To explore the association of serum retinol-binding protein 4 (RBP4) levels and risk for the development of type 2 diabetes in individuals with prediabetes. RESEARCH DESIGN AND METHODS A population-based prospective study was conducted among 1,011 Chinese participants with prediabetes (average age 55.6 6 7.2 years). Incident type 2 diabetes was diagnosed according to the American Diabetes Association 2010 criteria. Serum RBP4 levels were measured using a commercially available ELISA. We analyzed the association of serum RBP4 levels with the risk of incident type 2 diabetes using the Cox proportional hazards model. RESULTS During a median follow-up period of 3.1 years, 153 participants developed incident type 2 diabetes. A U-shaped association was observed between serum RBP4 levels and the risk of incident type 2 diabetes, with the lowest risk in the RBP4 range of 31-55 mg/mL. Multivariate Cox regression model analysis showed that serum RBP4 levels <31 mg/mL and RBP4 levels >55 mg/mL were associated with an increased risk of incident type 2 diabetes. The adjusted hazard ratios (95% CI) were 2.01 (1.31-3.09) and 1.97 (1.32-2.93), respectively, after adjusting for age, sex, BMI, waist circumference, g-glutamyltransferase, HOMA of insulin resistance index, fasting plasma glucose, 2-h plasma glucose, and glycated hemoglobin (HbA 1c) levels. CONCLUSIONS A U-shaped relationship exists between serum RBP4 levels and the risk of incident type 2 diabetes in subjects with prediabetes. Retinol-binding protein 4 (RBP4) was initially identified as the primary vitamin A transport protein that facilitates the delivery of retinol from liver to peripheral tissues (1). Circulating RBP4 primarily comes from hepatocytes and, to a lesser extent, from adipocytes and other cell types (2). RBP4 has recently been recognized as an adipokine, and multiple epidemiological studies suggested that elevated serum RBP4 levels play a critical role in the development of metabolic diseases, including insulin resistance and type 2 diabetes (3-6). According to the results of animal studies, increasing serum RBP4 concentrations through transgenic overexpression or an injection of the purified recombinant RBP4 protein induces insulin resistance in wildtype mice (7). However, decreasing serum RBP4 levels with a fenretinide treatment or

BackgroundChina has the highest absolute disease burden of diabetes worldwide. For diabetic patients, diabetes-related vascular complications are major causes of morbidity and mortality. The roles of lipoprotein-associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2) as inflammatory markers have been recently evaluated in the pathogenesis of both diabetes and atherosclerosis. We aimed to determine the mechanism through which patients with newly diagnosed type 2 diabetes gain long-term vascular benefit from intensive insulin therapy by evaluating the change in Lp-PLA2 and sPLA2 levels after early intensive insulin treatment and its relevance with insulin resistance and pancreatic β-cell function.MethodsIn total, 90 patients with newly diagnosed type 2 diabetes mellitus were enrolled. All patients received continuous subcutaneous insulin infusion (CSII) for approximately 2 weeks. Intravenous glucose-tolerance test (IVGTT) and oral glucose-tolerance test (OGTT) were performed, and plasma concentrations of Lp-PLA2 and sPLA2 were measured before and after CSII.ResultsLevels of Lp-PLA2 and sPLA2 were significantly higher in diabetic patients with macroangiopathy than in those without (P < 0.05). After CSII, the sPLA2 level decreased significantly in all diabetic patients (P < 0.05), while the Lp-PLA2 level changed only in those with macroangiopathy (P < 0.05). The area under the curve of insulin in IVGTT and OGTT, the acute insulin response (AIR3–5), early phase of insulin secretion (ΔIns30/ΔG30), modified β-cell function index, and homeostatic model assessment for β-cell function (HOMA-β) increased after treatment even when adjusted for the influence of insulin resistance (IR; P < 0.001). The HOMA-IR was lower after treatment, and the three other indicators adopted to estimate insulin sensitivity (ISIced, IAI, and QUICKI) were higher after treatment (P < 0.05). Correlation analysis showed that the decrease in the Lp-PLA2 and sPLA2 levels was positively correlated with a reduction in HOMA-IR after CSII (P < 0.05). Additionally, multiple linear regression analysis showed that Lp-PLA2 and sPLA2 independently correlated with HOMA-IR (P < 0.05).ConclusionsLp-PLA2 and sPLA2 are closely related to insulin resistance and macroangiopathy in diabetic patients. Intensive insulin therapy might help improve IR and protect against diabetic macroangiopathy by influencing the Lp-PLA2 and sPLA2 levels.Trial registration ChiCTR-TRC-10001618 2010 September 16.

Short-term intensive insulin therapy is effective for type 2 diabetes because it offers the potential to achieve excellent glycemic control and improve β-cell function. We observed that the time to glycemic goal (TGG) was adjustable. Original data of 138 newly diagnosed type 2 diabetic patients received intensive insulin therapy by continuous subcutaneous insulin infusion for 2-3 weeks were retrospectively collected. Subjects underwent an intravenous glucose tolerance test (IVGTT) and an oral glucose tolerance test (OGTT) pre and post treatment. The glycemic goal was achieved within 6 (4-8) days. Patients were divided into two groups by TGG above (TGG-slow) and below (TGG-fast) the median value. Patients in both groups had significantly better glycemic control. Compared with TGG-fast, TGG-slow required a few more total insulin and performed more improvement of HOMA-β and IVGTT-AUCIns, but less improvement of HOMA-IR and QUICKI. Multiple linear regression analysis revealed that TGG was always an explanatory variable for the changes (HOMA-β, IVGTT-AUCIns, HOMA-IR and QUICKI). The hypoglycemia prevalence was lower in TGG-slow (1.48% vs. 3.40%, P<0.01). Multivariate logistic regression analysis indicated that individuals in TGG-slow had a lower risk of hypoglycemia (adjusted OR, 0.700; 95% CI, 0.567-0.864; P<0.05). Multiple linear regression analysis confirmed that the ratio of the incremental insulin to glucose responses over the first 30 min during OGTT (ΔIns30/ΔG30), average insulin dose before achieving targets, initial insulin dose and LDL-c were independent predictors for TGG. It is intriguing to hypothesize that patients with fast time to glycemic goal benefit more in improving insulin sensitivity, but patients with slow time benefit more in improving β-cell function and reducing the risk of hypoglycemia.