沈晓霞
中国医学科学院阜外医院 内分泌科
PURPOSE:This study aimed to examine the modifiable predictors of T2DM and the roles of insulin resistance (IR) and β-cell function over a 6-year study and 30-year follow-up.METHODS:A total of 462 non-diabetic participants, 282 with impaired glucose tolerance (IGT), and 180 with normal glucose tolerance (NGT) were enrolled in this analysis. The Matsuda IR index and area under the curve of insulin-to-glucose ratio (AUCI/G-R) were used as IR and β-cell function indices in the analysis.RESULTS:In all participants, multivariable analysis showed that BMI, glucose status, Matsuda IR index and systolic blood pressure (SBP) at baseline were independently associated with an increased risk of T2DM over 30 years, whereas lifestyle intervention and AUCI/G-R were inversely associated with this risk. The predictive effect of the Matsuda IR index and AUCI/G-R in participants with IGT was consistent with the results of all participants, whereas in those with NGT, only the Matsuda IR index, not the AUCI/G-R, predicted the development of T2DM (HR = 1.42, 95% CI 1.07-1.89 vs HR = 1.09, 95% CI 0.76-1.56). The predictive effect of the Matsuda IR index on T2DM existed even in participants with BMI < 25 (p = 0.049).CONCLUSION:The modifiable predictors of T2DM in Chinese adults were high BMI, hypertension, mild hyperglycaemia, IR, and β-cell dysfunction. Both IR and β-cell function contributed to the development of T2DM in the long term; however, IR remains the initial and long-standing key risk factor for T2DM.
Journal of endocrinological investigation 2023
BACKGROUND:We aimed to explore if hyperglycaemia and hyperinsulinemia in the diabetes and prediabetes population were associated with increased risk of cancer occurence.METHODS:Overall, 1700 participants with different glycaemic statuses were screened from the 110,660 residents of Da-Qing, China, in 1985. They were followed up to 30 years to access cancer outcomes.RESULTS:Cancer was identified in 15.2% (259/1700) of the participants. The incidence of cancer in the normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes groups was 6.06, 6.77, and 7.18 per 1000 person-years, respectively (P = 0.02). In the Fine-Gray model with all cause death as competing risk, compared with the NGT controls, both IGT and diabetes groups demonstrated significantly higher risk of cancer (for the IGT group, adjusted hazard ratio (aHR) = 1.77, 95% CI 1.38-2.27, P < 0.0001; for the diabetes, aHR = 3.34, 95% CI 2.64-4.22, P < 0.0001). Among the IGT participants, progress to diabetes (aHR = 2.28, 95%CI 1.24-4.20, P = 0.008) and insulin-area under the curve at baseline (for 1 SD increase, aHR = 1.39, P = 0.02) were also associated with the risk of cancer after adjustment of covariables.CONCLUSIONS:Hyperglycaemia in patients with diabetes, hyperinsulinemia, and progression to diabetes in people with IGT is significantly associated with the long-term increased risk of cancer occurrence.
British journal of cancer 2022
AIM:To investigate the relationship between circulating growth differentiation factor (GDF-15) levels and the risk of cardiovascular disease and cancer in people with diabetes.METHODS:Totally, 510 participants with type 2 diabetes were enrolled from the long-term follow-up of the Da Qing Impaired Glucose Tolerance (IGT) and Diabetes Study (2006-2009). Plasma GDF-15 levels were assessed. Outcomes of cardiovascular events, cancer, and related death were followed up until 2016.RESULTS:Over a 7.5-year follow-up period, 143 (28.0%) of the participants died, and 155 and 56 experienced cardiovascular events and cancer respectively. Multivariable Cox analysis showed that higher circulating GDF-15 levels were significantly associated with the increased risk of cardiovascular and cancer death. The HRs after adjustment of traditional confounders were 1.90 (95%CI 1.31-2.74) and 2.50 (95%CI 1.34-4.67) respectively for an increase in one unit of loge transformed GDF-15 (pg/ml). The cause-specific hazard model analysis further confirmed the results after adjusting the same confounders. In addition, the higher GDF-15 levels were also significantly associated with the increased risk of cardiovascular events (HR=1.35, 95%CI: 1.04-1.76) and cancer (HR=1.62, 95%CI 1.06-2.47).CONCLUSIONS:Elevated circulating levels of GDF-15 predicted a significant increase in the dual risk of cancer and cardiovascular diseases in Chinese people with type 2 diabetes. Thus, it may be a potential predictor of these outcomes in people with diabetes.
Diabetes & metabolism 2022
AIM:This study aimed to assess whether a higher insulin response increased the long-term risk of mortality in a non-diabetic population.METHODS:A total of 446 people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) who participated in the Da Qing Diabetes Study, were stratified into quartiles subgroups according to their baseline insulin area under the curve (AUC) during oral glucose tolerance test, defined as Q1, Q2, Q3 and Q4. The participants were followed from 1986 to 2016 to assess the risk of death in association with the magnitude of post-load insulin response.RESULTS:Over 30 years, the rates of all cause death were 9.94, 14.81, 15.02, and 17.58 per 1000 person-years across the four groups respectively. The rate for cardiovascular disease (CVD) death was 5.14, 6.50, 6.80 and 10.47 per 1000 person-years. Compared with Q1, the risk of all-cause death was significantly higher in participants in Q4 (HR = 2.14, 95% CI 1.34-3.42), Q3 (HR = 1.94, 95% CI 1.20-3.14), and Q2 group (HR = 1.70, 95% CI 1.06-2.74). In the Fine-Gray model with non-CVD death as competing risk, the increased insulin AUC were also significantly associated with the CVD death (Q4 vs Q1, HR = 2.04, 95% CI 1.10-3.79). In the fractional polynomial regression analysis, a nonlinear association between insulin AUC and all-cause and CVD death was demonstrated. In addition, insulin AUC was associated with a progressively higher risk of all-cause death and CVD death (fractional power 3, P < 0.001).CONCLUSION:A higher post-load insulin response was significantly associated with a long-term increased risk of all-cause and CVD deaths in the Chinese non-diabetic population. It suggests that people featured by this phenotype is a potential important target for further intervention.
Diabetology & metabolic syndrome 2022
BACKGROUND:To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.METHODS:This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.RESULTS:Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).CONCLUSIONS:In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.
Journal of diabetes research 2021
OBJECTIVE:To investigate if insulin resistance per se or the accompanying hyperinsulinemia induced hypertension and its underlying mechanisms.METHODS:Sprague-Dawley rats were randomized into normal diet-fed group (ND group) and high-fat diet-fed group (HFD group). Then, the HFD group was further randomly divided into the control group (HFD_C group), the PIO group (treated with pioglitazone), the STZ_DM group (to induce diabetes with streptozotocin) and the DM+Ins group (streptozotocin injection followed by insulin treatment). Insulin sensitivity, plasma insulin, endothelin-1, norepinephrine, aldosterone, angiotensinⅡ and 24-h urinary sodium excretion (USE) levels of the groups were measured and analyzed. A multiple stepwise regression analysis method was applied to exam our hypothesis.RESULTS:Compared to HFD_C group, the groups with lower plasma insulin, the PIO group and STZ_DM group, showed higher USE and lower blood pressure. The groups with higher plasma insulin (but same level of insulin resistance), the HFD_C group and DM+Ins group, showed lower USE and higher blood pressure. The 24-h urinary sodium excretion was the most important contributor to the significant changes of blood pressure with an R2 of 25.2% in this animal experiment.CONCLUSIONS:It is the compensatory hyperinsulinemia rather than insulin resistance per se that causes blood pressure elevation. The urinary sodium excretion is the key mediator among the multiple mechanisms. Therapies targeting hyperinsulinemia and restricting salt intake may favor a better control of hypertension associated with insulin resistance.
Clinical and experimental hypertension (New York, N.Y. : 1993) 2020
BACKGROUND:Hypertension is more prevalent in subjects with impaired glucose tolerance (IGT), but whether higher blood pressure per se or the mild hyperglycemia in combination with the hypertension enhanced the risk of cardiovascular disease (CVD) remains unclear.METHODS:Five hundred and sixty-eight participants with IGT in the original Daqing diabetes prevention study, 297 with hypertension (HBP) and 271 without hypertension (NBP), were enrolled in 1986 and the intervention phase lasted for 6 years. In 2009, they were followed up to assess the outcomes of cardiovascular events (including stroke and myocardial infarction) and incidence of diabetes.RESULTS:Over 23 years, the incidence of diabetes was 93.9/1000 person-years in HBP and 72.2/1000 person-years in the NBP group, with an age- and sex-adjusted hazard ratio of 1.26 (95% confidence interval [CI], 1.04-1.54, P = 0.02). The yearly incidence of CVD events was 27.7/1000 person-years and 16.6/1000 person-years, indicating a 35% higher risk in HBP than in the NBP group (95% CI, 1.01-1.81; P = 0.04). Cox proportional hazard analysis showed that a 10-mm Hg increase of the baseline systolic blood pressure was associated with 9% increased risk of the development of diabetes (P = 0.02), together with a 7% higher risk of the CVD events (P = 0.02).CONCLUSIONS:Hypertension predicted diabetes and enhances long-term risk of CVD events in patients with IGT. An individualized strategy that targets hypertension as well as hyperglycemia is needed for diabetes and its cardiovascular complications.
Journal of diabetes 2019
BACKGROUND:Limited information is available on the long-term risk of cardiovascular disease (CVD) associated with hypertriglyceridaemia (HTG) in the Chinese population. We estimated this risk over a 23-year period in participants recruited from among those included in the Da Qing Diabetes Study.METHODS:A total of 833 Chinese adults including 379 with normal glucose levels and 454 with hyperglycaemia were identified by their oral glucose tolerance in 1986 in Da Qing, China. CVD outcomes were monitored until 2009. Thirty-four percent (280/833) of the participants had HTG, which was defined as a fasting plasma triglyceride (TG) level ≥ 1.7 mmol/L, at the baseline time point.RESULTS:Over the 23-yearfollow-up period, 149 subjects in the HTG group and 190 subjects in the non-HTG group (NTG group) experienced their first CVD event, including fatal or nonfatal myocardial infarction (MI) and stroke. The age and sex-adjusted annual incidence of the first CVD event per 1000 person-years was 30.23 for the HTG group vs 18.68 for the NTG group. The corresponding rates for MI and stroke were 7.71 vs 3.89 and 19.55 vs 13.98, respectively. After adjusting for confounders, the HTG group had a 28% higher risk of the first CVD event than the NTG group. This association was significant among only the subjects with a serum cholesterol level > 5.7 mmol/L and those with diabetes or impaired glucose tolerance (IGT).CONCLUSION:HGT predicted a substantially higher subsequent long-term risk of the first CVD event in Chinese adults, especially in those with hypercholesterolaemia and hyperglycaemia.
Diabetes/metabolism research and reviews 2019
BACKGROUND AND AIM:We sought to determine the effect of regression to normal glucose tolerance (NGT) or progression to diabetes in early years of impaired glucose tolerance (IGT) on subsequent risk of stroke.METHODS:In 1986, 576 adults aged 25 years and older with impaired glucose tolerance in Da Qing, China, were randomly assigned by clinic to control, diet, exercise, or diet plus exercise intervention groups for a six-year period. Subsequently participants received medical care in their local clinics. We tracked participants for additional 17 years to ascertain stroke events and other outcomes.RESULTS:At the end of 6-year intervention trial follow-up, 272 (50.2%) had progressed to diabetes, 169 (31.2%) regressed to normal glucose tolerance, and 101 (18.6%) remained impaired glucose tolerance. During the subsequent 17-year follow-up, 173 (31.9%) developed a stroke, 26.7% of normal glucose tolerances, 30.7% of impaired glucose tolerances, and 36.1% of those with diabetes. After controlling for age, sex, baseline blood pressure, smoking, total cholesterol, previous cardiovascular disease and intervention group, those who developed diabetes in the first six years had a higher incidence of stroke than those who reverted to normal glucose tolerance (HR = 1.49, 95% CI 1.01-2.19, p = 0.04), whereas for those who remained impaired glucose tolerance compared to those who regressed to normal glucose tolerance the HR was 1.25 (95% CI 0.80-1.93; p = 0.30). A 1-mmol/L increase in both fasting and 2-h post-load plasma glucose from entry to end of the six-year trial was significantly associated with a higher risk of development of stroke in the subsequent 17 years, respectively (HR = 1.07, 95% CI 1.03-1.11, p < 0.0001 for fasting glucose, HR = 1.05, 95% CI 1.02-1.09, p = 0.007 for 2-h post-load plasma glucose).CONCLUSIONS:Among Chinese adults with impaired glucose tolerance, early progression to diabetes predicted a higher risk of stroke, compared those who regressed to normal glucose tolerance.
International journal of stroke : official journal of the International Stroke Society 2018
AIM/HYPOTHESIS:The objective of this study was to assess how long-term exposure to high glucose affects the α cell function and whether the increased glucagon secretion is mediated via insulin resistance.MATERIALS AND METHODS:We established a β cell-depleted rat model to obtain pure primary α cells. Furthermore, isolated rat islets and TC1-6 cells (a clonal α cell line) were exposed to high glucose (25 or 30 mmol/L) and low glucose (5.5 mmol/L) for up to 5 days to evaluate the influence of chronic glucose toxicity on glucagon secretion and glucagon gene expression. Moreover, we added insulin and/or Wortmannin to examine if the inhibitory effect of insulin on glucagon secretion was impaired by high glucose via the phosphatidylinositol 3 kinase/PKB protein kinase B pathway.RESULTS:Both glucagon secretion and glucagon gene expression were increased in response to 5 days exposure to high glucose. While a moderate insulin concentration slightly inhibits glucagon secretion from rat islets and α TC1-6 cells at high glucose, a pronounced increase in glucagon secretion was observed at low glucose. We found that the insulin-mediated activity of the phosphatidylinositol 3 kinase/PKB protein kinase B pathway in the α cell was markedly impaired by chronic exposure to high glucose.CONCLUSION:The hypersecretion of glucagon induced by glucotoxicity may be secondary to insulin resistance of the α cell induced by impaired activity of the insulin signaling pathway.
Endocrine research 2012
