Ⅱ型糖尿病合并高血压对脂代谢及胰岛素敏感性的影响

目的：观察Ⅱ型糖尿病合并高血压对脂代谢及胰岛素敏感性的影响。方法：对20例Ⅱ型糖尿病合并高血压患者和20例Ⅱ型糖尿病无高血压患者的空腹血糖（FBG）,血脂,胰岛素（FINS）,C肽（FCP）,胰岛素敏感指数（ISI）进行对照,结果：Ⅱ型糖尿病合并高血压组与无高血压组比较,甘油三酯（TG）,FINS,FCP水平显著升高（P＜0．05）,高密度脂蛋白（HDL）,ISI水平显著降低（P＜0．05）,结论：Ⅱ型糖尿病合并高血压时脂代谢紊乱及胰岛素抵抗更加明显。     

The dysregulated adipose tissue: a connecting link between insulin resistance, type 2 diabetes mellitus and atherosclerosis

An emerging paradigm supports the view that adipose tissue (AT) dysregulation might play a crucial role in the pathogenesis of insulin-resistance and atherosclerosis. The net result of such a dysregulation is a state of low-grade, chronic, systemic inflammation that, in turn, links both the metabolic and the vascular pathologies. Overwhelming evidence shows that high circulating levels of markers of chronic inflammation predict the development of T2DM and atherosclerotic manifestations. Therefore, atherosclerotic cardiovascular disease and T2DM seem to arise from a "common soil", and chronic inflammation is a candidate. In this scenario, the dysfunctional AT provide a common hallmark for these apparently divergent disorders. An important question then is whether dysregulated and inflamed AT can be converted to healthy fat and, consequently, the development or the progression of metabolic and vascular impairment can be prevented or reversed by the modulation of the inflammatory profile. The beneficial effects of weight loss on obesity-related complications are clearly associated with the modification of the inflammatory profile in the AT. Furthermore, the thiazolidinediones (TZDs) possess both anti-inflammatory and anti-atherogenic properties. Intriguingly, in contrast to the paradoxical weight gain, TZDs influence favorably the pattern of adipokines. In conclusion, accepting the paradigm of AT dysfunction, the use of TZDs will represent an additional therapeutic approach that, in association with lifestyle interventions, would improve inflammation, ameliorate insulin sensitivity, and alleviate the related risk of atherosclerosis.     

TCF7L2 gene expression in human visceral and subcutaneous adipose tissue is differentially regulated but not associated with type 2 diabetes mellitus

Variants in the TCF7L2 gene have been associated with type 2 diabetes mellitus (T2DM), but the causal variant(s) is still unknown. We studied the TCF7L2 messenger RNA (mRNA) expression in paired samples of visceral and subcutaneous adipose tissue from 49 subjects using quantitative real-time polymerase chain reaction and its relation to obesity and T2DM. All subjects were genotyped for the previously described TCF7L2 diabetes risk variants. Independent of age, sex, obesity, and diabetes status, we found >3-fold higher TCF7L2 mRNA expression in subcutaneous compared with visceral adipose tissue. There was no correlation between visceral and subcutaneous TCF7L2 expression. No differences in adipose tissue TCF7L2 mRNA expression levels were found between diabetic and nondiabetic subjects, or between lean and obese subjects (all Ps > .05). In addition, there was no association between TCF7L2 genetic variants and mRNA expression. Based on our data, TCF7L2 mRNA expression is fat-depot specific but does not seem to provide the mechanistic link explaining genetic association with T2DM.     

Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.     

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue

Aims/hypothesis

Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive.

Methods

We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy.

Results

As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1β after 6 months of insulin therapy compared with those who had not gained weight.

Conclusions/interpretation

We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status.

Trial registration

ClinicalTrials.gov: NCT00781495.

Funding

The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.     

Visceral adipose tissue as an indicator of insulin resistance in nonobese patients with new onset type 2 diabetes mellitus.

BACKGROUND: Obesity and type 2 diabetes mellitus are characterized by insulin resistance. We determined the relationship between insulin resistance and visceral adipose tissue (VAT) and their correlation with bioimpedance analysis in nonobese new onset type 2 diabetes patients. METHODS: A number of 30 new onset type 2 diabetes patients and 20 healthy control subjects with similar features, age between 45 - 72 years old, BMI < 27 kg/m (2), C-peptide > 0.6 nmol/L, were included in study. Fasting blood glucose, HbA1c, serum lipids, BMI, insulin, C-peptide, HOMA-IR, bioimpedance analysis and visceral and subcutaneous adipose tissue (by computed tomography) were measured. RESULTS: In the patient group, VAT was significantly higher compared to healthy control group (33.17 +/- 10.23 % vs. 16.53 +/- 7.85 %, p < 0.001). In the patient group VAT was correlated with HOMA-IR (r = 0.62, p = 0.003), but no significant correlation was observed between VAT and bioimpedance analysis. CONCLUSIONS: The amount of VAT is significantly higher in nonobese new onset patients with type 2 diabetes than the healthy control group. In these patients, VAT measured by CT is an important indicator of insulin resistance. Although bioimpedance analysis can give an idea about total body fat and obesity, it is not sufficient in evaluating fat distribution and therefore is not effective in predicting insulin resistance.     

Bone metabolism in type 2 diabetes mellitus

Several conditions have been described to cause osteoporosis, including diabetes mellitus. While the relationship between type 1 diabetes and osteopenia is well documented in the literature, data on the presence of this complication in type 2 diabetes have not been well established. We studied a population composed of 66 post-menopausal women with type 2 diabetes and a control population. We examined bone mineral density with the dual-energy X-ray absorptiometry (DXA) technique at the lumbar and femoral levels and, in a subgroup of patients, we also measured the levels of markers of bone remodelling. We found significantly higher levels of bone mineral density at the femoral (but not lumbar) level in the diabetic subjects compared with the control population in all the examined subregions, except Ward's triangle. Moreover, we found higher levels of some markers of bone resorption (urinary calcium and hydroxyproline, telopeptide) in the patients with diabetes, while urinary crosslinks were higher in the controls. On the basis of these results, we suggest that osteoporosis cannot be considered a complication of type 2 diabetes and that, from a metabolic point of view, bone resorption is greater in diabetic patients than in normal subjects, as suggested by the high levels of most of the markers of osteoclastic activity. Received: 16 March 1998 / Accepted in revised form: 24 February 1999     

Ciprofibrate effects on carbohydrate and lipid metabolism in type 2 diabetes mellitus subjects

BACKGROUND AND AIMS: Atherosclerosis is the most common cause of morbidity and mortality in type 2 diabetes mellitus. Hyperglycemia, dyslipoproteinemia, arterial hypertension and coagulation abnormalities are the most important cardiovascular risk factors. Hypertriglyceridemia and low high density lipoprotein-cholesterol (HDLc) seem to be related with insulin resistance. Fibric acid derivates (fibrates) are effective in the treatment of dyslipoproteinemia in diabetes. Our aim was to evaluate the efficacy and safety of ciprofibrate in improving dyslipoproteinemia and its effect on fibrinogen plasma concentrations, carbohydrate metabolism variations and insulin action. METHODS AND RESULTS: 13 subjects with type 2 diabetes mellitus were treated with diet and placebo for 4 weeks and then randomized to one of two treatments: ciprofibrate 100 mg or placebo for four weeks. After a four-week wash-out period they were crossed over as shown in Figure 1. Total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDLc), very low density lipoprotein-cholesterol (VLDLc), HDLc, Apolipoprotein B100, fibrinogen, insulin and Lp(a) were measured. Insulin erythrocytes union was made by the Gambhir method. There was a 15% decrease in total cholesterol (p < 0.05) and 47% decrease in triglycerides (p < 0.01); similar changes were observed in VLDL-cholesterol and VLDL-triglycerides; 17% increase in HDL-cholesterol (p < 0.05). No significant differences were observed in LDL-cholesterol, apolipoprotein B100 and lipoprotein (a). Fibrinogen decreased 10% (p < 0.05). A non-significant 10% decrease in insulin secretion (area under curve) after oral glucose was observed with ciprofibrate. These findings indicate a decrease in receptor affinity. A non-significant decrease in insulin receptor number/cells was also observed. CONCLUSIONS: Ciprofibrate has a potent hypolipidemic effect, especially a decrease in triglycerides, VLDL and fibrinogen, and an increase in HDL-cholesterol, but does not influence glycemic control nor insulin action. Decreased insulin secretion may be due to peripheral use of glucose due to the drug's antilipolytic action.     

Lipoprotein phenotype and insulin resistance in familial combined hyperlipidemia

The study objective was to investigate the relationship of insulin resistance (IR) with the lipoprotein phenotype in familial combined hyperlipidemia (FCH). Thirty-seven FCH men diagnosed by clinical and biochemical criteria and classified as lipoprotein phenotype IIa (n = 9), IIb (n = 17), or IV (n = 11) were compared with a healthy control group of 30 men of similar age, body mass index (BMI), waist to hip ratio (WHR), and systolic and diastolic blood pressure. In all subjects, the plasma lipoprotein profile and baseline and post-oral glucose tolerance test (OGTT) glucose and insulin plasma values were measured. An intravenous glucose tolerance test was performed and IR was studied by the peripheral insulin sensitivity index (Si). After the OGTT, significantly higher values for insulinemia (at 0, 60, 90, and 120 minutes) and the area under the curve (AUC) of insulin secretion were observed in FCH. The AUC of insulin was greater in FCH subjects with the hypertriglyceridemic phenotype as compared with the controls and significantly lower Si levels, indicating greater IR, were found in the three FCH groups (control, 3.48 +/- 1.87 mU/L/min; FCH IIa, 2.09 +/- 1.08; FCH IIb, 1.54 +/- 0.77; FCH IV, 1.47 +/- 0.93; P < .001). The prevalence of IR (Si < 2 x 10(-4) mU/L/min) was greater in FCH, independent of the lipoprotein phenotype, as compared with the controls (P < .0001). Higher plasma glucose and insulin levels at 120 minutes and lower Si values were found in the FCH IIa group compared with the controls (P < .05), indicating a state of IR in this subgroup of normotriglyceridemic subjects. In conclusion, IR was found in the three FCH lipoprotein phenotypes, being more severe in subjects with hypertriglyceridemia. Hence, the therapeutic goals in FCH should include measures to normalize plasma lipids and improve peripheral insulin sensitivity.     

2型糖尿病家系中血浆肿瘤坏死因子α水平与胰岛素抵抗

目的　探讨 2型糖尿病 (T2 DM)家系成员血浆肿瘤坏死因子 α(TNF- α)水平与胰岛素敏感性的关系。　方法　采用放射免疫法检测了 32例家族性 T2 DM患者、37例家族性 T2 DM患者的非 DM一级亲属 ,4 0例正常人的血浆 TNF- α水平。　结果　家族性 T2 DM患者血浆 TNF- α为 (1.19± 0 .2 1) μg/ L,明显高于正常对照组 (1.0 0± 0 .18) μg/ L(P<0 .0 5 )。家族性 T2 DM患者的非 DM一级亲属血浆 TNF- α为 (1.0 1± 0 .2 8) μg/ L,与正常对照组比较 ,差异无显著性。逐步回归分析显示 ,血浆 TNF- α水平与胰岛素敏感性指数 (ISI)呈负相关 ,TNF- α参与了 ISI的变异 ,血浆总胆固醇(TC)、体重指数 (BMI)、TNF- α对 ISI总的影响程度为 39%。　结论　循环 TNF- α可能参与了家族性 T2 DM患者胰岛素抵抗的形成     

2型糖尿病胰岛素抵抗与超敏C反应蛋白血尿酸和血脂代谢之间的关系探讨

目的探讨2型糖尿病(T2DM)胰岛素抵抗与超敏C反应蛋白(hs-CRP)、血尿酸(SUA)和血脂代谢之间的关系。方法收集T2DM患者共128例,测定患者空腹血糖(FPG)、餐后2 h血糖(2h PG)、空腹胰岛素(FIns)、SUA、hs-CRP及高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、总胆固醇(TC)、甘油三酯(TG)等水平,按HOMA-IR水平的四分位间距进行分组,比较和分析组间各指标测定值。结果各组间hs-CRP、SUA、TG、HDL-C水平比较差异有统计学意义(P0.05),Pearson相关性分析显示HOMA-IR水平与hs-CRP、SUA、TG水平呈正相关,与HDL-C水平呈负相关(P0.05)。多重线性回归分析显示hs-CRP、SUA、HDL-C进入方程,方程式为y=53.284+0.237X1+0.098X2-1.618X3。结论 hs-CRP、SUA、HDL-C与T2DM胰岛素抵抗严重程度密切相关。     

Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content

We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [¹⁸F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.     

C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients

This study aimed to assess the role of complement C3, hormone-sensitive lipase (HSL), and peroxisome proliferator-activated receptor gamma (PPARgamma) gene expression in familial combined hyperlipidemia (FCHL). mRNA expression of these 3 determinants of adipose tissue fatty acid (FA) metabolism was quantified in subcutaneous adipose tissue of 41 Finnish FCHL patients and 14 normolipidemic control subjects. No difference in steady-state mRNA expression level of C3, HSL, or PPARgamma mRNA was detected between the FCHL patients and the control subjects. Adipose tissue C3 mRNA expression level correlated with the area under the curve (AUC) for glucose and for insulin in FCHL patients and control subjects. HSL mRNA level was positively correlated with waist-to-hip ratio in patients, whereas the correlation was negative in control subjects. A significant correlation was observed for PPARgamma with free FA (FFA)-AUC in the FCHL group, and an inverse correlation with serum triglycerides (TG) in the control subjects. Although no difference in adipose tissue gene expression of C3, HSL, or PPARgamma was observed between the FCHL patients and the control subjects, several significant correlations were observed between the mRNA levels and FCHL-related metabolic parameters. Thus, the genes of C3, HSL, and PPARgamma may exert a modifying effect on lipid and glucose metabolism in FCHL. However, defects in adipose tissue expression of these genes are not likely to play a primarily role in the pathogenesis of FCHL in Finnish FCHL families.     

Duration of obesity is not a risk factor for type 2 diabetes mellitus, arterial hypertension and hyperlipidemia

Background:  Obesity is known to be a risk factor for type 2 diabetes mellitus (DM), arterial hypertension (HT) and hyperlipidaemia (HL), but the relationship between the duration of obesity and these outcomes is variable in the literature.
Aims:  The aims of this study were 1) to evaluate whether the duration of obesity is a risk factor for type 2 DM, HT and HL, 2) to determine the incidence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), type 2 DM, HT and HL in the patients attending our clinic because of obesity and 3) to determine the correlation between DM, HT and HL and age, body mass index (BMI), duration of obesity and waist-hip ratio (WHR).
Methods:  Informed consent was obtained from 200 consecutive women presenting to our Endocrinology and Metabolism Unit for the first time because of obesity. The patient's history of the age at onset of obesity, HT and family history of DM were obtained. Anthropometric measurements and a 75-g oral glucose tolerance test (OGTT) were performed.
Results:  On OGTT, 15 (7.5%) had IFG, 36 (18%) had IGT and 18 (9%) had type 2 DM; in addition, 96 (48%) had HT and 76 (38%) had HL. Upon multivariate logistic regression analysis, age was a common risk factor for IGT, type 2 DM, HT and HL, and a family history of diabetes was an additional risk factor for type 2 DM.
Conclusion:  The duration of obesity, as reported by women presenting for treatment of obesity, is not a risk factor for type 2 DM, HT and HL.     

Abnormalities in insulin secretion in type 2 diabetes mellitus

Type 2 diabetes mellitus is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. beta-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal beta-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. When permanent hyperglycaemia is present, progressive severe insulin secretory failure with time ensues, due to glucotoxicity and lipotoxicity, and oxidative stress. A marked reduction in beta-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in beta-cell apoptosis non-compensated by neogenesis.