Search

Objective: To investigate whether the association between insulin resistance and cardiovascular disease (CVD) differs by glucose tolerance status.Research Design and Methods: We analyzed a nationwide sample of 111,576 adults without CVD at baseline, using data from the China Cardiometabolic Disease and Cancer Cohort Study. Insulin resistance was estimated by sex-specific HOMA of insulin resistance (HOMA-IR) quartiles for participants with normal glucose tolerance, prediabetes, or diabetes, separately, and by 1 SD of HOMA-IR for the overall study participants. We used Cox proportional hazards models to examine the association between insulin resistance and incident CVD according to glucose tolerance status and evaluate the CVD risk associated with the combined categories of insulin resistance and obesity in prediabetes and diabetes, as compared with normal glucose tolerance. Models were adjusted for age, sex, education attainment, alcohol drinking, smoking, physical activity, and diet quality.Results: In participants with normal glucose tolerance, prediabetes, and diabetes defined by three glucose parameters, multivariable-adjusted hazard ratios (95% CIs) for incident CVD associated with the highest versus the lowest quartile of HOMA-IR were 1.03 (0.82-1.30), 1.23 (1.07-1.42), and 1.61 (1.30-2.00), respectively; the corresponding values for CVD per 1-SD increase in HOMA-IR were 1.04 (0.92-1.18), 1.12 (1.06-1.18), and 1.15 (1.09-1.21), respectively (P for interaction = 0.011). Compared with participants with normal glucose tolerance, in participants with prediabetes, the combination of the highest HOMA-IR quartile and obesity showed 17% (95% CI 2-34%) higher risk of CVD, while the combination of the lowest two HOMA-IR quartiles and nonobesity showed 15-17% lower risk of CVD. In participants with diabetes, the upper two HOMA-IR quartiles exhibited 44-77% higher risk of CVD, regardless of obesity status. Consistent findings were observed for glucose tolerance status defined by different combinations of glycemic parameters.Conclusions: Glucose intolerance status exacerbated the association between insulin resistance and CVD risk. Compared with adults with normal glucose tolerance, adults with prediabetes who were both insulin resistant and obese exhibited higher risks of CVD, while in adults with diabetes, the CVD risk related to insulin resistance remained, regardless of obesity. [ABSTRACT FROM AUTHOR]

Objective: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults.Research Design and Methods: We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression.Results: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid (P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset.Conclusions: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]

Objective: We aim to investigate the impact of ideal cardiovascular health metrics (ICVHMs) on the association between famine exposure and adulthood diabetes risk.Research Design and Methods: This study included 77,925 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study who were born around the time of the Chinese Great Famine and free of diabetes at baseline. They were divided into three famine exposure groups according to the birth year, including nonexposed (1963-1974), fetal exposed (1959-1962), and childhood exposed (1949-1958). Relative risk regression was used to examine the associations between famine exposure and ICVHMs on diabetes.Results: During a mean follow-up of 3.6 years, the cumulative incidence of diabetes was 4.2%, 6.0%, and 7.5% in nonexposed, fetal-exposed, and childhood-exposed participants, respectively. Compared with nonexposed participants, fetal-exposed but not childhood-exposed participants had increased risks of diabetes, with multivariable-adjusted risk ratios (RRs) (95% CIs) of 1.17 (1.05-1.31) and 1.12 (0.96-1.30), respectively. Increased diabetes risks were observed in fetal-exposed individuals with nonideal dietary habits, nonideal physical activity, BMI ≥24.0 kg/m2, or blood pressure ≥120/80 mmHg, whereas significant interaction was detected only in BMI strata (P for interaction = 0.0018). Significant interactions have been detected between number of ICVHMs and famine exposure on the risk of diabetes (P for interaction = 0.0005). The increased risk was observed in fetal-exposed participants with one or fewer ICVHMs (RR 1.59 [95% CI 1.24-2.04]), but not in those with two or more ICVHMs.Conclusions: The increased risk of diabetes associated with famine exposure appears to be modified by the presence of ICVHMs. [ABSTRACT FROM AUTHOR]

The notion that IGF-I stimulates islet cell growth has been challenged recently by IGF-I and receptor gene targeting. In order to test the effect of a general, more profound increase in circulating IGF-I, we have characterized MT-1GF mice which overexpress the IGF-I gene under the metallothionein I promoter. In previous reports, a 1.5-fold elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. Here it was demonstrated that the transgene expression, although widespread, was highly concentrated in the pancreatic islets. Yet, islet cell percentage and morphology were unaffected. However, IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, improved glucose tolerance and normal insulin sensitivity. Pyruvate tolerance test indicated suppressed hepatic gluconeogenesis. Due to a partial prevention of β-cell death against onset of diabetes and/or the insulin-like effect of IGF-I overexpression, MT-IGF mice were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia, weight loss and death. Thus, although IGF-I does not promote islet cell growth, its overexpression is clearly anti-diabetic. Figure 1. Normal insulin sensitivity, Increased glucose clearance and decreased gluconeogenesis in MT-IGF mice. Mice of 2.5-month-old, mixed male and female, were used. A, Insulin tolerance test. Wild-type and MT-IGF mice in random fed state were injected with insulin (0.75 IU/kg ip). Blood glucose levels were measured at 0, 20, 40 and 60 min. Percentage values relative to time 0 were expressed as means ± SE. (N = 4) B, Glucose tolerance tests. Mice were fasted for 24 h and injected with glucose (1.0 g/kg ip). (N = 4∼6) C, Pyruvate tolerance tests. Mice were fasted for 24 h and injected with pyruvate (2.0 g/kg ip). (N = 4∼5) D, Glutamine tolerance tests. Mice were fasted for 24 h and injected with L-glutamine (1.5 g/kg ip). (N = 7∼12) *P<0.05, **P<0.01, ***P<0.001 vs. wild-typo littermates. [ABSTRACT FROM AUTHOR]