Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer.

Prediabetes and colorectal cancer (CRC) represent compelling health burdens responsible for high mortality and morbidity rates, sharing several modifiable risk factors. It has been hypothesized that metabolic abnormalities linking prediabetes and CRC are hyperglycemia, hyperinsulinemia, and adipokines imbalance. The chronic stimulation related to these metabolic signatures can favor CRC onset and development, as well as negatively influence CRC prognosis. To date, the growing burden of prediabetes and CRC has generated a global interest in defining their epidemiological and molecular relationships. Therefore, a deeper knowledge of the metabolic impairment determinants is compelling to identify the pathological mechanisms promoting the onset of prediabetes and CRC. In this scenario, this review aims to provide a comprehensive overview on the metabolic alterations of prediabetes and CRC as well as an overview of recent preventive and therapeutic approaches for both diseases, focusing on the role of the metabolic state as a pivotal contributor to consider for the development of future preventive and therapeutic strategies.

Trajectories of glycaemic traits exhibit sex-specific associations with hepatic iron and fat content: Results from the KORA-MRI study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a major disease burden in the population. While the bidirectional association between NAFLD and diabetes is established, little is known about the association of hepatic iron content and glycaemia. Moreover, analyses of sex-specific effects and of dynamic changes in glycaemia are scarce. METHODS: We investigated 7-year sex-specific trajectories of glycaemia and related traits (HbA1c, fasting glucose, fasting insulin, HOMA-IR, 2-h glucose and cross-sectional 2-h insulin) in a sample from a population-based cohort (N = 365; 41.1% female). Hepatic iron and fat content were assessed by 3T-Magnetic Resonance Imaging (MRI). Two-step multi-level models adjusted for glucose-lowering medication and confounders were applied. RESULTS: In women and men, markers of glucose metabolism correlated with hepatic iron and fat content. Deterioration of glycaemia was associated with increased hepatic iron content in men (normoglycaemia to prediabetes: beta = 2.21 s-1 , 95% CI [0.47, 3.95]). Additionally, deterioration of glycaemia (e.g. prediabetes to diabetes: 1.27 log(%), [0.84, 1.70]) and trajectories of glucose, insulin and HOMA-IR were significantly associated with hepatic fat content in men. Similarly, deterioration of glycaemia as well as trajectories of glucose, insulin and HOMA-IR was significantly associated with increased hepatic fat content in women (e.g. trajectory of fasting insulin: 0.63 log(%), [0.36, 0.90]). CONCLUSIONS: Unfavourable 7-year trajectories of markers of glucose metabolism are associated with increased hepatic fat content, particularly in women, whereas the association with hepatic iron content was less clear. Monitoring changes of glycaemia in the sub-diabetic range might enable early identification of hepatic iron overload and steatosis.

Association of MRI-based adrenal gland volume and impaired glucose metabolism in a population-based cohort study.

OBJECTIVES: The aim of this study was to assess adrenal gland volume by using magnetic resonance imaging (MRI) and to study its role as an indirect marker of impaired glucose metabolism and hypothalamic-pituitary-adrenal (HPA) axis activation in a population-based cohort. METHODS: Asymptomatic participants were enrolled in a nested case-control study and underwent a 3-T MRI, including T1w-VIBE-Dixon sequences. For the assessment of adrenal gland volume, adrenal glands were manually segmented in a blinded fashion. Impaired glucose metabolism was determined using fasting glucose and oral glucose tolerance test. Cardiometabolic risk factors were also obtained. Inter- and intrareader reliability as well as univariate and multivariate associations were derived. RESULTS: Among 375 subjects included in the analysis (58.5% male, 56.1 ± 9.1 years), 25.3% participants had prediabetes and 13.6% had type 2 diabetes (T2DM). Total adrenal gland volume was 11.2 ± 4.2 ml and differed significantly between impaired glucose metabolism and healthy controls with largest total adrenal gland volume in T2DM (healthy controls: 10.0 ± 3.9 ml, prediabetes: 12.5 ± 3.8 ml, T2DM: 13.9 ± 4.6 ml; p < 0.001). In the multivariate analysis, association of T2DM and increased adrenal gland volume was independent of age, sex, hypertension, triglycerides and body mass index (BMI), but was attenuated in subjects with prediabetes after adjustment for BMI. CONCLUSIONS: T2DM is significantly associated with increased adrenal gland volume by MRI in an asymptomatic cohort, independent of age, sex, dyslipidaemia, hypertension and BMI. Adrenal gland volume may represent an indirect marker of impaired glucose metabolism and HPA axis dysfunction.

High Throughput Study for Molecular Mechanism of Metformin Pre-Diabetic Protection via Microarray Approach.

BACKGROUND: Metformin is a biguanide that exhibits antidiabetic, anticarcinogenic, and anti-inflammatory properties. Despite well-known pancreatic protective effects, metformin's influence on pancreatic islet ß-cell is yet considerably unknown. Protecting the functional insulin-producing ß-cells in the pancreas is a key therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). OBJECTIVE: The current study aimed to analyze the protective effects of metformin on streptozocin- induced diabetic rats in T1DM in hepatic tissues. METHODS: In the present study, male Wistar rats (n=24) were randomly assigned into 2 groups (n=12 for each control and test), and metformin (100 mg/kg/day) was given for 7 weeks. Afterward, diabetes was induced by streptozocin (STZ) at a single dose of 150 mg/kg. Blood glucose was examined daily before and after STZ induction. The animals were euthanized by cervical dislocation 5 days after streptozocin injection, after which liver and pancreas were harvested from each rat. RESULTS: The biochemical analyses revealed that metformin resulted in significantly reduced plasma glucose levels and higher pancreatic insulin levels in the test group. Using a restrictive cut-off of at least 2-FC and an adjusted p-value (q-value) of ≤0.05, a sum of 747 genes for the metformin group were shown to be differentially regulated compared to controls (320 Down and 427 Up), by which they were obtained from the liver. Furthermore, the evidence is attained that metformin may hinder the loss of critical ß-cells by reducing inflammatory and apoptosis signaling, promoting fatty acid ß-oxidation, and inducing metabolism. CONCLUSION: Collectively, this study has demonstrated a decrease in blood glucose levels and a rise in insulin-levels and thus consequent prophylactic effects in metformin-given STZ-induced diabetic rats.

Association of Mixed Use of Electronic and Conventional Cigarettes and Exposure to Secondhand Smoke With Prediabetes.

CONTEXT: Despite previous studies regarding the association between smoking and diabetes, the effects of electronic cigarettes and secondhand smoke (SHS) on glucose metabolism and insulin sensitivity have not been fully elucidated. OBJECTIVE: To examine the association of mixed electronic and conventional cigarette use and exposure to SHS with prediabetes. DESIGN: Data from the 2014-2018 Korean National Health and Nutrition Examination Survey were analyzed. SETTING: Nationwide population-based. PARTICIPANTS: Of 39 199 participants, 22 385 participants (9490 men, 12 895 women) without diabetes were included. The main independent variables were smoking behaviors, including exposure to SHS. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prediabetes (hemoglobin A1C of 5.7-6.4%). RESULTS: Of 22 385 participants without diabetes, 6735 had prediabetes. Mixed cigarette use was associated with a 1.57-fold increase in the odds of prediabetes when compared with never-smoking [odds ratio (OR) = 1.57, 95% CI = 1.29-1.92] and a 1.27-fold increase when compared with conventional cigarette use only (OR = 1.27, 95% CI = 1.07-1.52). Participants who were current nonsmokers, but mixed users in the past had an increased risk of prediabetes (OR = 1.54, 95% CI = 1.04-2.13). There was no significant association between prediabetes and current nonsmoking in individuals with previous conventional cigarette use only. Among never-smokers, exposure to SHS significantly increased the risk of prediabetes (OR = 1.16, 95% CI = 1.04-1.30). CONCLUSIONS: Mixed use of electronic and conventional cigarettes and exposure to SHS increased the risk of prediabetes. Further studies are required to comprehensively investigate the molecular biology underlying the effects of previous and current mixed use of electronic cigarettes and SHS on glucose metabolism.

Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes.

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

A Narrative Review of Human Clinical Trials on the Impact of Phenolic-Rich Plant Extracts on Prediabetes and Its Subgroups.

Phenolic-rich plant extracts have been demonstrated to improve glycemic control in individuals with prediabetes. However, there is increasing evidence that people with prediabetes are not a homogeneous group but exhibit different glycemic profiles leading to the existence of prediabetes subgroups. Prediabetes subgroups have been identified as: isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined impaired fasting glucose and glucose intolerance (IFG/IGT). The present review investigates human clinical trials examining the hypoglycemic potential of phenolic-rich plant extracts in prediabetes and prediabetes subgroups. Artemisia princeps Pampanini, soy (Glycine max (L.) Merrill) leaf and Citrus junos Tanaka peel have been demonstrated to improve fasting glycemia and thus may be more useful for individuals with IFG with increasing hepatic insulin resistance. In contrast, white mulberry (Morus alba Linn.) leaf, persimmon (Diospyros kaki) leaf and Acacia. Mearnsii bark were shown to improve postprandial glycemia and hence may be preferably beneficial for individuals with IGT with increasing muscle insulin resistance. Elaeis guineensis leaf was observed to improve both fasting and postprandial glycemic measures depending on the dose. Current evidence remains scarce regarding the impact of the plant extracts on glycemic control in prediabetes subgroups and therefore warrants further study.

Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial and polygenetic disease, although its exact etiology remains poorly understood. The objective of this study was to identify key biomarkers and potential molecular mechanisms in the development of T2D. Human RNA-Seq datasets across different tissues (GSE18732, GSE41762, and GSE78721) were collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) between T2D and controls were identified using differential analysis. A total of 90 overlapping DEGs were identified, among which YTHDF2, DDX21, and MDM2 were considered as key genes due to their central positions in the PPI network and the same regulatory pattern in T2D. Logistic regression analysis showed that low expression of the key genes increased the risk of T2D. Enrichment analysis revealed that the key genes are involved in various important biological functions and signaling pathways including Notch, Fork head box O (FOXO), and phosphoinositide 3-kinase (PI3K)-Akt. RT-qPCR and Western blot analysis showed that all three key genes were down-regulated in pancreatic islets of both prediabetic and diabetic mouse models. Finally, the insulin-sensitizer, pioglitazone was used to treat db/db mice and immunofluorescence analysis showed that the expression of all three key genes was significantly down-regulated in db/db islets, an effect that was overcome by pioglitazone treatment. Together, these results suggest that the identified key genes could be involved in the development of T2D and serve as potential biomarkers and therapeutic targets for this disease.

Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.

Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.

WJCPR11 reverses the TNF-α-induced inhibition of adipocyte differentiation and glucose uptake.

Berberine is a natural isoquinoline alkaloid present in various herbs and is effective against metabolic syndrome in the pre-diabetic stage and high insulin resistance. The present study aimed to determine the effectiveness of WJCPR11, a berberine derivative that is commonly used for diabetes treatment, in ameliorating insulin resistance and diabetes treatment. WJCPR11 promoted adipocyte differentiation to a higher extent than other berberine derivatives and showed no noticeable toxicity in its effective concentration range. It increased the mRNA expression levels and protein abundance of adipogenic markers, including peroxisome proliferator-activated receptor γ (PPARγ), glucose transporter type 4 (GluT4), and fatty acid synthase (FAS), and markedly enhanced the level of adiponectin, a distinct marker of insulin sensitivity. Meanwhile, the mRNA levels of inflammatory markers such as plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6) were reduced after WJCPR11 treatment. Furthermore, the tumor necrosis factor-α (TNF-α)-induced inhibition of adipocyte differentiation and downregulation of glucose uptake were markedly reversed by WJCPR11 treatment. Collectively, the findings of this study indicate that WJCPR11 has great potential for diabetes treatment.

Development of type 2 diabetes in adolescent girls with polycystic ovary syndrome and obesity.

OBJECTIVE: Adult women with polycystic ovary syndrome (PCOS) and obesity have an 8-fold increased risk of developing type 2 diabetes (T2D). Our goal was to determine the incidence and risk factors for T2D in adolescents with PCOS and obesity. RESEARCH DESIGN AND METHODS: Retrospective chart review of girls aged 11-21 years with confirmed PCOS (oligomenorrhea and hyperandrogenism) diagnosis between July 2013 and Aug 2018 and at least one follow-up visit and BMI >85%ile. T2D incidence, defined with an HbA1c ≥6.5%, was calculated. A nested case-control study with 1:3 matching by race, ethnicity, and BMI was performed to determine predictors of T2D diagnosis. RESULTS: Four hundred ninety-three patients with PCOS (age 15.6 ± 1.9 years, BMI 36.2 ± 6.3 kg/m2 ) were identified with a follow-up of 1018 person-years. Twenty-three developed T2D (incidence 22.6/1000 person-years) with diagnosis a median of 1.8 years (2 months-5.5 years) after PCOS diagnosis. T2D risk was higher in girls with a prediabetes HbA1c (5.7%-6.4%) (HR 14.6 [4.8-44.5]) and among Hispanic girls with an elevated HbA1c and alanine aminotransferase (HR 19.0 [3.7-97.2]) at the time of PCOS diagnosis. In the 1:3 matched cohort, T2D risk was 18.7 times higher (OR 18.66 [2.27-153.24]) for every 0.1% increase in HbA1c at the time of PCOS diagnoses. CONCLUSIONS: Girls with PCOS and obesity have an 18-fold increase in T2D incidence compared to published rates in non-PCOS youth. Hispanic girls with elevated HbA1c and ALT are at particular risk. Due to the morbidity associated with youth onset T2D, these findings argue for better screening and prevention approaches in this population.

Incidence and disease course of new-onset diabetes mellitus in breast and colorectal cancer patients undergoing chemotherapy: A prospective multicenter cohort study.

AIMS: To investigate the incidence of and risk factors for new-onset type 2 diabetes mellitus (DM) developed during chemotherapy that included steroids in cancer patients without DM. METHODS: This multicenter, prospective, and observational cohort study enrolled 299 cancer patients without DM (aged > 18 years), planning 4-8 cycles of adjuvant chemotherapy. The endpoints were the incidence, remission rate, and independent determinants of new-onset DM during chemotherapy. RESULTS: Between April 2015 and March 2018, 270 subjects with colorectal cancer or breast cancer (mean age, 51.0 years) completed the follow up (mean 39 months). Of whom, 17 subjects (6.3%) developed DM within a median time of 90 days (range, 17-359 days). Male sex (hazard ratio [HR], 15.839; 95% confidence interval [CI], 2.004-125.20) and impaired fasting glucose (IFG) at baseline (HR, 8.307; CI, 1.826-37.786) were independent risk factors. Six months after chemotherapy completion, 11/17 subjects (64.7%) experienced DM remission, associated with a significantly higher C-peptide level at baseline (C-peptide levels, 1.3 ng/mL in subjects with remission and 0.9 ng/mL in subjects without remission, age- and sex-adjusted P = 0.007). CONCLUSIONS: DM incidence was 6.3% in patients who received chemotherapy with dexamethasone. Close monitoring for hyperglycemia is recommended, especially for men with IFG. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03062072).

Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.

BACKGROUND: Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. METHODS: T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. FINDINGS: Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 µg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group. INTERPRETATION: Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. FUNDING: Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Differential risk factors and morbidity/mortality pattern in type 2 diabetes: A study among two Mendelian populations with different ancestry (India).

BACKGROUND AND AIMS: Association studies of type 2 diabetes mellitus (T2DM) with risk factors have shown variable results. Moreover, population-specific comparative investigations are negligible. Therefore, the present study aimed to evaluate the association of dyslipidemia and obesity with impaired fasting glucose (IFG) and T2DM among two ethnically, geographically and culturally different populations in India. METHODS: This was a cross-sectional study among Jats and Meiteis, each inhabiting a separate geographical region. A total of 2371 individuals, age ≥30 years were recruited through household survey. Obesity variables were captured using anthropometric measurements while fasting blood (2.5 mL) was drawn to measure lipid and glucose levels using enzymatic assay by spectrophotometer. Participants were categorized under normal, IFG and T2DM groups, indicative of diabetes progression stages. Statistical analysis was performed using SPSS 16.0 version. RESULTS: Significant differential distribution of lipid and obesity variables among IFG and T2DM in both populations were observed. Odds ratio revealed high TC and all obesity variables except BMI posed significant increased risk for T2DM among Jats. Abnormal TG, VLDL, WC, and WHtR posed significant increased risk for T2DM among Meiteis. Age-cohort wise prevalence of T2DM showed increasing trend at ≥60 years among Jats and decreasing trend at ≥60 years among Meiteis, suggesting a potential higher morbidity in the former and mortality in latter because of T2DM. CONCLUSIONS: The present study observed a differential association of risk factors for T2DM among Jats and Meiteis. This study emphasize the need to implement community-specific intervention programs for prevention, treatment and management of T2DM.

Benchmarking the Cost-Effectiveness of Interventions Delaying Diabetes: A Simulation Study Based on NAVIGATOR Data.

OBJECTIVE: To estimate using the UK Prospective Diabetes Study Outcomes Model Version 2 (UKPDS-OM2) the impact of delaying type 2 diabetes onset on costs and quality-adjusted life expectancy using trial participants who developed diabetes in the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) study. RESEARCH DESIGN AND METHODS: We simulated the impact of delaying diabetes onset by 1-9 years, utilizing data from the 3,058 of 9,306 NAVIGATOR trial participants who developed type 2 diabetes. Costs and utility weights associated with diabetes and diabetes-related complications were obtained for the U.S. and U.K. settings, with costs expressed in 2017 values. We estimated discounted lifetime costs and quality-adjusted life years (QALYs) with 95% CIs. RESULTS: Gains in QALYs increased from 0.02 (U.S. setting, 95% CI 0.01, 0.03) to 0.15 (U.S. setting, 95% CI 0.10, 0.21) as the imposed time to diabetes onset was increased from 1 to 9 years, respectively. Savings in complication costs increased from $1,388 (95% CI $1,092, $1,669) for a 1-year delay to $8,437 (95% CI $6,611, $10,197) for a delay of 9 years. Interventions costing up to $567-$2,680 and £201-£947 per year would be cost-effective at $100,000 per QALY and £20,000 per QALY thresholds in the U.S. and U.K., respectively, as the modeled delay in diabetes onset was increased from 1 to 9 years. CONCLUSIONS: Simulating a hypothetical diabetes-delaying intervention provides guidance concerning the maximum cost and minimum delay in diabetes onset needed to be cost-effective. These results can inform the ongoing debate about diabetes prevention strategies and the design of future intervention studies.

Gender differences in the modifiable risk factors associated with the presence of prediabetes: A systematic review.

BACKGROUND: Prediabetes is a risk state for the future development of type 2 diabetes. Previously, it was evident that the risk factors for diabetes differ by gender. However, conclusive evidence regarding the gender difference in modifiable risk factors associated with the presence of pre-diabetes is still lacking. AIMS: To systematically identify and summarize the available literature on whether the modifiable risk factors associated with prediabetes displays similar relationship in both the genders. METHODS: A systematic search was performed on electronic databases i.e. PubMed, EBSCOhost, and Scopus using "sex", "gender", "modifiable risk factors" and "prediabetes" as keywords. Reference list from identified studies was used to augment the search strategy. Methodological quality and results from individual studies were summarized in tables. RESULTS: Gender differences in the risk factor association were observed among reviewed studies. Overall, reported association between risk factors and prediabetes apparently stronger among men. In particular, abdominal obesity, dyslipidemia, smoking and alcohol drinking habits were risk factors that showed prominent association among men. Hypertension and poor diet quality may appear to be stronger among women. General obesity showed stringent hold, while physical activity not significantly associated with the risk of prediabetes in both the genders. CONCLUSIONS: Evidence suggests the existence of gender differences in risk factors associated with prediabetes, demands future researchers to analyze data separately based on gender. The consideration and the implementation of gender differences in health policies and in diabetes prevention programs may improve the quality of care and reduce number of diabetes prevalence among prediabetic subjects.

Model for Studying the Effects of Chronic Metabolic Disease on Endogenous Bone Marrow Stem Cell Populations.

Disease-associated impairment/dysfunction of stem cell populations is prominent in chronic metabolic and inflammatory diseases, such as type 2 diabetes mellitus (DM) where the multifunctional properties (viability, proliferation, paracrine secretion, multilineage differentiation) of bone marrow resident mesenchymal stem cells (MSCs) can be affected. The growth and viability impairments make it difficult to study the underlying molecular mechanisms related to the dysfunction of these cells in vitro. We have consequently optimized the isolation and culture conditions for impaired/dysfunctional bone marrow MSCs from B6.Cg-Lepob/J obese prediabetic mice. The method described here permits ex vivo investigations into disease-associated functional impairments and the dysregulated molecular mechanisms in these primary MSCs through direct comparisons with their healthy wild-type C57BL6/J control mouse counterparts.

Screening for chronic conditions with reproductive factors using a machine learning based approach.

A large proportion of cases with chronic conditions including diabetes or pre-diabetes, hypertension and dyslipidemia remain undiagnosed. To include reproductive factors (RF) might be able to improve current screening guidelines by providing extra effectiveness. The objective is to study the relationships between RFs and chronic conditions' biomarkers. A cross-sectional study was conducted. Demographics, RFs and metabolic biomarkers were collected. The relationship of the metabolic biomarkers were shown by correlation analysis. Principal component analysis (PCA) and autoencoder were compared by cross-validation. The better one was adopted to extract a single marker, the general chronic condition (GCC), to represent the body's chronic conditions. Multivariate linear regression was performed to explore the relationship between GCC and RFs. In total, 1,656 postmenopausal females were included. A multi-layer autoencoder outperformed PCA in the dimensionality reduction performance. The extracted variable by autoencoder, GCC, was verified to be representative of three chronic conditions (AUC for patoglycemia, hypertension and dyslipidemia were 0.844, 0.824 and 0.805 respectively). Linear regression showed that earlier age at menarche (OR = 0.9976) and shorter reproductive life span (OR = 0.9895) were associated with higher GCC. Autoencoder performed well in the dimensionality reduction of clinical metabolic biomarkers. Due to high accessibility and effectiveness, RFs have potential to be included in screening tools for general chronic conditions and could enhance current screening guidelines.

Prediabetes, diabetes, metabolic syndrome, and small fiber neuropathy.

INTRODUCTION: This study was conducted to evaluate the association between prediabetes (PD), elements of the metabolic syndrome (MetS), and small fiber neuropathy (SFN). METHODS: A total of 268 patients with SFN symptoms and normal electrophysiology underwent tests to assess small fibers. SFN was diagnosed based on abnormality of at least two among intraepidermal nerve fiber density (IEFND), quantitative sensory testing, and quantitative sudomotor axon reflex testing. RESULTS: There was no difference in IENFD or abnormal skin biopsy frequency between PD and normoglycemia (NG). However, IENFD was lower in people with diabetes mellitus (DM) than in those with NG. An association between HbA1C and IENFD was observed only if DM patients were included. Attributes of the MetS were more common in those with an abnormal skin biopsy but not among those with autonomic dysfunction or meeting SFN criteria. DISCUSSION: DM, but not PD alone, is associated with SFN. Other MetS elements appear to preferentially impact small fiber structure over function.

The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening.

AIMS/HYPOTHESIS: Young 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. METHODS: Type 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. RESULTS: Age 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/INTERPRETATION: Type 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.