Guang Ning

Prevalence and Control of Diabetes in Chinese Adults

IMPORTANCE Noncommunicable chronic diseases have become the leading causes of mortality and disease burden worldwide. OBJECTIVE To investigate the prevalence of diabetes and glycemic control in the Chinese adult population. DESIGN, SETTING, AND PARTICIPANTS Using a complex, multistage, probability sampling design, we conducted a cross-sectional survey in a nationally representative sample of 98,658 Chinese adults in 2010. MAIN OUTCOMES AND MEASURES Plasma glucose and hemoglobin A1c levels were measured after at least a 10-hour overnight fast among all study participants, and a 2-hour oral glucose tolerance test was conducted among participants without a self-reported history of diagnosed diabetes. Diabetes and prediabetes were defined according to the 2010 American Diabetes Association criteria; whereas, a hemoglobin A1c level of <7.0% was considered adequate glycemic control. RESULTS The overall prevalence of diabetes was estimated to be 11.6% (95% CI, 11.3%-11.8%) in the Chinese adult population. The prevalence among men was 12.1% (95% CI, 11.7%-12.5%) and among women was 11.0% (95% CI, 10.7%-11.4%). The prevalence of previously diagnosed diabetes was estimated to be 3.5% (95% CI, 3.4%-3.6%) in the Chinese population: 3.6% (95% CI, 3.4%-3.8%) in men and 3.4% (95% CI, 3.2%-3.5%) in women. The prevalence of undiagnosed diabetes was 8.1% (95% CI, 7.9%-8.3%) in the Chinese population: 8.5% (95% CI, 8.2%-8.8%) in men and 7.7% (95% CI, 7.4%-8.0%) in women. In addition, the prevalence of prediabetes was estimated to be 50.1% (95% CI, 49.7%-50.6%) in Chinese adults: 52.1% (95% CI, 51.5%-52.7%) in men and 48.1% (95% CI, 47.6%-48.7%) in women. The prevalence of diabetes was higher in older age groups, in urban residents, and in persons living in economically developed regions. Among patients with diabetes, only 25.8% (95% CI, 24.9%-26.8%) received treatment for diabetes, and only 39.7% (95% CI, 37.6%-41.8%) of those treated had adequate glycemic control. CONCLUSIONS AND RELEVANCE The estimated prevalence of diabetes among a representative sample of Chinese adults was 11.6% and the prevalence of prediabetes was 50.1%. Projections based on sample weighting suggest this may represent up to 113.9 million Chinese adults with diabetes and 493.4 million with prediabetes. These findings indicate the importance of diabetes as a public health problem in China.

Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine.

CONTEXT Berberine, a natural plant alkaloid, is usually used as an antibiotic drug. The potential glucose-lowering effect of berberine was noted when it was used for diarrhea in diabetic patients. In vitro and in vivo studies have then showed its effects on hyperglycemia and dyslipidemia. OBJECTIVE The objective of the study was to evaluate the efficacy and safety of berberine in the treatment of type 2 diabetic patients with dyslipidemia. DESIGN One hundred sixteen patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1.0 g daily) and the placebo for 3 months. The primary outcomes were changes in plasma glucose and serum lipid concentrations. Glucose disposal rate (GDR) was measured using a hyperinsulinemic euglycemic clamp to assess insulin sensitivity. RESULTS In the berberine group, fasting and postload plasma glucose decreased from 7.0 +/- 0.8 to 5.6 +/- 0.9 and from 12.0 +/- 2.7 to 8.9 +/- 2.8 mm/liter, HbA1c from 7.5 +/- 1.0% to 6.6 +/- 0.7%, triglyceride from 2.51 +/- 2.04 to 1.61 +/- 1.10 mm/liter, total cholesterol from 5.31 +/- 0.98 to 4.35 +/- 0.96 mm/liter, and low-density lipoprotein-cholesterol from 3.23 +/- 0.81 to 2.55 +/- 0.77 mm/liter, with all parameters differing from placebo significantly (P < 0.0001, P < 0.0001, P < 0.0001, P = 0.001, P < 0.0001, and P <0.0001, respectively). The glucose disposal rate was increased after berberine treatment (P = 0.037), although no significant change was found between berberine and placebo groups (P = 0.063). Mild to moderate constipation was observed in five participants in the berberine group. CONCLUSIONS Berberine is effective and safe in the treatment of type 2 diabetes and dyslipidemia.

Structural Changes of Gut Microbiota during Berberine-Mediated Prevention of Obesity and Insulin Resistance in High-Fat Diet-Fed Rats

Berberine, a major pharmacological component of the Chinese herb Coptis chinensis, which was originally used to treat bacterial diarrhea, has recently been demonstrated to be clinically effective in alleviating type 2 diabetes. In this study, we revealed that berberine effectively prevented the development of obesity and insulin resistance in high-fat diet (HFD)-fed rats, which showed decreased food intake. Increases in the levels of serum lipopolysaccharide-binding protein, monocyte chemoattractant protein-1, and leptin and decrease in the serum level of adiponectin corrected for body fat in HFD-fed rats were also significantly retarded by the co-administration of berberine at 100 mg/kg body weight. Bar-coded pyrosequencing of the V3 region of 16S rRNA genes revealed a significant reduction in the gut microbiota diversity of berberine-treated rats. UniFrac principal coordinates analysis revealed a marked shift of the gut microbiota structure in berberine-treated rats away from that of the controls. Redundancy analysis identified 268 berberine-responding operational taxonomic units (OTUs), most of which were essentially eliminated, whereas a few putative short-chain fatty acid (SCFA)-producing bacteria, including Blautia and Allobaculum, were selectively enriched, along with elevations of fecal SCFA concentrations. Partial least square regression models based on these 268 OTUs were established (Q2>0.6) for predicting the adiposity index, body weight, leptin and adiponectin corrected for body fat, indicating that these discrete phylotypes might have a close association with the host metabolic phenotypes. Taken together, our findings suggest that the prevention of obesity and insulin resistance by berberine in HFD-fed rats is at least partially mediated by structural modulation of the gut microbiota, which may help to alleviate inflammation by reducing the exogenous antigen load in the host and elevating SCFA levels in the intestine.

Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance.

CONTEXT Bisphenol A (BPA) is one of the worlds highest-volume chemicals in use today. Previous studies have suggested BPA disturbs body weight regulation and promotes obesity and insulin resistance. But epidemiological data in humans were limited. OBJECTIVE Our objective was to determine whether BPA associates with obesity and insulin resistance. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 3390 adults aged 40 yr or older, in Songnan Community, Baoshan District, Shanghai, China. MAIN OUTCOME MEASURES Questionnaire, clinical and biochemical measurements, and urinary BPA concentration were determined. Generalized overweight was defined as body mass index (BMI) of 24 to less than 28 kg/m(2) and obesity was defined as BMI of 28 kg/m(2) or higher. Abdominal obesity was defined as waist circumference at least 90 cm for men and at least 85 cm for women. Insulin resistance was defined as the index of homeostasis model assessment of insulin resistance higher than 2.50. RESULTS The participants in the highest quartile of BPA had the highest prevalence of generalized obesity [odds ratio (OR) = 1.50; 95% confidence interval (CI) = 1.15-1.97], abdominal obesity (OR = 1.28; 95% CI = 1.03-1.60), and insulin resistance (OR = 1.37; 95% CI = 1.06-1.77). In participants with BMI under 24 kg/m(2), compared with the lowest quartile, the highest quartile of BPA increased the prevalence of insulin resistance by 94% (OR = 1.94; 95% CI = 1.20-3.14), but this association was not observed in those with BMI of 24 kg/m(2) or higher. CONCLUSIONS BPA was positively associated with generalized obesity, abdominal obesity, and insulin resistance in middle-aged and elderly Chinese adults.

Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

OBJECTIVE The two major classes of antidiabetic drugs, sulfonylureas and metformin, may differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type 2 diabetic patients who had a history of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = 63.3 years (range, 36–80 years), were enrolled. Participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. RESULTS At the end of study drug administration, both groups achieved a significant decrease in the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30–0.90; P = 0.026) for the composites of cardiovascular events among the patients that received metformin, compared with glipizide. The secondary end points and adverse events were not significantly different between the two groups. CONCLUSIONS Treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients.

Activating Hotspot L205R Mutation in PRKACA and Adrenal Cushing's Syndrome

Adrenal Cushing’s syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), adrenocorticotropic hormone–independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing’s syndrome. Adrenal Cushing’s syndrome involves recurrent mutations in a key signal transduction pathway [Also see Perspective by Kirschner] Candidate Cushings culprit identified Cushings syndrome is a rare condition resulting from the excess production of cortisol. About 15% of Cushings syndrome cases are associated with an adrenocortical tumor. However, the genetic etiology of these adrenocortical tumors is ill defined (see the Perspective by Kirschner). Cao et al. and Sato et al. both performed whole-exome sequencing of tumors from individuals with adrenal Cushings syndrome and compared it with the patients own matched non-tumor DNA and identified recurrent mutations in the protein kinase A catalytic subunit alpha (PRKACA) gene, as well as less frequent mutations in other putative pathological genes. The most common recurrent mutation activated the kinase, which may suggest a potential therapeutic target. Science, this issue p. 913, p. 917; see also p. 804

Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics

A comprehensive metabonomic method, in combination with fingerprint analysis and target analysis, was performed to reveal potential mechanisms of berberine action in the treatment of patients with type 2 diabetes and dyslipidemia. Serum samples of 60 patients before and after treatment with either berberine or placebo were collected. Ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS) coupled with pattern recognition analysis were used to identify changes in global serum metabolites. Compared with placebo, patients before and after berberine treatment could be separated into distinct clusters as displayed by the orthogonal signal correction filtered partial least-squares discriminant analysis (OSC-PLS-DA) score plot, which indicated changes in circulating metabolites after berberine treatment. Among them, free fatty acids changed markedly. These were further quantified by UPLC combined with single quadrupole mass spectrometry (UPLC SQ MS). There was a highly significant decrease in the concentrations of 13 fatty acids following berberine administration. 10 fatty acids also differed statistically from placebo. These results suggest that berberine might play a pivotal role in the treatment of type 2 diabetes through down-regulating the high level of free fatty acids and that comprehensive metabonomic measurements are potentially very useful for studying the mechanisms of action of traditional Chinese medicines.

Berberine activates thermogenesis in white and brown adipose tissue.

Obesity develops when energy intake exceeds energy expenditure. Promoting brown adipose tissue formation and function increases energy expenditure and hence may counteract obesity. Berberine (BBR) is a compound derived from the Chinese medicinal plant Coptis chinensis. Here we show that BBR increases energy expenditure, limits weight gain, improves cold tolerance and enhances brown adipose tissue (BAT) activity in obese db/db mice. BBR markedly induces the development of brown-like adipocytes in inguinal, but not epididymal adipose depots. BBR also increases expression of UCP1 and other thermogenic genes in white and BAT and primary adipocytes via a mechanism involving AMPK and PGC-1α. BBR treatment also inhibits AMPK activity in the hypothalamus, but genetic activation of AMPK in the ventromedial nucleus of the hypothalamus does not prevent BBR-induced weight loss and activation of the thermogenic programme. Our findings establish a role for BBR in regulating organismal energy balance, which may have potential therapeutic implications for the treatment of obesity.

Frequency, Immunogenetics, and Clinical Characteristics of Latent Autoimmune Diabetes in China (LADA China Study): A Nationwide, Multicenter, Clinic-Based Cross-Sectional Study

Adult non–insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes–susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.

Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study.

The association between diabetes and cancer has been realized as a very important issue in the field of diabetes and diabetes care. Epidemiological evidence suggests a link between diabetes and an increased risk of many forms of cancer. However, how diabetes is linked with cancer and whether the duration of diabetes, the type, dose and duration of antidiabetic therapy, and the degree of glycemic control modify the risk of cancer are not well defined. Better characterization of aspects of diabetes (such as the age at onset, diabetes duration, therapy, and degree of glycemic control), in relation to the risk of cancer is especially needed in the Chinese population, and these issues can be better addressed in well-conducted and appropriately-designed prospective observational studies. ‘‘Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study’’ is an effort to evaluate thoroughly the risk of site-specific cancers in Chinese diabetic individuals. The primary aim of REACTION is to demonstrate the association of type 2 diabetes and pre-diabetes with the risk of cancer in the Chinese population and to identify factors that modify the risk of cancer among individuals with diabetes and pre-diabetes. REACTION is sponsored by the Chinese Society of Endocrinology and led by Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Using a community-based approach, REACTION is a multicenter prospective observational study investigating the association between diabetes and the risk of cancer among individuals with or without type 2 diabetes. Several experts from the USA, including Dr. Zachary T. Bloomgarden, an endocrinologist from Mount Sinai Medical Center, Dr. Donghui Li, a cancer epidemiologist from MD Anderson Cancer center, and Dr. Shenghan Lai, a statistician from Johns Hopkins University School of Medicine serve on the scientific advisory board. The study has been approved by the ethics committee of Shanghai Jiao Tong University. The overall design of REACTION includes two phases: the baseline investigation and cohort followup. In phase I, a study population of more than 200 000 people will be identified from 20 to 25 communities across China. These communities were selected from both rural and urban areas of different geographic regions, with different degrees of urbanization and economic development status. These communities have different cancer incidences and represent the general population of China. Two or three hospitals or local health clinics in each community have been identified as the recruitment and follow-up sites. Individuals aged 40 years and older will participate in this survey, with a required response rate of over 85%. A personal interview will be conducted to collect information on known risk factors for type 2 diabetes and cancer, such as cigarette smoking, alcohol consumption, physical activity, body mass index, and any family history of cancer. Each study participant without a history of diabetes will be screened for diabetes and pre-diabetes using the oral glucose tolerance test. In phase II of the study, we will focus on follow-up of the various cohorts: prevalent diabetes, newly diagnosed diabetes, pre-diabetes, and normal glucose regulation. The eligibility criteria for enrollment include: (i) being aged 40–75 years; (ii) having signed an informed consent form; and (iii) having no prior or current history of cancer. There is no restriction on sex or ethnicity. The exclusion criteria include having: (i) a history of cancer; (ii) a history of latent autoimmune diabetes of adults or other autoimmune diseases; Correspondence Guang Ning, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China. Tel: +86-21-64370045 ext. 665340 Fax: +86-21-64373514 Email: gning@sibs.ac.cn *Members of the REACTION Study Group are given in the Appendix. Received 26 December 2011; accepted 29 December 2011. doi: 10.1111/j.1753-0407.2012.00182.x Journal of Diabetes 4 (2012) 172–173