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Vasodilatory Actions of Glucagon-Like Peptide 1 Are Preserved in Skeletal and Cardiac Muscle Microvasculature but Not in Conduit Artery in Obese Humans With Vascular Insulin Resistance

期刊: DIABETES CARE, 2020; 43 (3)

OBJECTIVE Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. RESEARCH DESIGN AND METHODS Fifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. RESULTS Insulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by similar to 30% and similar to 40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by similar to 20%. Insulin, GLP-1, and GLP-1 + insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes. CONCLUSIONS In obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study

期刊: DIABETES CARE, 2020; 43 (3)

OBJECTIVE This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. RESULTS A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. CONCLUSIONS Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.

Establishment and Validation of a Risk Prediction Model for Early Diabetic Kidney Disease Based on a Systematic Review and Meta-Analysis of 20 Cohorts

期刊: DIABETES CARE, 2020; 43 (4)

BACKGROUND Identifying patients at high risk of diabetic kidney disease (DKD) helps improve clinical outcome. PURPOSE To establish a model for predicting DKD. DATA SOURCES The derivation cohort was from a meta-analysis. The validation cohort was from a Chinese cohort. STUDY SELECTION Cohort studies that reported risk factors of DKD with their corresponding risk ratios (RRs) in patients with type 2 diabetes were selected. All patients had estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m(2) and urinary albumin-to-creatinine ratio (UACR) DATA EXTRACTION Risk factors and their corresponding RRs were extracted. Only risk factors with statistical significance were included in our DKD risk prediction model. DATA SYNTHESIS Twenty cohorts including 41,271 patients with type 2 diabetes were included in our meta-analysis. Age, BMI, smoking, diabetic retinopathy, hemoglobin A(1c), systolic blood pressure, HDL cholesterol, triglycerides, UACR, and eGFR were statistically significant. All these risk factors were included in the model except eGFR because of the significant heterogeneity among studies. All risk factors were scored according to their weightings, and the highest score was 37.0. The model was validated in an external cohort with a median follow-up of 2.9 years. A cutoff value of 16 was selected with a sensitivity of 0.847 and a specificity of 0.677. LIMITATIONS There was huge heterogeneity among studies involving eGFR. More evidence is needed to power it as a risk factor of DKD. CONCLUSIONS The DKD risk prediction model consisting of nine risk factors established in this study is a simple tool for detecting patients at high risk of DKD.

Dietary Nonheme, Heme, and Total Iron Intake and the Risk of Diabetes in Adults: Results From the China Health and Nutrition Survey

期刊: DIABETES CARE, 2020; 43 (4)

OBJECTIVE Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population. RESEARCH DESIGN AND METHODS We included 17,026 adults (8,346 men and 8,680 women) who were part of the China Health and Nutrition Survey (1991-2015) prospective cohort. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. Diabetes cases were identified through a questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS A total of 547 men and 577 women developed diabetes during 202,138 person-years of follow-up. For men, the adjusted HRs (95% CIs) for quintiles of nonheme iron intake were 1.00, 0.77 (0.58-1.02), 0.72 (0.54-0.97), 0.63 (0.46-0.85), and 0.87 (0.64-1.19) (P-nonlinearity = 0.0015). The corresponding HRs (95% CIs) for women were 1.00, 0.63 (0.48-0.84), 0.57 (0.43-0.76), 0.58 (0.43-0.77), and 0.67 (0.49-0.91) (P-nonlinearity < 0.0001). The dose-response curves for the association between nonheme iron and total iron intake and diabetes followed a reverse J shape in men and an L shape in women. No significant associations were observed between heme iron intake and diabetes risk. CONCLUSIONS Total iron and nonheme iron intake was associated with diabetes risk, following a reverse J-shaped curve in men and an L-shaped curve in women. Sufficient intake of nonheme or total iron might be protective against diabetes, while excessive iron intake might increase the risk of diabetes among men.

Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank

期刊: DIABETES CARE, 2020; 43 (4)

OBJECTIVE Glucosamine is a widely used supplement typically taken for osteoarthritis and joint pain. Emerging evidence suggests potential links of glucosamine with glucose metabolism, inflammation, and cardiometabolic risk. We prospectively analyzed the association of habitual glucosamine use with risk of type 2 diabetes (T2D) and assessed whether genetic susceptibility and inflammation status might modify the association. RESEARCH DESIGN AND METHODS This study analyzed 404,508 participants from the UK Biobank who were free of diabetes, cancer, or cardiovascular disease at baseline and completed the questionnaire on supplement use. Cox proportional hazards models were used to evaluate the association between habitual use of glucosamine and risk of incident T2D. RESULTS During a median of 8.1 years of follow-up, 7,228 incident cases of T2D were documented. Glucosamine use was associated with a significantly lower risk of T2D (hazard ratio 0.83, 95% CI 0.78-0.89) after adjustment for age, sex, BMI, race, center, Townsend deprivation index, lifestyle factors, history of disease, and other supplement use. This inverse association was more pronounced in participants with a higher blood level of baseline C-reactive protein than in those with a lower level of this inflammation marker (P-interaction = 0.02). A genetic risk score for T2D did not modify this association (P-interaction = 0.99). CONCLUSIONS Our findings indicate that glucosamine use is associated with a lower risk of incident T2D.

Trends in Bone Mineral Density, Osteoporosis, and Osteopenia Among US Adults With Prediabetes, 2005-2014

期刊: DIABETES CARE, 2020; 43 (5)

OBJECTIVE We aimed to evaluate trends in bone mineral density (BMD) and the prevalence of osteoporosis/osteopenia in U.S. adults with prediabetes and normal glucose regulation (NGR) and further investigate the association among prediabetes, osteopenia/osteoporosis, and fracture. RESEARCH DESIGN AND METHODS We collected and analyzed data from the U.S. National Health and Nutrition Examination Surveys during the period from 2005 to 2014. Femoral neck and lumbar spine BMD data were available for 5,310 adults with prediabetes and 5,162 adults with NGR >40 years old. RESULTS A shift was observed toward a lower BMD and a higher prevalence of osteopenia/osteoporosis at the femoral neck and lumbar spine in U.S. adults >40 years old with prediabetes since 2005, especially in men 40 years old with NGR. Moreover, prediabetes was associated with a higher prevalence of hip fracture, although participants with prediabetes had higher BMD and a lower prevalence of osteopenia/osteoporosis at the femoral neck. CONCLUSIONS There was a declining trend in BMD from 2005 to 2014 in U.S. adults >40 years old with prediabetes and NGR, and this trend was more significant in men <60 years old. Populations with prediabetes may be exposed to relatively higher BMD but a higher prevalence of fracture.

Wilson Disease With Novel Compound Heterozygote Mutations in the ATP7B Gene Presenting With Severe Diabetes

期刊: DIABETES CARE, 2020; 43 (6)

OBJECTIVE To determine the relationship between ATP7B mutations and diabetes in Wilson disease (WD). RESEARCH DESIGN AND METHODS A total of 21 exons and exon-intron boundaries of ATP7B were identified by Sanger sequencing. RESULTS Two novel compound heterozygous mutations (c.525 dupA/ Val176Serfs*28 and c.2930 C>T/ p.Thr977Met) were detected in ATP7B. After d-penicillamine (D-PCA) therapy, serum aminotransferase and ceruloplasmin levels in this patient were normalized and levels of HbA(1c) decreased. However, when the patient ceased to use D-PCA due to an itchy skin, serum levels of fasting blood glucose increased. Dimercaptosuccinic acid capsules were prescribed and memory recovered to some extent, which was accompanied by decreased insulin dosage for glucose control by 5 units. CONCLUSIONS This is the first report of diabetes caused by WD.

Dietary Manganese, Plasma Markers of Inflammation, and the Development of Type 2 Diabetes in Postmenopausal Women: Findings From the Women's Health Initiative

期刊: DIABETES CARE, 2020; 43 (6)

OBJECTIVE To examine the association between manganese intake and the risk of type 2 diabetes in postmenopausal women and determine whether this association is mediated by circulating markers of inflammation. RESEARCH DESIGN AND METHODS We included 84,285 postmenopausal women without a history of diabetes from the national Women's Health Initiative Observational Study (WHI-OS). Replication analysis was then conducted among 62,338 women who participated in the WHI-Clinical Trial (WHI-CT). Additionally, data from a case-control study of 3,749 women nested in the WHI-OS with information on biomarkers of inflammation and endothelial dysfunction were examined using mediation analysis to determine the relative contributions of these known biomarkers by which manganese affects type 2 diabetes risk. RESULTS Compared with the lowest quintile of energy-adjusted dietary manganese, WHI-OS participants in the highest quintile had a 30% lower risk of type 2 diabetes (hazard ratio [HR] 0.70 [95% CI 0.65, 0.76]). A consistent association was also confirmed in the WHI-CT (HR 0.79 [95% CI 0.73, 0.85]). In the nested case-control study, higher energy-adjusted dietary manganese was associated with lower circulating levels of inflammatory biomarkers that significantly mediated the association between dietary manganese and type 2 diabetes risk. Specifically, 19% and 12% of type 2 diabetes risk due to manganese were mediated through interleukin 6 and hs-CRP, respectively. CONCLUSIONS Higher intake of manganese was directly associated with a lower type 2 diabetes risk independent of known risk factors. This association may be partially mediated by inflammatory biomarkers.

Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A(1c) in the ADVANCE Trial

期刊: DIABETES CARE, 2020; 43 (6)

OBJECTIVE To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A(1c) (HbA(1c)) at baseline. RESEARCH DESIGN AND METHODS We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. RESULTS During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA(1c) level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA(1c) levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA(1c) at baseline (P = 0.09 and 0.18, respectively). CONCLUSIONS The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA(1c).

Circulating Retinol-Binding Protein 4 Is Inversely Associated With Pancreatic beta-Cell Function Across the Spectrum of Glycemia

期刊: DIABETES CARE, 2020; 43 (6)

OBJECTIVE The aim of this study was to examine the association of circulating retinol-binding protein 4 (RBP4) levels with beta-cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 291 subjects aged 35-60 years with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT), or type 2 diabetes were screened by a standard 2-h oral glucose tolerance test (OGTT) with the use of traditional measures to evaluate beta-cell function. From these participants, 74 subjects were recruited for an oral minimal model test, and beta-cell function was assessed with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS Circulating RBP4 levels were significantly and inversely correlated with beta-cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indices, but not with HOMA of beta-cell function, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with beta-cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion. CONCLUSIONS Circulating RBP4 levels are inversely and independently correlated with beta-cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

Prognostic Significance of Long-term HbA(1c) Variability for All-Cause Mortality in the ACCORD Trial

期刊: DIABETES CARE, 2020; 43 (6)

OBJECTIVE The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA(1c) variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population. RESEARCH DESIGN AND METHODS We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA(1c) variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI. RESULTS Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA(1c) (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA(1c) variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA(1c) variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA(1c) mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17-3.61; P < 0.01) only in the intensive-therapy group. CONCLUSIONS Long-term visit-to-visit HbA(1c) variability was a strong predictor of all-cause mortality. HbA(1c) VIM combined with HbA(1c) mean conferred an increased risk for all-cause mortality in the intensive-therapy group.

Contrasting Associations Between Diabetes and Cardiovascular Mortality Rates in Low-, Middle-, and High-Income Countries: Cohort Study Data From 143,567 Individuals in 21 Countries in the PURE Study

期刊: DIABETES CARE, 2020; 43 (12)

OBJECTIVE We aimed to compare cardiovascular (CV) events, all-cause mortality, and CV mortality rates among adults with and without diabetes in countries with differing levels of income. RESEARCH DESIGN AND METHODS The Prospective Urban Rural Epidemiology (PURE) study enrolled 143,567 adults aged 35-70 years from 4 high-income countries (HIC), 12 middle-income countries (MIC), and 5 low-income countries (LIC). The mean follow-up was 9.0 +/- 3.0 years. RESULTS Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1,000 person-years, P < 0.001), all-cause mortality (LIC 13.8, MIC 7.2, HIC 4.2 per 1,000 person-years, P < 0.001), and CV mortality (LIC 5.7, MIC 2.2, HIC 1.0 per 1,000 person-years, P < 0.001) were considerably higher in LIC compared with MIC and HIC. Within LIC, mortality was higher in those in the lowest tertile of wealth index (low 14.7%, middle 10.8%, and high 6.5%). In contrast to HIC and MIC, the increased CV mortality in those with diabetes in LIC remained unchanged even after adjustment for behavioral risk factors and treatments (hazard ratio [95% CI] 1.89 [1.58-2.27] to 1.78 [1.36-2.34]). CONCLUSIONS CVD rates, all-cause mortality, and CV mortality were markedly higher among those with diabetes in LIC compared with MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society.

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