight (Ptrend <0.001) and waist circumference (Ptrend = 0.002) at 6 months, after multivariate adjustment. Compared with individuals without sleep disturbance at all from baseline to 6 months, those with slight, moderate, or great sleep disturbance showed an elevated risk of failure to lose weight (-5% or more loss) at 6 months, when the maximum weight loss was achieved, with an odds ratio of 1.24 (95% CI 0.87, 1.78), 1.27 (95% CI 0.75, 2.13), or 3.12 (95% CI 1.61, 6.03), respectively. In addition, we observed that the repeatedly measured levels of sleep disturbance over 2 years were inversely associated with the overall weight loss rate (weight changes per 6 months) (Ptrend <0.001). Further, sleep disturbances during weight loss from baseline to 6 months and weight regain from 6 months to 24 months were significantly predictive of total fat, total fat mass percent, and trunk fat percent changes during the 2 years. Our results also indicated that food cravings for carbohydrates/starches, fast food fats, and sweets; cravings, prospective consumption, hunger of appetite measurements; and dietary restraint, disinhibition, and hunger subscales measured at 6 months significantly mediated the effects of sleep disturbance on weight loss. In conclusion, our results suggested that more severe sleep disturbance during weight loss was associated with an elevated risk of failure to lose weight during the dietary intervention. Food cravings and eating behaviors may partly mediate these associations.

Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.