Risk Of T2D Research Articles

Causal associations of insulin and Lp(a) levels: a Mendelian randomization study

Abstract Background Numerous observational studies have demonstrated circulating lipoprotein(a) [Lp(a)] to be inversely related to occurrence of type 2 diabetes [T2D]. However, this is not consistently supported by Mendelian randomization [MR] studies. In vitro studies have shown insulin to downregulate Lp(a) expression, which might be another mechanism behind the correlation observed between Lp(a) and T2D. Purpose In this MR study, we investigated the influence of genetically predicted levels of insulin on genetically predicted Lp(a) levels to elucidate the potential causal links between Lp(a) and diabetes. Methods Independent genetic variants associated with insulin levels were acquired from a meta-analysis of genome-wide association studies (GWAS, N=151,013). Summary data for Lp(a) were acquired from a GWAS study in the UK Biobank (N=361,194). Inverse-variance-weighted (IVM) method was used to perform a two sample MR study. Sensitivity analysis was conducted via MR Egger, weighted median (WME), as well as leave-one-out analysis. Results Genetically predicted insulin levels were negatively associated with Lp(a) levels according to IVM estimate (p=0.003). In sensitivity analysis, WME supported this result (p=0.0002), while MR-Egger was not statistically significant (p=0.11). Leave-one-out analysis did not show the results to depend on any single variant. Conclusion This MR study provides robust evidence supporting the association between plasma insulin levels and decreased Lp(a) concentration. These findings suggest that hyperinsulinemia triggered by insulin resistance can be in part responsible for the observed negative correlation between low Lp(a) and T2D risk. Figure 1. Genetic associations between insulin levels and Lp(a). Each genetic variant included in the analysis is represented as a point + 95% CI. Localization on the horizontal axis represents the correlation of the variant with exposure (plasma fasting insulin, inverse variance normal transformed values). Localization on the vertical axis represents the correlation of the variant with outcome (Lp(a), natural log transformed values). Lines represent estimates of different MR methods.Figure 1.

The development and testing of a single-arm feasibility and acceptability study of a whole foods diet intervention for adults with prediabetes and their offspring

BackgroundDiet is considered a first-line treatment option for prediabetes, a condition that affects 96 million United States (U.S.) adults. Diet patterns that prioritize whole foods (e.g., Mediterranean) are currently recommended to treat prediabetes. However, no studies have tested whether a U.S.-style diet pattern that prioritizes whole foods can be used to treat prediabetes. The purpose of this study was to assess the feasibility and acceptability of a whole foods diet for adults with prediabetes and their offspring prior to conducting a larger clinical trial.MethodsA 2-week single-arm pre-post experimental controlled-feeding intervention of a 2020–2025 Dietary Guidelines for Americans adapted whole foods diet (e.g., primarily focused on foods that have undergone limited processing or refinement) was conducted in adults (25–59 years) with prediabetes and their biological offspring (6–17 years). Families received 2 weeks of menus and grocery delivery and weekly counseling by a registered dietitian. Families were invited to attend an optional focus group session. Feasibility was based on having a ≥ 50% family completion rate with ≥ 80% completion of study outcomes. Measures included adult–child anthropometrics (weight [kg], body mass index [BMI] including BMI% and Z-scores for offspring, waist circumference [cm]) and child diet quality estimated using the 2015 Healthy Eating Index (HEI) from a single random food record. Wilcoxon signed rank was used to compare differences between baseline and 2-week anthropometrics measures and offspring total HEI scores. Qualitative data were analyzed using thematic analysis to understand factors attributed to diet adherence and acceptability.ResultsEight families enrolled (n = 8 adults, n = 12 offspring), with 7 families completing the study (12% attrition) and completing 100% of study outcome measures. Adults experienced a median weight loss of − 1.0 kg from baseline to 2 weeks (79.5 kg to 78.5 kg). Offspring had a 24-point increase in total 2015 HEI scores (median difference 50 to 74). Focus group participants (n = 4 adults) reported being satisfied with the program and expressed a willingness to continue the diet despite identified barriers.ConclusionsA whole foods diet that provides dietary support was found to be feasible and acceptable for families at risk for T2D. Future studies are needed to test the effects of the diet on prediabetes outcomes, diet quality, and diet adherence in adults and families.Trial registrationNCT05483972 at ClinicalTrials.gov. Registered July 25, 2022. https://clinicaltrials.gov/study/NCT05483972?cond=prediabetes&term=whole%20foods%20&rank=1

8513 Toxic Metals Are Associated With Increased Diabetes And Obesity Through Gut Microbiota Changes In Five African-Origin Populations

Abstract Disclosure: J. Jorgensen: None. C. Choo-Kang: None. L. Issa: None. J.A. Gilbert: None. G. Ecklu-Mensah: None. A. Luke: None. K. Bedu-Addo: None. T. Forrester: None. P. Bovet: None. E.V. Lambert: None. D. Rae: None. M. Argos: None. Y. Dai: None. R.M. Sargis: None. L.R. Dugas: None. B.T. Layden: None. Obesity is associated with an increased risk for cardiometabolic diseases, such as type 2 diabetes mellitus (T2D). Prior research has shown an association between toxic metals/metalloid (hereafter, “metals”) exposures, including arsenic (As), lead (Pb), mercury (Hg), and cadmium (Cd), and increased T2D risk. Importantly, metal exposure has been suggested to impact the gut microbiome. Gut microbiome composition and metabolism are key to the development and progression of obesity and diabetes, thus we propose a potential novel interaction via the gut microbiota between metals and T2D, although the exact pathway remains unclear. We studied a large African-origin cohort from Ghana, South Africa, Jamaica, Seychelles, and the US (n=188, 51% female, mean age=43.0±6.5 yr). Analyzing 16S rRNA Amplicon sequencing, anthropometrics, and creatinine-adjusted urinary metal levels, we observed metal levels were significantly associated with country of origin and in most countries were significantly associated with decreased microbial diversity. Metal levels were highest in Ghana and lowest in the US, and were significantly different between Ghana and the US for As and Pb (p-value < 2.2e-16). Individually, Pb levels were significantly associated with fasting blood glucose and BMI, As levels were associated with T2D diagnosis, and Hg levels were associated with obesity diagnosis. Pb levels were significantly associated with a lower proportion of potential acetate- and butyrate-producing microbial strains. Similarly, As levels were associated with decreased proportion of potential butyrate-producing genera. Microbial strains in individuals with high Pb levels showed significant association with obesity and T2D risk and strains in individuals with significant high As levels were associated with only T2D risk. Hg and Cd were not significantly associated with microbes and clinical status. These taxa are significantly associated with increased heme metabolism. With this study, we aimed to begin to describe the effect of metals and the risks for obesity and diabetes through its action within the gut microbiome. We demonstrate that toxic metal exposures were associated with differences in the gut microbiome and predicted metabolism that may also be associated with increased obesity and T2D risk. Presentation: 6/1/2024

7700 Two Years Of Testosterone Therapy Reduces Glycemia In Males At High Risk Of Type 2 Diabetes Without Affecting Beta Cell Function: Results From A Randomised Controlled Trial And Cellular Model

Abstract Disclosure: M. Umapathysivam: None. S. Nawaz: None. K. Robledo: None. C.A. Allan: None. K. Bracken: None. M. Grossmann: None. D.J. Handelsman: None. W.J. Inder: None. D. Jesudason: None. B. Stuckey: None. B. Yeap: None. A. Januszewski: None. A. Jenkins: None. A. Conway: None. B. Hastoy: None. G.A. Wittert: Consulting Fee; Self; I-Nova. Grant Recipient; Self; Lawley pharmaceuticals, Bayer, Weight Watchers, Eli Lilly & Company. Speaker; Self; Bayer, Inc., Amgen Inc, Besin Health Care. Background: In the Testosterone for the prevention of type 2 diabetes (T4DM) Study, treatment with testosterone (T)-undecanoate (1000 mg IM 3 monthly) vs placebo decreased fat mass and reduced the risk of T2D by 40% after 2 years. However, the mechanism(s) by which T therapy prevents or reverts T2D remain unclear. Aim: To assess (1) the impact of T treatment on insulin resistance (IR) and beta-cell function in the T4DM study and (2) the in-vitro effect of graded T exposure on glucose stimulated insulin secretion (GSIS) from the human beta-cell line EndoC-βH1. Methods: (1) T4DM study: Men (n= 1007) from the T4DM study aged, 50-74 years, waist circumference (WC) >95cm, with prediabetes, or newly diagnosed T2D (by OGTT) and serum testosterone (T) ≤ 14 nmol/L (chemiluminescent assay) treated with T-undecanoate (1000 mg IM 3 monthly) or placebo for 2 years. Men were included if they had fasting bloods at baseline, weeks 18, 66, and 102 (N=743). We compared the change in glycated albumin, and derived measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA-IR) using fasting glucose and c-peptide in T and placebo treated men using linear regression models.(2) EndoC-βH1 were incubated with T 5nM, 10nM and 15nM for 20 min and 15nM T for 2-days. Insulin secretion and content were measured at baseline (1mM glucose) and after 20 min exposure 20mM glucose. Results: Treatment with T compared to placebo reduced glycated albumin (-3.4 umol/L; 95%CI:1.4-5.4, p<0.001) maximally at week 66, along with C-peptide (corrected for baseline C-peptide and change in fasting glucose) (-0.12 nmol/L;-0.22,-0.02; p=0.01), HOMA2-B (-6.1; 95%CI: -16, 3.7; p=0.2) and HOMA-IR (-0.20; 95%CI: -0.59,0.20; p=0.3). In-vitro, acute exposure of EndoC-βH1 to 5nM and 10nM of T had no effect on GSIS, and 15nM T reduced GSIS (<20%, p=0.002). T, at 15nM for 2 days was without effect on GSIS. EndoC-βH1 insulin content was not altered at any concentration or timeframe of T exposure. Conclusion: In men with pre-diabetes or early T2D, T treatment reduces glycemia without evidence either in vivo or in-vitro of an affect to increase insulin secretion. Presentation: 6/1/2024

Potency of lysine and tryptophan protect from lysosomal dysfunction and from phenylketonuria, and Mitochondrial disorder mediated by activating lysosomes and OPA1

The phenylketonuria due to decreasing in lysine “AAG” and in Lys/ phosphorylation (which necessary for lysosomal digestive function), and associated with sever decreasing in Trp “TGG” , followed by mitochondrial dysfunction and lysosomal dysfunction, that followed by sever decreasing in phe /hydroxylase and in Tyr/ hydroxylase , and followed by decreasing in lysine acylation and in SFACs productiin which followed by decreasing in RA productive pathway and associated with increasing in both of TNFa and cholesterol accumulation, which reflect decreasing in estrogen synthesis and in dopamine production, that followed by increasing in the risk of ischemic damage and diabetes. And we can conclude that both of Lys “AAG” and Trp “TGG” are so necessary for activating mitochondrial oxidative functions and necessary for promoting transport system where Mitochondria is so necessary to activate antioxidant function and promoting all of Phe hydroxylase, Tyr hydroxylase, and Lys acylation production which necessary for dopamine and RA synthesis respectively, where the PKU characterized by sever decreasing in antioxidant function, and sever decreasing in both Phe/ hydroxylase & Trp/ hydroxylase production, followed by decreasing in dopamine production and decreasing in retinoic acid production (which due to the reduction in SFACs synthesis). Retionic acid “RA” synthesis is activated by lysine acylation and is regulated by lysine acylation mediated by short fatty acid synthesis, which regulate aminoacyl-tRNAs production regulated by mitochondrial enzymes and regulate the mRNA production by E coli (regulated by phenylalanine) that necessary to run antioxidant functions and cellular biosynthesis. The antihypertensive pathway mechanism is : the Lysine ¬¬> activate ATPase and both lysosomes and Mitochondrial oxidative functions which activate lysine acylation ¬¬> which activate short fatty acid synthesis ¬¬> which stimulate retinoic acid “RA” synthesis - ¬¬¬> where both Lys and Trp activate mitochondria repair and oxidative functions, which activate, Phe/ hydroxylase, and activate Tyr/ hydroxylase which activate dopamine , and Trp /oxygenases followed by protection against PKU, pulmonary disease ischemic damage and CVD. The activation of antihypertensive pathway associated by activating lysosomes and Mitochondrial oxidative functions, that associated by activating NR4As pathway which responsible for activating GC-beta and both of Oxytocin and Nrf2, followed by Ang2-AT2 and VEGF-A productive functions and heme oxygenase production (notice dopamine regulate heme oxygenase mediated by dopamine beta-hydroxylase which regulated by Mitochondrial oxidative functions) followed by activating anti-inflammatory growth and processes. Lysine Methylation has important role to enhance and adopt hypertension through activating RA and pervious Antihypertensive pathway mediated by Phe /hydroxylase synthesis and Tyr /hydroxylase production followed by activating both of dopamine and NR4As pathway. Where dopamine synthesis reflect its productive functions to activate Antioxidant functions that prevent cholesterol accumulation, and in turn increase the estrogen production (which it’s synthesis reflect potential protection from pulmonary disease), and activate the NR4As pathway which regulate all of Oxytocin, Nrf2 production, followed by Ang2-AT2 and VEGF-A production, which followed by activating heme oxygenase and anti-inflammatory growth and processes that prevent LV-hypertrophy, and prevent coronary calcification . Also, the increasing in Lys AAA with decreasing in Lys AAG and decreasing Trp TGG will cause decreasing in lysosome proper function, and cause Decreasing in GTPase and decreasing in the Mitochondrial oxidative functions, that will cause decreasing in Phe hydroxylase and in Tyr hydroxylase followed by decreasing in lysine acylation, and associated with increasing in cholesterol accumulation, and also associated with decreasing in both of IL17 production and estrogen functional pathway , that will increase the risk of T2D, pulmonary disease, and increase the risk of PKU and CVD. Both Lys and Trp are necessary to activate transport system across cells membranes that activate antibacterial function and anti-atherosclerosis. Both Lys and Trp are having the Potency to activate lysosomes and Mitochondrial oxidative functions which activate lipid and protein digestion and enhance Phe hydroxylase and Tyr hydroxylase followed by activating lysine acylation which activate SFACs production and promote the RA synthesis and enhance antioxidant functions followed by dopamine synthesis and protection from ischemic damage and from both of diabetes and PKU

Type 2 diabetes mellitus has a positive role in osteomyelitis: A Mendelian randomization analysis.

According to clinical evidence, type 2 diabetes mellitus (T2D) and osteomyelitis (OM) are currently the 2 major causes of mortality and morbidity in humans. Despite accounts of their coexistence, there is still no understanding of their fundamental connection. We attempted to assess the causal effect of T2D on OM using the two-sample Mendelian randomization method. The whole gene-wide association study's aggregate data were examined. Single-nucleotide polymorphisms, which have a substantial correlation with T2D, were used as instrumental variables in a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between T2D and OM risk using the inverse variance weighting, MR-egger regression, and weighted median approaches, respectively. A total of 114 single-nucleotide polymorphism were used as instrumental variables in this analysis. The inverse variance-weighted analysis showed a significant causal relationship between T2D and OM, indicating that T2D has a detrimental effect on OM risk. The odds ratio for the causal effect of T2D on OM was 1.317, with a 95% confidence interval of (1.140, 1.522) (P < .001). To assess heterogeneity, Cochran Q test statistics and MR-Egger regression were applied in the inverse variance-weighted technique. The P-value of .737 indicated a considerable level of heterogeneity was not absent in the data. This study used Mendelian randomization analysis to establish a causal relationship between T2D and OM. The findings suggest that T2D may increase the risk of OM.

Early life socioeconomic inequalities and type 2 diabetes incidence: Longitudinal analyses in the Maastricht study

AimType 2 diabetes (T2D) is a common chronic disease that disproportionally affects groups with a low socioeconomic position (SEP). This study aimed to examine associations between childhood SEP and incident T2D, independent of adult SEP. MethodsLongitudinal data from The Maastricht Study were used (N=6,727, 55.2 % female, mean (SD) age 58.7(8.7) years). Childhood SEP was determined by asking for the highest completed educational level for the father and mother and childhood income inadequacy. Adult SEP was determined by highest completed educational level, equivalent household income, and occupational position. Incident T2D was self-reported yearly (up to 12 years of follow-up). Associations were studied with Cox regression analyses. ResultsIn participants without T2D at baseline, 3.7% reported incident T2D over 8.2 (median) years of follow-up. Incident T2D was most common in people with low childhood and adult SEP and lowest in those with high childhood and adult SEP (1.7 vs. 7.5 per 1,000 person years). The association between childhood SEP and incident T2D was mainly explained by adult SEP, except for childhood income inadequacy which was independently associated with incident T2D. ConclusionSocioeconomic inequalities in childhood and adulthood are risk factors for incident T2D. More attention is needed to reduce childhood poverty and improve adult SEP to reduce the T2D risk.

A mendelian randomisation study of the causal effect of exercise intensity on the development of type 2 diabetes.

This study examines the causal effects of varying exercise intensities on type 2 diabetes mellitus (T2D) through Mendelian randomization (MR) analysis, using genetic variants as instrumental variables. A two-sample MR analysis was performed, employing Inverse Variance Weighted (IVW) as the primary method, supported by weighted median, MR-Egger regression, MR-PRESSO, and MR robustness-adjusted contour scores. Data were obtained from the International Exercise Genetics Database (IEGD) and the Global Diabetes Research Consortium (GRC), encompassing over 150,000 individuals for exercise intensity and around 200,000 T2D patients and controls. SNPs linked to exercise intensity were selected based on genome-wide significance (P < 5 × 10^-8) and linkage disequilibrium criteria (distance >10,000kb, r^2 < 0.001). The IVW analysis suggested that high-intensity exercise might reduce T2D risk, but the association was not statistically significant (OR = 0.667, 95% CI = 0.104-4.255, P = 0.667). The wide confidence interval indicates uncertainty in the effect estimate. Low-intensity exercise showed no significant effect on T2D risk (OR ∼ 1.0). Sensitivity analyses, including weighted median and MR-Egger regression, confirmed no significant association between high-intensity exercise and T2D risk. The MR-PRESSO analysis found no significant outliers, and the global test for pleiotropy was non-significant (P = 0.455). Cochran's Q test for heterogeneity in the IVW analysis was non-significant (Q = 12.45, P = 0.234), indicating consistency among SNP-derived estimates. High-intensity exercise potentially reduces T2D risk, but the association is not statistically significant. Further research is needed to understand the complex relationship between exercise intensity and T2D.

From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

ABSTRACTBackgroundType 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia, and hyperinsulinemia. A significant portion of individuals with T2D are unaware of their condition until it has reached advanced stages. T2D is also associated with an increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Understanding the mechanisms underlying the emergence of insulin resistance is critical for improving early detection and therapeutic interventions.MethodsAn updated framework is proposed to describe the emergence of insulin resistance that precedes the development of T2D. The model focuses on the impact of diminishing capacity to store excess glucose, which can occur due to a multitude of factors, including age‐related muscle loss. The model is used to simulate responses to oral glucose tolerance tests (OGTTs) to capture the transition from a normal to a diabetic phenotype, as defined by the Kraft criteria. Additionally, the model is used to explore how the metabolic environment influences tumor progression, drawing on experimental data regarding the impact of transient diabetic phenotypes and hyperinsulinemia on cancer therapy efficacy.ResultsThe model successfully demonstrates that reduced glucose storage capacity can qualitatively reproduce the progression from normal to diabetic phenotypes observed in OGTT responses. Furthermore, it shows that tumor progression or regression is highly dependent on the host's metabolic environment, particularly hyperinsulinemia. This aligns with experimental results that connect drug‐induced hyperinsulinemia to a loss of therapeutic efficacy against tumors, whereas the reversal of the diabetic phenotype could restore drug sensitivity and treatment response.ConclusionsThis study highlights the critical role of hyperinsulinemia, even in normoglycemic individuals, in both the progression of T2D and the modulation of cancer therapy outcomes. Addressing hyperinsulinemia emerges as a promising strategy to enhance cancer treatment efficacy and improve overall health outcomes in patients with or at risk for T2D.

The Association of Dietary Inflammatory Index with the Risk of Type 2 Diabetes: A Case-Control Study

Background: The prevalence rate of type 2 diabetes (T2DM) is increasing worldwide, and the role of diet in its etiology has been established. The Dietary inflammatory index (DII) has attracted significant attention in evaluating associations between diet and diseases due to the role of chronic inflammation as an underlying cause of numerous disease processes. Therefore, the relationship between DII score and the risk of T2DM is evaluated in the Iranian population for the first time. Methods: 113 newly diagnosed T2DM patients and 226 apparently disease-free control cases aged 23-59 participated in this case-control study. A valid semi-quantitative food frequency questionnaire was used to assess dietary intake. Then, energy-adjusted DII (E-DII) scores were computed and categorized into quartiles based on values in the population study. A logistic regression model was used to estimate the association between DII and the risk of T2DM after controlling for important potential confounders and effect modifiers. Results: A significant association was observed between E-DII score and T2DM in the crude model (P-trend&lt;0.001), model I (adjusted for physical activity, gender, education level, and family history of T2DM, P-trend&lt;0.001), model II (adjusted for model I + body mass index, P-trend=0.005) (ORquartile4vs1 =2.98 (95% CI: 1.18, 9.12; P= 0.005). Conclusions: A direct association was observed between DII score and the risk of T2D, implying that consuming a more anti-inflammatory diet would help to prevent T2DM. Future longitudinal studies should be conducted to further explore this association.

Low muscle mass index is associated with type 2 diabetes risk in a Latin-American population: a cross-sectional study.

Diabetes mellitus is a growing disease with severe complications. Various scores predict the risk of developing this pathology. The amount of muscle mass is associated with insulin resistance, yet there is no established evidence linking muscle mass with diabetes risk. This work aims to study that relationship. This cross-sectional study included 1,388 employees. The FINDRISC score was used to assess type 2 diabetes risk, and bioimpedance was used for body composition analysis. Appendicular skeletal muscle mass adjusted by body mass index (ASM/BMI) was analyzed. Sociodemographic, clinical and anthropometric measures were evaluated, logistic regression models with sex stratification were conducted and ROC curves were calculated to determine the ability of ASM/BMI index to predict T2D risk. It was observed that patients with higher ASM/BMI had a lower FINDRISC score in both men and women (p < 0.001). A logistic regression model showed and association between ASM/BMI and diabetes risk in women [OR: 0.000 (0.000-0.900), p = 0.048], but not in men [OR: 0.267 (0.038-1.878), p = 0.185]. However, when the body mass index variable was excluded from the model, an association was found between muscle mass adjusted to BMI and diabetes risk in both men [OR: 0.000 (0.000-0.016), p < 0.001], and women [OR:0.001 (0.000-0.034), p < 0.001]. Other risk factors were having a low level of physical activity, waist circumference, age and sedentary lifestyle. A ROC curve was built and the optimal ASM/BMI cut-of value for predicting T2D risk was 0.82 with a sensitivity of 53.71% and specificity of 69.3% [AUC of 0.665 (0.64-0.69; p < 0.0001)]. When quantifying the risk of type 2 diabetes in both women and men, assessing muscle mass can help detect adult individuals with a high risk of developing type 2 diabetes.

On the use of the healthy lifestyle index to investigate specific disease outcomes

The healthy lifestyle index (HLI), defined as the unweighted sum of individual lifestyle components, was used to investigate the combined role of lifestyle factors on health-related outcomes. We introduced weighted outcome-specific versions of the HLI, where individual lifestyle components were weighted according to their associations with disease outcomes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the association between the standard and the outcome-specific HLIs and the risk of T2D, CVD, cancer, and all-cause premature mortality. Estimates of the hazard ratios (HRs), the Harrell’s C-index and the population attributable fractions (PAFs) were compared. For T2D, the HR for 1-SD increase of the standard and T2D-specific HLI were 0.66 (95% CI: 0.64, 0.67) and 0.43 (0.42, 0.44), respectively, and the C-index were 0.63 (0.62, 0.64) and 0.72 (0.72, 0.73). Similar, yet less pronounced differences in HR and C-index were observed for standard and outcome-specific estimates for cancer, CVD and all-cause mortality. PAF estimates for mortality before age 80 were 57% (55%, 58%) and 33% (32%, 34%) for standard and mortality-specific HLI, respectively. The use of outcome-specific HLI could improve the assessment of the role of lifestyle factors on disease outcomes, thus enhancing the definition of public health recommendations.

Dried fruit intake and lower risk of type 2 diabetes: a two-sample mendelian randomization study

BackgroundPrevious studies have shown controversy about whether dried fruit intake is associated with type 2 diabetes. This study aimed to examine the potential causal effect of dried fruit intake on type 2 diabetes by conducting a two-sample Mendelian randomization study.MethodsWe used genome-wide association study (GWAS) summary statistics for MR analysis to explore the causal association of dried fruit intake with T2D. The inverse-variance weighted (IVW) method was used as the main analytical method for MR analysis. In addition, the MR-Egger method and the weighted median method were applied to supplement the IVW method. Furthermore, Cochrane’s Q test, MR-Egger intercept test, and leave-one-out analysis were used to perform sensitivity analysis. The funnel plot was used to assess publication bias.ResultsThe results from the IVW analysis indicated that dried fruit intake could reduce the risk of T2D [odds ratio (OR) = 0.392, 95% confidence interval (CI): 0.241–0.636, p-value = 0.0001]. In addition, the result of additional method Weighted median is parallel to the effects estimated by IVW. Furthermore, the sensitivity analysis illustrates that our MR analysis was unaffected by heterogeneity and horizontal pleiotropy. Finally, the results of the leave-one-out method showed the robustness of our MR results. And the funnel plot shows a symmetrical distribution.ConclusionOur study provides evidence for the benefits of dried fruit intake on T2D. Therefore, a reasonable consumption of dried fruit may provide primary prevention.

Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: The Study of Women’s Health Across the Nation Multi-Pollutant Study

BackgroundOrganochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. ObjectivesWe investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999–2016) in midlife women. MethodsWe measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1040 midlife women aged 45–56 years from the Study of Women’s Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). ResultsFor most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR = 1.04 [0.53, 2.07]). ConclusionExposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Potential Association of The Pathogenic Kruppel-like Factor 14 (KLF14) and Adiponectin (ADIPOQ) SNVs with Susceptibility to T2DM.

To evaluate the associations of the pathogenic variants in Kruppel-like Factor 14 (KLF 14) and Adiponectin (ADIPOQ) with susceptibility to type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a pandemic metabolic disease characterized by increased blood sugar and caused by resistance to insulin in peripheral tissues and damage to pancreatic beta cells. Kruppel-like Factor 14 (KLF-14) is proposed to be a regulator of metabolic diseases, such as diabetes mellitus (DM) and obesity. Adiponectin (ADIPOQ) is an adipocytokine produced by the adipocytes and other tissues and was reported to be involved in T2DM. To study the possible association of the KLF-14 rs972283 and ADIPOQ-rs266729 with the risk of T2DM in the Saudi population. We have evaluated the association of KLF-14 rs972283 C>T and ADIPOQ-rs266729 C>G SNV with the risk to T2D in the Saudi population using the Amplification Refractory Mutation System PCR (ARMS-PCR), and blood biochemistry analysis. For the KLF-14 rs972283 C>T SNV we included 115 cases and 116 healthy controls, and ADIPOQ-rs266729 C>G SNV, 103 cases and 104 healthy controls were included. Results indicated that the KLF-14 rs972283 GA genotype and A allele were associated with T2D risk with OR=2.14, p-value= 0.014 and OR=1.99, p-value=0.0003, respectively. Results also ADIPOQ-rs266729 CG genotype and C allele were associated with an elevated T2D risk with an OR=2.53, p=0.003 and OR=1.66, p-value =0.012, respectively. We conclude that SNVs in KLF-14 and ADIPOQ are potential loci for T2D risk. Future large-scale studies to verify these findings are recommended. These results need further verifications in protein functional and large-scale case control studies before being introduced for genetic testing.

Association between HLA alleles and haplotypes with age at diagnosis of type 1 diabetes in an admixed Brazilian population: A nationwide study.

To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-raceand identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.

Genome-wide linkage and association of novel genes and pathways with type 2 diabetes in Italian families

BackgroundType 2 diabetes mellitus (T2D) stands as one of the most prevalent chronic diseases globally, posing substantial health and economic burdens on society. Within the spectrum of T2D, familial cases emerge as a distinct entity characterized by a strong familial clustering of the disease. This phenomenon has long suggested that genetics contributes substantially to T2D susceptibility, motivating extensive research into the genetic determinants of familial T2D. MethodsWe recruited 212 multigenerational Italian families with multiple cases of T2D. The families were genotyped using genomic array (≥ 600k) derived from the UK Biobank Axiom Array platform. Informative markers were tested via Pseudomarker for linkage to and linkage disequilibrium (i.e., linkage joint to association) with T2D across the following models: dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2). ResultsWe identified a total of 566 variants reaching genome-wide significant (P < 0.00005) linkage and/or association to/with the risk of T2D in Italian families. Of the 355 genes identified in our study, 341 (96%) are novel and have not been reported with T2D or any of its related phenotypes (i.e., obesity, metabolic syndrome, insulin resistance, polycystic ovary syndrome, and hyperglycemia). ConclusionOur study constitutes the first familial T2D-linkage and association study in the Italian population. However, the functional relevance of the novel variants and genes reported in our study remains to be explored.

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells.

The HLA region, especially HLA class I and II genes, which encode molecules for antigen presentation to T cells, plays a major role in the predisposition to autoimmune disorders. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation by microarrays to cover over 850,000 CpG sites in the CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6, n = 14), associated with a strongly decreased T1D risk, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2, n = 19), or DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8, n = 17), associated with a moderately increased T1D risk. In total, we discovered 14 differentially methylated CpG probes, of which 10 were located in the HLA region and six in the HLA-DRB1 locus. The main differences were between the protective genotype DR2-DQ6 and the risk genotypes DR3-DQ2 and DR4-DQ8, where the DR2-DQ6 group was hypomethylated compared to the other groups in all but four of the differentially methylated probes. The differences between the risk genotypes DR3-DQ2 and DR4-DQ8 were small. Our results indicate that HLA variants have few systemic effects on methylation and that their effect on autoimmunity is conveyed directly by HLA molecules, possibly by differences in expression levels or function.

Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.

Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D. Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci. Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 × 10-8). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 × 10-9). Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.

A new era for food in health? The FDA announces a qualified health claim for yogurt intake and type 2 diabetes mellitus risk reduction

IntroductionOver the last two decades research has grown regarding dairy intake and health. It has been reported by many that yogurt intake may be associated with reduced risk of type 2 diabetes mellitus (T2D). In this report, the United States Food and Drug Administration (FDA) decision to announce a qualified health claim for yogurt products regarding reduced risk of T2D in response to a Danone North America petition is discussed. MethodsRelevant literature cited in the petition along with supporting evidence from PubMed and Google Scholar databases until April 1st, 2024 were used. Literature was found using relevant keywords. ResultsOn March 1st, 2024, the United States Food and Drug Administration (FDA) announced the first ever qualified health claim, stating that eating yogurt regularly may reduce the risk of T2D according to limited scientific evidence. The enforcement discretion letter was critically reviewed and discussed regarding its future implications for people with T2M and public health. ConclusionsIt is unclear how this FDA decision will affect public health and nutrition in the long-term. Limited scientific evidence suggests that at least 3 servings of yogurt per week may reduce the risk of T2D incidence for the general population. Yogurt will not cure or treat people with T2D.