Chien-Ning Huang

Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4

Objective:Abundant evidence has demonstrated that long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). Our previous study reveals a significant association between promoter polymorphisms of Th2-derived cytokine interleukin-4 (IL-4) and T2DM, which suggests possible roles of IL-4 in metabolism. In this study, we focused on examining the putative regulation of glucose and lipid metabolism by IL-4.Methods:C57BL/6 mice were intraperitoneally injected with either adenovirus containing full-length IL-4 encoding gene (AdIL-4) or recombinant IL-4 for mimicking the status of transient and long-term IL-4 overexpression, respectively, and the effects of the overexpressed IL-4 to glucose/lipid metabolism and insulin sensitivity were subsequently investigated.Results:Our results reveal that IL-4 improves insulin sensitivity and glucose tolerance through upregulating Akt phosphorylation while attenuating GSK-3β activities. IL-4 is also involved in lipid metabolism by inhibiting lipid accumulation in fat tissues, which lead to decreased weight gain and fat mass.Conclusions:Our results suggest that IL-4 regulates glucose and lipid metabolism by promoting insulin sensitivity, glucose tolerance and inhibiting lipid deposits. This study uncovers the novel roles of IL-4 in metabolism and provides new insights in the interaction between cytokines/immune responses, insulin sensitivity and metabolism.

Improvement in health‐related quality of life, independent of fasting glucose concentration, via insulin pen device in diabetic patients

RATIONALE AND AIMS Using an insulin pen may improve the quality of life (QOL) for diabetic individuals. However, glycemic control and its relationship to better QOL are controversial. The aim of this study was to determine the relationship between health-related QOL and glycemic control in diabetic patients using insulin pen. METHODS All of the participants were diabetic patients receiving insulin therapy by syringe injection for longer than 1 month. One group of enrolled subjects changed over to use of insulin pen for 12 weeks, while the other group (age-matched control subjects) continued to use syringe for insulin-injection during the same period. Fasting plasma glucose, HbA1c and a 36-Item Short-Form Health Survey (SF-36) were assessed in both groups before and after the 12-week study. RESULTS A total of 32 subjects in the insulin pen group and 33 subjects in the syringe group completed the assessment. In comparison with baseline, fasting glucose significantly decreased in the insulin pen group (-57 +/- 14 mg dL(-1), P < 0.001), and the reduction was significantly greater than that in the syringe group (P = 0.003). The summary scale of physical components but not mental components in the SF-36 was significantly higher in the insulin pen group than in the syringe group (P = 0.037). This improvement was independent of the change in fasting glucose. CONCLUSIONS Using insulin pen for insulin-injection improved glycemic control and health-related QOL in diabetic patients. The better functional health status as a result of physical improvement was independent of the glycemic control.

Association of interleukin-4 promoter polymorphisms in Taiwanese patients with type 2 diabetes mellitus

Many factors have been implicated in the onset of type 2 diabetes mellitus (T2DM). Recently, immune response and inflammation were suggested to play certain roles in the development and complications of T2DM. The aim of this study is to investigate the putative correlation between the promoter polymorphisms of interleukin-4 (IL-4), one of the immune-regulatory type 2 helper T-cell cytokines, and T2DM. Genomic DNA from 425 Taiwanese T2DM patients and 148 nondiabetic control study subjects were extracted, and their IL-4 promoter polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Both of the distribution of IL-4 C-589T (P = .013) and C-34T (P = .05) genotypes were significantly different between T2DM patients and control subjects. Significant association between IL-4 C-589T alleles (P = .002) and T2DM, as well as C-34T alleles and T2DM (P =.024), was also identified. In addition, a statistically significant association between homologous IL-4 -589 C/C genotype and lower circulatory high-density lipoprotein cholesterol levels was observed. Our results suggested that IL-4 promoter polymorphisms are associated with T2DM. A significant association between IL-4 -589 C/C genotype and lower circulatory high-density lipoprotein cholesterol level was observed as well. The above results suggested that IL-4 may participate in lipid metabolism and diabetic susceptibility.

Prevalence of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Taiwanese patients with Type 2 diabetic mellitus.

OBJECTIVES Deficiency and/or decreased activity of methyltetrahydrofolate reductase (MTHFR) resulted from MTHFR variants are associated with hyperhomocysteinemia, an independent risk factor for vasculopathies in diabetic patients. The aim of this study was to examine MTHFR genotypes between healthy and type 2 diabetes mellitus (T2DM) subjects. DESIGN AND METHODS MTHFR C677T and A1298C genotypes were analyzed in 56 T2DM and 62 healthy subjects by PCR-RFLP. Association between MTHFR genotypes and T2DM as well as the lipid/glucose metabolic indexes among T2DM subjects was statistically analyzed. RESULTS No significance in the distribution of MTHFR genotypes between healthy and T2DM subjects is found. Besides, no significant associations between lipid/glucose metabolic indexes with MTHFR genotypes among diabetic patients are observed. CONCLUSIONS These data indicate the previous observation that MTHFR polymorphisms may play some roles in the pathogenesis and complications of T2DM in Caucasians are unlikely to be applied in Taiwanese patients.

Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes.

AIM To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). METHODS Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. RESULTS Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. CONCLUSIONS Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D.

Aggravation of albuminuria by metabolic syndrome in type 2 diabetic Asian subjects

AIMS We investigated the relationship of urinary albumin excretion (UAE) to metabolic syndrome and type 2 diabetes in Asian. METHODS A total of 446 subjects (187 without diabetes and 259 with type 2 diabetes) were enrolled in this study. The components of metabolic syndrome, high sensitivity C-reactive protein (hs-CRP) and UAE were assessed. Based on metabolic syndrome and diabetes status, participants were categorized into one of the following groups: neither metabolic syndrome nor diabetes (MS-DM-), metabolic syndrome without diabetes (MS+DM-), diabetes without metabolic syndrome (MS-DM+) and both metabolic syndrome and diabetes (MS+DM+). RESULTS The UAE in the MS+DM- group was higher than that in the MS-DM- group (P<0.001) and lower than that in the MS+DM+ group (P<0.001), but not significantly different from that in the MS-DM+ group (P=0.349). The trend of increasing UAE in these four groups was independent of hs-CRP. CONCLUSION UAE was lowest in subjects with neither metabolic syndrome nor diabetes and highest in subjects with both metabolic syndrome and type 2 diabetes; however, there was no significant difference between the metabolic syndrome alone group and the type 2 diabetes alone group.

Continuous subcutaneous insulin infusion providing better glycemic control and quality of life in Type 2 diabetic subjects hospitalized for marked hyperglycemia

Intensive glycemic control is effective in prevention of diabeticcomplications [1–3]. Continuous subcutaneous insulin infusion(CSII) therapy provides a continuous and stable delivery ofinsulin by an external pump. It has been reported that CSII helpslower plasma glucose and prevents hypoglycemia in Type 1 dia-betic patients attempting to improve glycemic control [4]. On theother hand, the majority of Type 2 diabetic patients receive oralanti-diabetic drugs for glycemic control. However, the treatmentmay gradually fail because of deterioration of b-cell functionand/or glucotoxicity [5,6]. Previous studies indicated that inten-sive insulin treatment by CSII is more effective in glycemiccontrol in Type 2 diabetes than conventional insulin therapy[7].Acute hyperglycemia may result in many pathophysiologicaldisorders, such as immune dysfunction, endothelial dysfunctionand neural damage [8–10]. Transient CSII applications in ambu-latory diabetes cases are helpful for glucose control [11–13].However, it is not known whether use of CSII provides betterglycemic control and improvement of quality of life as comparedwith conventional subcutaneous insulin injection and intravenousinsulin infusion in hospitalized Type 2 diabetic subjects withmarked hyperglycemia. Thus, we conducted this study to comparethe effects of these three types of treatment.

Missense mutations in the human insulin promoter factor-1 gene are not a common cause of Type 2 diabetes mellitus in Taiwan

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by a hyperglycemia resulting from defect in insulin secretion and insulin action. Recent studies showed that dominant negative mutations in the insulin promoter factor-1 (IPF-1), a pancreatic β-cell specific transcription factor, cause maturity-onset diabetes of the young (MODY), a subtype of T2DM with early onset and monogenic autosomal inheritance. In addition to MODY, IPF-1 mutations are suggested to predispose to common late-onset T2DM with different penetration of the mutations reflected in their:in vitro activity. Thus, we investigated IPF-1 C18R, Q59L, D76N and R197H mutations in Taiwanese patients with common late-onset T2DM, because research into IPF-1 variants in Taiwanese diabetic patients — a population with the lowest range of diabetic incidence — has never been documented. Peripheral blood samples were collected and genomic DNA was extracted from 434 patients with T2DM and 194 non-diabetes control study subjects. IPF-1 genetic variations were analyzed by PCR and restriction fragment length polymorphism (RFLP) analysis. We did not find any of these four IPF-1 mutations in our patients. Our results suggested that IPF-1 mutations were not a common cause associated with Taiwanese T2DM.

Metabolic syndrome abating the beneficial effect of pravastatin treatment on adhesion of endothelium by monocytes in subjects with hypercholesterolemia

Statin, a potent lipid-lowering agent, ameliorates the interaction of monocytes and endothelium, a critical step in the atherosclerotic process. However, it remains unclear whether this effect of statin depends on different doses or the presence of metabolic syndrome. In this prospectively double-blind study, 21 hypercholesterolemia subjects, with low-density lipoprotein cholesterol between 130 and 170 mg/dL, received low-dose (10 mg/d) or high-dose (40 mg/d) pravastatin treatment for 8 weeks. We assessed the reduction of monocyte adhesion to cultured endothelium between different-dose groups and the relationship to metabolic syndrome. Total cholesterol and low-density lipoprotein cholesterol were significantly decreased after 40-mg pravastatin treatment (-23.3% +/- 3.7%, P < .001 and -28.8% +/- 3.0%, P < .001), and the reductions were greater than those in the 10-mg group (P = .041 and P = .045, respectively). There was no significant difference in monocyte adhesion between high-dose and low-dose pravastatin treatment. When all subjects were divided into an improvement group and a no improvement group, according to the median of change percentage of monocyte adhesion after pravastatin treatment, there were significantly more subjects with metabolic syndrome in the no improvement than the improvement group (6 vs 1 person, P =.024). Using logistic regression analysis, metabolic syndrome, rather than dose effect of pravastatin, was an independent predictor of interaction between monocytes and endothelium (95% confidence interval = 0.001-0.865, P = .041). Attenuating adhesion between monocytes and endothelium is altered by the presence of metabolic syndrome when hypercholesterolemia subjects receive pravastatin treatment.

Cyotkines, Metabolism, and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is usually caused by insulin resistance, and often combined with progressive defect in insulin secretion. However, the etiology of T2DM remained unknown. Among various factors which lead to the onset of T2DM, host genetics and environmental factors are the focus of discussion. Identification and characterization of specific genes that can result in metabolic abnormalities are helpful for the effective prevention and therapeutic intervention of diabetes mellitus. Accumulating evidences have proved that T2DM is closely correlated with chronic inflammation, with increased levels of circulatory acute response proteins and cytokines in affected subjects. The aim of this article is to provide a general overview on the epidemiology, classification, and roles of cytokines in metabolism and T2DM. In addition to focusing on the cytokines-related literatures of diabetic studies, a summary of our study results concerning the polymorphisms of cytokine genes among diabetic patients is also included. Accomplishments of the immune-related genetic studies in a particular ethnic population can lead not only to the understanding of the interactions between immune responses and T2DM, but also potential clues for the designing of personalized type 2 diabetic treatment in the future.