Cardiometabolic risk profile of participants with prediabetes diagnosed by HbA1c criteria in an urban Hong Kong Chinese population over 40 years of age.

AIMS: To investigate the usefulness of the additional measurement of HbA1c , compared with performing only the oral glucose tolerance test (OGTT), in identifying participants at increased cardiometabolic risk, in an urban Chinese population. METHODS: All participants from the fourth visit of the population-based Hong Kong Cardiovascular Risk Factors Prevalence Study, without known diabetes, were included. All had their glycaemic status assessed by OGTT and HbA1c , according to American Diabetic Association 2010 criteria. RESULTS: Based on OGTT criteria alone, 3.5% of the study cohort (N = 1300) had diabetes and 19.2% had prediabetes. Based on HbA1c criteria only, 6.2% had diabetes and 61.2% had prediabetes. The measurement of HbA1c , in addition to the OGTT, increased the proportion of participants with diabetes to 7.8% and with prediabetes to 65.3%. Subjects with prediabetes having raised HbA1c but normal glycaemia (N = 600) had waist circumference, systolic blood pressure, fasting glucose, insulin resistance index (HOMA-IR), Gutt Index and Framingham 10-year cardiovascular risk scores intermediate between those with both normal HbA1c and glycaemia (N = 350), and those with impaired fasting glucose and/or impaired glucose tolerance (N = 249; all P < 0.01). CONCLUSION: The measurement of HbA1c in our population, in addition to the OGTT, results in the detection of a large number of participants with prediabetes having raised HbA1c but normal glycaemia who have a cardiometabolic risk profile intermediate between impaired fasting glucose and/or impaired glucose tolerance and normal participants, and would benefit from early lifestyle intervention.

C-reactive protein as a predictor of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) cohort.

Inflammation contributes to the development of hypertension. Whether C-reactive protein (CRP) has a causal role in hypertension remains unknown. We studied the relationship between circulating CRP levels and hypertension. The role of single-nucleotide polymorphisms (SNPs) in the CRP gene as determinants of its plasma levels and the propensity to develop hypertension was investigated. Plasma CRP and genotypes of nine SNPs were determined in 1925 unrelated subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000-2004. Among 1378 subjects normotensive in CRISPS-2, 1115 subjects had been followed up in CRISPS-3 after a median interval of 5.3 years, 236 of whom had developed hypertension. Plasma CRP was independently associated with the development of hypertension in CRISPS-3 (odds ratio per quartile=1.26, P=0.010). Six SNPs were associated with plasma CRP (all P<0.001). However, none of the SNPs was significantly associated with blood pressure, prevalent or incident hypertension, or change in blood pressure. In conclusion, plasma CRP predicts the development of hypertension. Genetic variants in the CRP gene are significantly associated with plasma CRP but not with hypertension. The future risk of hypertension is therefore more related to plasma CRP than SNPs in the CRP gene in this population.

Evaluation of the combined use of adiponectin and C-reactive protein levels as biomarkers for predicting the deterioration in glycaemia after a median of 5.4 years.

AIMS/HYPOTHESIS: Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years. METHODS: In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not. RESULTS: Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status. CONCLUSIONS/INTERPRETATION: Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT.

Serum adipocyte fatty acid-binding protein associated with ischemic stroke and early death.

OBJECTIVE: Adipocyte fatty acid-binding protein (A-FABP) is an adipokine shown to have adverse metabolic and proinflammatory effects, and contributes to atherosclerosis in mice. However, its role in cardiovascular diseases in humans remains to be established. In this case-control study, we investigated the association of serum A-FABP with ischemic stroke, and examined its association with early mortality. METHODS: Serum A-FABP was measured, using ELISA, in 306 subjects with acute ischemic stroke and 306 age-, sex-, and body mass index-matched controls. All controls were free of cardiovascular diseases. Serum A-FABP was also measured in another 60 ischemic stroke subjects who died within 3 months of acute stroke. RESULTS: Serum A-FABP was higher in subjects with ischemic stroke as compared to controls (19.6 ng/mL [14.3-28.4 ng/mL] vs 15.2 ng/mL [10.6-23.6 ng/mL] in men and 32.4 ng/mL [24.5-45.7 ng/mL] vs 22.0 ng/mL [14.3-34.0 ng/mL] in women, stroke vs control, p<0.001). On logistic regression analyses with the model including hypertension, diabetes, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, lipid-lowering treatment, smoking, and A-FABP, serum A-FABP was independently associated with stroke (odds ratio 2.10, 95% confidence interval 1.50-2.94, p<0.001), and the associations of A-FABP with ischemic stroke were additive to conventional risk factors, as demonstrated on likelihood ratio tests (p<0.001). Furthermore, high serum A-FABP was associated with increased 3-month mortality in ischemic stroke subjects (odds ratio 2.65, 95% confidence interval 1.18-5.96, p=0.018), independent of age and NIH Stroke Scale score. CONCLUSIONS: Serum A-FABP was significantly associated with ischemic stroke in our case-control study, and may serve as a useful prognostic indicator for early mortality.

Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes.

AIMS/HYPOTHESIS: Interfering with the activation of receptor for AGE (RAGE) by using a soluble form of the AGE receptor (sRAGE) prevents or ameliorates the vascular complications of diabetes in experimental studies. Relatively little is known about factors that influence endogenous circulating sRAGE in humans. We investigated the impact of improving glycaemic control on serum total sRAGE and endogenous secretory RAGE (esRAGE), a splice variant of sRAGE, and compared the effect of rosiglitazone with that of sulfonylurea. METHODS: A randomised, open-label, parallel group study was performed with 64 participants randomised to receive add-on therapy with either rosiglitazone or sulfonylurea. Serum total sRAGE and esRAGE and metabolic parameters were measured before and after 6 months of treatment. RESULTS: At 6 months, both rosiglitazone and sulfonylurea resulted in a significant reduction in HbA(1c), fasting glucose and AGE. However, significant increases in total sRAGE and esRAGE were only seen in the rosiglitazone group. As a result, serum esRAGE was higher in the rosiglitazone group than in the sulfonylurea group at 6 months (p < 0.01), whereas the differences in sRAGE between the two groups did not reach statistical significance. Stepwise linear regression analysis showed that treatment modality made a greater contribution than the changes in HbA(1c) to the subsequent changes in esRAGE levels at 6 months. CONCLUSIONS/INTERPRETATION: Treating type 2 diabetic patients with thiazolidinedione can increase circulating levels of esRAGE and sRAGE. Whether modulation of circulating sRAGE has a beneficial effect on diabetic complications will have to be evaluated in long-term prospective studies.

Polymorphisms of the gene encoding adiponectin and glycaemic outcome of Chinese subjects with impaired glucose tolerance: a 5-year follow-up study.

AIMS/HYPOTHESIS: Polymorphisms of the gene encoding adiponectin (ADIPOQ) have previously been associated with type 2 diabetes in Europid and Japanese subjects, but not in Pima Indians. The aim of this study was to determine the contribution made by ADIPOQ gene variants to glycaemic status in southern Chinese individuals. SUBJECTS AND METHODS: Sixty unrelated subjects were screened for single-nucleotide polymorphisms (SNPs) in the ADIPOQ gene by direct sequencing. The association of tagging SNPs with the outcome of glycaemic status in 262 subjects with impaired glucose tolerance (IGT) was examined in a 5-year prospective study. RESULTS: We identified 15 polymorphisms in the ADIPOQ gene, ten of them constituting the tagging SNPs. At 5 years, 39.7% of the subjects with IGT had regressed to NGT, 41.2% had persistent IGT or impaired fasting glucose and 19.1% had developed diabetes. Only the T45G polymorphism was associated with persistent hyperglycaemia at 5 years (p=0.001). Haplotypes formed by the addition of other SNPs, as haplotype blocks or pairs, did not confer greater association than T45G alone. On logistic regression analysis, T45G independently predicted persistent hyperglycaemia at 5 years (OR=2.25, 95% CI 1.29-3.95, G carriers vs TT; p=0.005). It also predicted persistent hyperglycaemia in a nested case-control study involving 158 sex- and age-matched controls with persistent NGT (p=0.012, adjusted for BMI), and that of diabetes or glycaemia progression (p<0.05) in a meta-analysis that also included two published studies in Europid subjects. CONCLUSIONS/INTERPRETATION: Our findings support a significant role of this common ADIPOQ gene polymorphism in predicting glycaemic status in southern Chinese people.

Determinants of postprandial triglyceride and remnant-like lipoproteins in type 2 diabetes.

BACKGROUND: Postprandial changes in remnant-like lipoprotein particles (RLP) contribute to the severity of coronary heart disease in type 2 diabetes. Since the determinants of postprandial response in RLP are not well understood, this study investigated the roles of fasting triglyceride, apolipoprotein (apo) E polymorphism and insulin resistance in a group of overweight/obese Chinese type 2 diabetic subjects. METHODS: Postprandial triglyceride (TG) and RLP-cholesterol (RLP-C) were determined after a mixed meal containing 70-g fat at 2-h intervals for 8 h in 32 normotriglyceridemic (NTG) and 31 hypertriglyceridemic (HTG) subjects. RLP-C was measured using an immunoseparation assay and apo E genotypes using polymerase chain reaction and restriction mapping. Insulin resistance was defined as homeostasis model assessment index (HOMA-IR). RESULTS: The HTG subjects had greater postprandial increase in TG and RLP-C than NTG (p < 0.001), but there were no significant differences in HOMA-IR and apo E allele frequencies. Subjects who were non-E3-carriers had the largest postprandial increment in TG and RLP-C. On stepwise linear regression analysis, log(HOMA-IR) was only an independent determinant of fasting TG but not postprandial TG or RLP-C. The major determinants of fasting and postprandial RLP-C were fasting TG and apo E genotype, accounting for 53 and 6% of the variance of fasting RLP-C (p < 0.01) and 31 and 13% of the variance of postprandial RLP-C respectively (p < 0.01). CONCLUSIONS: Insulin resistance is mainly a determinant of fasting triglyceride in Chinese type 2 diabetic subjects, whereas apo E genotype is a better predictor of both fasting and postprandial concentrations of RLP.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland. DESIGN: In order to define the prevalence of MEN1 germ-line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first-degree relatives. RESULTS: Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ-line mutations at the MEN1 gene were identified, including three novel mutations [248-249delTT in exon 2, K559X(AAG --> TAG) in exon 10 and IVS 2nt + 2(G --> T) in intron 2]. All patients with familial MEN1 syndrome were heterozygous carriers of a germ-line mutation and MEN1-related disorders were only evident in their first-degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy. CONCLUSIONS: The finding of MEN1 germ-line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1-related tumours.

Acute effect of orlistat on post-prandial lipaemia and free fatty acids in overweight patients with Type 2 diabetes mellitus.

AIMS: Post-prandial lipaemia is prolonged and exaggerated in patients with Type 2 diabetes mellitus, with an accumulation of atherogenic triglyceride-rich lipoprotein remnants. We postulate that orlistat, a gastrointestinal lipase inhibitor, may cause changes in post-prandial lipoprotein metabolism by reducing dietary triglyceride absorption. METHODS: The acute effect of a single dose of 120 mg orlistat on post-prandial glucose, lipids, remnant lipoproteins and free fatty acids (FFA) was evaluated in a randomized, double-blind, placebo-controlled cross-over study of 63 overweight patients with Type 2 diabetes mellitus (body mass index 30.4 +/- 3.8 kg/m2). Either a single dose of orlistat or placebo was given before a standard mixed meal containing 70 g of fat and plasma triglyceride (TG), remnant-like particles cholesterol (RLP-C) and FFA were sampled at 2-h intervals for 8 h. RLP-C was measured by an immunoseparation assay and FFA by an enzymatic colorimetric method. RESULTS: The concentrations of plasma TG (P < 0.0001), RLP-C (P = 0.003), and FFA (P < 0.0001) were significantly lower at 2 h after orlistat compared with placebo. Both plasma RLP-C (P = 0.04) and FFA (P < 0.0001) remained lower after orlistat than placebo at 4 h. The incremental area under the curve (iAUC) above baseline fasting level for both TG and RLP-C was significantly more reduced after orlistat than placebo (iAUC-TG 5.8 (3.7-8.2) mmol/l x h-1 vs. 5.7 (4.1-10.9), respectively, P = 0.04; iAUC-RLP-C: 0.53 (0.23-1.04) mmol/l x h-1 vs. 0.56 (0.35-1.40), respectively, P = 0.02). The test meal was well tolerated by all subjects, with only three subjects reporting faecal urgency after orlistat. CONCLUSIONS: Orlistat has a beneficial effect on post-prandial lipaemia in overweight Type 2 diabetic patients and lowers plasma TG, RLP-C and FFA in the early post-prandial period.

Effect of Sandostatin LAR on serum leptin levels in patients with acromegaly.

Serum leptin levels are decreased in patients with acromegaly and rise after GH is normalized by surgical treatment. We have evaluated the effect of Sandostatin LAR on leptin levels in acromegalic patients since there are recent data to suggest that somatostatin, in addition to its GH lowering effect, also reduces serum leptin levels in humans. Nineteen patients with active acromegaly were studied. Eleven patients received monthly injection of Sandostatin LAR and eight patients underwent transsphenoidal surgery. Serum concentrations of leptin, GH, IGF-1 and insulin were measured before and after treatment. Serum leptin concentrations were lower in patients with active acromegaly than controls matched for age, sex and body mass index (BMI) [2.79 microg/l (2.60) vs. 4.41 microg/l (5.07); median (inter-quartile range); P < 0.01]. A positive correlation between serum leptin concentrations and BMI was observed in the controls (r = 0.46, P < 0.05) but not in the acromegalic patients before treatment (r = 0.32, ns). In the group of patients treated with Sandostatin LAR, a marked reduction in GH and IGF-1 was achieved by week 8 and GH and IGF-1 remained suppressed throughout the 6 months of treatment. There was no change in BMI. A significant increase in leptin levels only became evident after 6 months of treatment [2.99 microg/l (2.60) vs. 4.21 microg/l (3.84), P < 0.05]. Leptin levels also significantly increased after transsphenoidal surgery [3.05 microg/l (5.73) vs. 5.19 microg/l (4.93), P < 0.05]. The positive correlation between serum leptin concentrations and BMI was restored in acromegalic patients both after treatment with Sandostatin LAR (r = 0.62, P < 0.05) and after surgery (r = 0.81, P < 0.05). Leptin concentrations were decreased in patients with active acromegaly and lowering GH by either Sandostatin LAR or transsphenoidal surgery led to an increase in leptin concentrations.