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Background Advanced glycation endproducts (AGEs) contribute to the development of vascular complications of diabetes and have been recently implicated in the pathogenesis of diabetes. Since AGEs are generated within foodstuffs upon food processing, it is increasingly recognised that the modern diet is replete with AGEs. AGEs are thought to stimulate chronic low-grade inflammation and promote oxidative stress and have been linked to the development of insulin resistance. Simple therapeutic strategies targeted at attenuating the progression of chronic low-grade inflammation and insulin resistance are urgently required to prevent or slow the development of type 2 diabetes in susceptible individuals. Dietary modulation of the human colonic microbiota has been shown to confer a number of health benefits to the host, but its effect on advanced glycation is unknown. The aim of this article is to describe the methodology of a double-blind placebo-controlled randomised crossover trial designed to determine the effect of 12 week consumption of a prebiotic dietary supplement on the advanced glycation pathway, insulin sensitivity and chronic low-grade inflammation in adults with pre-diabetes. Methods/Design Thirty adults with pre-diabetes (Impaired Glucose Tolerance or Impaired Fasting Glucose) aged between 40–60 years will be randomly assigned to receive either 10 grams of prebiotic (inulin/oligofructose) daily or 10 grams placebo (maltodextrin) daily for 12 weeks. After a 2-week washout period, study subjects will crossover to receive the alternative dietary treatment for 12 weeks. The primary outcome is the difference in markers of the advanced glycation pathway carboxymethyllysine (CML) and methylglyoxal (MG) between experimental and control treatments. Secondary outcomes include HbA 1c , insulin sensitivity, lipid levels, blood pressure, serum glutathione, adiponectin, IL-6, E-selectin, myeloperoxidase, C-reactive protein, Toll-like Receptor 4 (TLR4), soluble receptor for AGE (sRAGE), urinary 8-isoprostanes, faecal bacterial composition and short chain fatty acid profile. Anthropometric measures including BMI and waist circumference will be collected in addition to comprehensive dietary and lifestyle data. Discussion Prebiotics which selectively stimulate the growth of beneficial bacteria in the human colon might offer protection against AGE-related pathology in people at risk of developing type 2 diabetes. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000130763 .

Background During an oral glucose tolerance test (OGTT), morphological features of the glucose curve (monophasic curve, glucose peak >30 minutes and 1‐hour glucose ≥ 155 mg/dL) maybe associated with higher prediabetes risk, but their reproducibility and predictive ability in adolescents with obesity are unknown. Methods Nondiabetic adolescent girls with obesity underwent a multiple‐sample OGTT at baseline (n = 93), 6 weeks (n = 83), and 1 year (n = 72). Short‐term reproducibility (baseline to 6 weeks) and the predictive ability for prediabetes (baseline to 1 year) for each feature were compared with standard fasting and 2‐hour OGTT diagnostic criteria. Results There was fair/moderate short‐term reproducibility (κ < 0.5) for all morphological features. At 1 year, compared with standard OGTT criteria, the areas under the receiver operating curve (ROC‐AUCs) for glucose peak > 30 minutes, 1 hour ≥155 mg/dL or a combination of the two criteria were comparable (all P > 0.05), but the monophasic curve had the lowest ROC‐AUC (P < 0.001). Conclusions In adolescent girls with obesity, glucose peak > 30 minutes and/or glucose ≥155 mg/dL had similar reproducibility and 1‐year predictive ability for prediabetes compared with standard OGTT criteria. The shortened 1‐hour OGTT may provide diagnostic equivalence for prediabetes risk with the additional advantage of a less time‐consuming risk assessment.

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD + metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP + and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

Aims/hypothesisYoung children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status.MethodsType 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1–49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study.ResultsAge was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%.Conclusions/interpretationType 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

Peripheral neuropathy is a common complication of type 2 diabetes, which is strongly associated with obesity 1 , causing sensory loss and, in some patients, neuropathic pain 2 , 3 . Although the onset and progression of diabetic peripheral neuropathy is linked with dyslipidaemia and hyperglycaemia 4 , the contribution of inflammation to peripheral neuropathy pathogenesis has not been investigated. Here we used a high-fat, high-fructose diet (HFHFD), which induces obesity and prediabetic metabolic changes, to study the onset of peripheral neuropathy. Mice fed the HFHFD developed persistent heat hypoalgesia after 3 months, but a reduction in epidermal skin nerve fibre density manifested only at 6 months. Using single-cell sequencing, we found that CCR2 + macrophages infiltrate the sciatic nerves of HFHFD-fed mice well before axonal degeneration is detectable. These infiltrating macrophages share gene expression similarities with nerve-crush-induced macrophages 5 and express neurodegeneration-associated microglial marker genes 6 , although there is no axon loss or demyelination. Inhibiting the macrophage recruitment by genetically or pharmacologically blocking CCR2 signalling resulted in more severe heat hypoalgesia and accelerated skin denervation, as did deletion of Lgals3 , a gene expressed in recruited macrophages. Recruitment of macrophages into the peripheral nerves of obese prediabetic mice is, therefore, neuroprotective, delaying terminal sensory axon degeneration by means of galectin 3. Potentiating and sustaining early neuroprotective immune responses in patients could slow or prevent peripheral neuropathy. A study in a mouse model of obesity and prediabetes demonstrates that recruitment of macrophages to nerves has a protective role in diet-induced peripheral neuropathy.

The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA1c levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes.Prediabetes phenotype can influence the effectiveness of lifestyle intervention-based diabetes prevention programmes. This Perspectives suggests that diabetes prevention programmes are not effective in individuals with isolated impaired fasting glucose and calls for further research to improve prevention of type 2 diabetes mellitus in this population.

Closed-loop insulin delivery systems, which integrate continuous glucose monitoring (CGM) and algorithms that continuously guide insulin dosing, have been shown to improve glycaemic control. The ability to predict future glucose values can further optimize such devices. In this study, we used machine learning to train models in predicting future glucose levels based on prior CGM and accelerometry data. We used data from The Maastricht Study, an observational population-based cohort that comprises individuals with normal glucose metabolism, prediabetes, or type 2 diabetes. We included individuals who underwent >48h of CGM (n = 851), most of whom (n = 540) simultaneously wore an accelerometer to assess physical activity. A random subset of individuals was used to train models in predicting glucose levels at 15- and 60-minute intervals based on either CGM data or both CGM and accelerometer data. In the remaining individuals, model performance was evaluated with root-mean-square error (RMSE), Spearman's correlation coefficient (rho) and surveillance error grid. For a proof-of-concept translation, CGM-based prediction models were optimized and validated with the use of data from individuals with type 1 diabetes (OhioT1DM Dataset, n = 6). Models trained with CGM data were able to accurately predict glucose values at 15 (RMSE: 0.19mmol/L; rho: 0.96) and 60 minutes (RMSE: 0.59mmol/L, rho: 0.72). Model performance was comparable in individuals with type 2 diabetes. Incorporation of accelerometer data only slightly improved prediction. The error grid results indicated that model predictions were clinically safe (15 min: >99%, 60 min >98%). Our prediction models translated well to individuals with type 1 diabetes, which is reflected by high accuracy (RMSEs for 15 and 60 minutes of 0.43 and 1.73 mmol/L, respectively) and clinical safety (15 min: >99%, 60 min: >91%). Machine learning-based models are able to accurately and safely predict glucose values at 15- and 60-minute intervals based on CGM data only. Future research should further optimize the models for implementation in closed-loop insulin delivery systems.

Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC–dependent mechanism in human β cells. Mice with β cell–specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

Recent studies suggest prediabetes is an independent risk factor for cardiovascular thrombotic events. However, the mechanisms that may promote platelet activation and thrombosis in prediabetes remain elusive. To determine mechanisms linking prediabetes and thrombosis as a function of age, we recruited military veterans with prediabetes and veterans who were normoglycemic, in young and middle-age groups. Compared with normoglycemic participants, platelets from those with prediabetes exhibited increased activation, mitochondrial oxidant load, mitochondrial membrane hyperpolarization, and greater thrombus formation ex vivo regardless of age. Preincubation of platelets with mitochondria-targeted antioxidants, such as SOD mimetic or mitoquinol (MitoQ), rescued this prothrombotic phenotype. These phenotypes were recapitulated in C57BL6/J mice exhibiting early onset of glucose intolerance when fed a high-fat (HF) diet for 2 weeks. Treatment of HF-fed mice with a SOD mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, not only lowered mitochondrial oxidants, hyperpolarization, Ca 2+ levels, and platelet activation but also protected against increased potential for carotid and pulmonary thrombosis. We also observed a bidirectional regulation of platelet activation by Ca 2+ and mitochondrial oxidants. These findings support the idea that mitochondrial oxidant–dependent platelet activation induces a prothrombotic state in clinical prediabetes and preclinical models of short-term glucose intolerance and can be reversed by mitochondria-targeted antioxidants.

The gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP). In 2013-16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100-125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders. Among 1,702 participants (59.9-77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D. T2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.