2型糖尿病的非糖尿病一级亲属的血管内皮功能受损

2型糖尿病患者及非糖尿病的2型糖尿病一级亲属血浆一氧化氮和内皮素1水平下降,且与肥胖、胰岛素抵抗呈正相关。     

Insulin action and secretion in healthy, glucose tolerant first degree relatives of patients with type 2 diabetes mellitus. Influence of body weight.

It is a matter of controversy, whether insulin action or secretion - or both - are disturbed in first degree relatives of patients with type 2 diabetes. We intended to assess both the compensatory and the obesity-related part of insulin secretion. In order to dissect out the latter, matching for insulin sensitivity was mandatory to normalize for the compensatory part of hyperinsulinemia. In 154 healthy, glucose tolerant first degree relatives of patients with type 2 diabetes we directly quantified both insulin sensitivity (by euglycemic-glucose-clamp technique) and insulin secretion (oral glucose load; stimulated serum c-peptide). Insulin sensitivity was scattered over a wide range with a considerable overlap of both first degree relatives of patients with type 2 diabetes and 97 controls without a family history of diabetes. Average insulin sensitivity was higher in controls (8.0+/-0.3 vs. 7.1 + 0.2 ml x kg-l x min-1, p < 0.05). Prevalence of insulin resistance (defined as controls, lowest tertile for insulin sensitivity) was 40% in first degree relatives of patients with type 2 diabetes. Insulin secretion after oral glucose was significantly increased in insulin resistant first degree relatives of patients with type 2 diabetes compared to insulin sensitive first degree relatives of patients with type 2 diabetes. Early phase relative insulin secretion (30 min) expressed as x-fold increase above basal was smaller in insulin resistant first degree relatives of patients with type 2 diabetes than in insulin sensitive counterparts (5.3+/-0.4 vs. 7.3+/-0.5; p < 0.01). Body mass index was distributed over the whole range in insulin resistant first degree relatives of patients with type 2 diabetes. In the insulin sensitive subgroup absolute and relative secretion did not differ in obese (Body mass index >25 kg/m2) and insulin sensitivity-matched lean. In obese insulin resistant first degree relatives of patients with type 2 diabetes absolute hyperinsulinemia was combined with reduced and delayed relative early insulin release. In summary, degree and prevalence of insulin resistance is higher in first degree relatives of patients with type 2 diabetes than in controls. However, both groups are of heterogenous metabolic composition and family history as major discriminator should not be overestimated. Our data suggest, that hyperinsulinemia cannot simply be explained as a compensatory event to balance insulin resistance. Hypersecretion is associated with insulin resistance predominantly in combination with obesity. It might be speculated that adipose tissue derived signals to the beta-cell might lead to hypersecretion only in the genetic background that also leads to insulin resistance.     

Insulin resistance and fasting plasma glucose in first degree relatives of patients with type 1 diabetes

BackgroundWe analyzed the relationship between fasting plasma glucose (FPG), the presence of autoantibodies, first phase of insulin secretion and insulin resistance in the first degree relatives of patients with type 1 diabetes.Materials and MethodsThe group studied consisted of 90 healthy relatives, divided into two groups: “high-normal” FPG group (≥ 88 mg/dl) and “low-normal” FPG group (< 88/mg/dl). All subjects underwent an intravenous glucose tolerance test, and the 1st phase insulin response (FPIR) and FPIR-to-HOMA-IR-ratio were calculated. Additionally, islet autoantibodies (GADA, IAA and IA-2A) were determined by radioimmunoassays.ResultsThe subjects with "high-normal" FPG were older (p = 0.0009), had higher BMI (p < 0.0001) and lower HOMA%B (p = 0.0004), FPIR (p = 0.006) and FPIR-to-HOMA-IR-ratio (p = 0.004) in comparison with the "low-normal" FPG group. Autoantibodies were present in 40.9% and in 21.7% of the subjects with "high-normal" and “low-normal” FPG, respectively. In the "high-normal" FPG group, FPG correlated positively with GADA (r = 0.31, p = 0.04), and HOMA-IR (r = 0.19, p = 0.02), and negatively with HOMA%B (r = ? 0.36, p = 0.001), whereas FPIR correlated positively with HOMA%B (r = 0.55, p = 0.0001) and BMI (r = 0.30, p = 0.04). After an adjustment for BMI, the difference in FPIR between the “high-normal” and “low-normal” FPG groups remained significant (p = 0.025), whereas the difference in FPIR-to-HOMA-IR-ratio became insignificant.ConclusionsOur results suggest that taking into account the impact of age and BMI on insulin sensitivity, it would be expected that the relatives of patients with type 1 diabetes with "high-normal" glucose levels would become gradually unable to compensate for increasing insulin resistance.     

Prediction of type 1 diabetes mellitus in first degree Czech relatives of diabetic patients

Diagnosis of autoimmune beta cell destruction by genetic risk analysis, autoantibody evaluation and the test of stimulated insulin secretion performance in first-degree relatives of diabetic patients. 208 Czech children and adults (101 boys and 107 girls, 186 siblings, 22 offspring of diabetic parents, aged 1-22 years, mean age 11.5 +/- 5.4 years) were enrolled in the study. Complete DQB1, DQA1 typing and DRB1*04 subtyping were performed by the PCR in 202 subjects. Sera of all children were investigated for anti-GAD65, anti-IA2 and insulin antibodies using RIA methods. The cut-off normal levels were determined as the 99th percentile of 105 non-diabetic children. IVGTT was performed in children with significant titre of one or more autoantibodies. Total level of stimulated insulin secretion < 48 mU/l was assessed as defect of FPIR. Risk genotype DQA1*05-DQB1*0201/DQA1*03-DQB1*0302 (OR = 100, CI 95% 13-730) was found in 24 of 202 first-degree relatives (12%). 22 children (11%) carried strong protective allele DQB1*0602 (OR = 0.03, CI 95% 0.01-0.12). Autoantibody positivity was recognised in 9 of 208 children (2.9%) and IVGTT was performed. Positivity of anti-GAD65, anti-IA2 or IAA was identified in 5 of 24 children with the highest risk genotype (21%) and in 4 children of 113 with lower risk or neutral genotypes (3.5%). Borderline positivity of one autoantibody was found in 1 boy with the highest risk genotype and in 2 children with lower risk genotypes. Only temporary anti-GAD65 positivity was found in girl with protective genotype. Type 1 diabetes mellitus was diagnosed in boy during IVGTT and disease manifested 6 months after IVGTT in girl with defect of FPIR. Standardised methods for prediction of Type 1 diabetes were introduced in first-degree relatives of diabetic patients. These methods are used for Czech registry of diabetic children.     

糖耐量正常的2型糖尿病一级亲属胰岛素敏感性与腹脂分布的相关性

目的 了解糖耐量正常的2型糖尿病一级亲属人群腹内脂肪面积(VA)与胰岛素敏感性的关系.方法 将糖耐量正常的2型糖尿病一级亲属按HOMR-IR划分为胰岛素敏感组(IS组)和胰岛素抵抗组(IR组).分别测定血脂、血糖、胰岛素、体重指数(BMI)、腰围(WC)、VA和腹部皮下脂肪面积(SA),计算VA/SA值和TA(腹部脂肪总VA+SA,稳态模型胰岛素抵抗指数来评估胰岛素敏感性.结果 IR组空腹TG、VLDL较IS组有升高趋势,但无统计学意义(P＞0.05);糖负荷后2 h后,IR组TG、VLDL、ApoB明显升高,均有统计学意义(P＜0.05或P＜0.01).IR组30 min血糖、60 min血糖明显升高,有统计学意义(P＜0.01).腰围、VA、VA/SA、TA在IR组显著高于IS组,有统计学意义(P＜0.01).多元回归分析显示VA是胰岛素敏感性的独立相关因素.结论 胰岛素抵抗组在糖耐量正常阶段已经出现脂代谢、糖代谢异常和腹内脂肪增多.     

Metabolic syndrome in first degree relatives of patients with type 2 diabetes: Incidence and risk factors

AimsFirst degree relatives (FDRs) of people with type 2 diabetes are at greater cardiovascular and diabetes risk. It is not known whether they are also at greater risk of metabolic syndrome (MetS). The objectives of present study were to assess the incidence of and risk factors for the development of MetS in FDRs of patients with type 2 diabetes.MethodsA total of 3217 (842 men and 2375 women) FDRs of consecutive patients with type 2 diabetes aged 30–70 years in 2003–2005 were followed through 2010. At baseline participants underwent a standard 75 g 2-h standard OGTT and HbA_1c measurements. MetS was defined by the NCEP-ATP III. The study group consisted of 734 participants without MetS and history of known diabetes at baseline and had at least one subsequent review in mean (SD) follow-up period of 5.5 (1.2) years.ResultsThe prevalence of MetS was 35.8% (95% CI: 34.2, 37.5). The incidence of MetS was 4.3% (95% CI: 3.7, 4.9) (4.6% men and 4.2% women) per year. Multivariate analysis revealed that impaired glucose tolerance (IGT) (RR 1.89 (95% CI: 1.28, 2.79)), impaired fasting glucose (IFG) (RR 1.39 (95% CI: 1.10, 1.73)) and lower HDL (RR 1.34 (95% CI: 1.12, 1.60)) were associated with MetS.ConclusionsThe findings of this study illustrate for the first time the incidence of MetS in FDRs of patients with type 2 diabetes in Iran. Risk of MetS may increases with IGT, IFG and lower HDL.     

Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus

Plasma glucose, FFA, and insulin responses to an oral glucose challenge, plasma lipid and lipoprotein concentrations, and the ability of insulin to stimulate glucose disposal were measured in 35 nondiabetic sedentary and overweight subjects. The subjects were divided into 2 groups on the basis of the presence (n = 19) or absence (n = 16) of a history of a first degree relative with noninsulin-dependent diabetes. The 2 groups were similar in age, body mass index, waist to hip ratio, and maximal aerobic capacity. The results demonstrated that the ability of insulin to stimulate disposal of a glucose load was significantly reduced in the subjects with a positive family history of noninsulin-dependent diabetes. In addition, these individuals had significantly higher plasma triglyceride and very low density lipoprotein cholesterol concentrations. Since all environmental factors known to modify insulin action and very low density lipoprotein metabolism were equal in the 2 groups, these data suggest that the metabolic differences noted are likely to be genetic in origin.     

Effect of parental history of diabetes on markers of inflammation,insulin resistance and atherosclerosis in first degree relatives of patients with type 2 diabetes mellitus

Aim and objective

To study the effect of parental history of diabetes on markers of inflammation, insulin resistance, adiposity indices and carotid intima media thickness (cIMT) in first degree relatives of patients with type 2 diabetes mellitus (T2DM).

Insulin resistance and alanine amino transaminase (ALT) levels in first degree relatives of type 2 diabetes mellitus

IntroductionInsulin resistance is established as an independent predictor of a range of disorders such as obesity, hypertension, dyslipidemia, type 2 diabetes mellitus and atherosclerotic cardiovascular diseases. There is an association of hyperinsulinemia with hypertriglycerdemia, low level of HDL and high level of LDL. In nonalcoholic fatty liver disease, there is an elevation of ALT, raising the possibility that the prospective relationship between ALT and type 2 diabetes may reflect cross-sectional associations with insulin resistance or obesity.Aim and objectiveTo find the significance of insulin resistance and alanine aminotransferase level in first degree relatives of type 2 diabetes mellitus.Materials and methodsThe study included 50 first degree relatives of type 2 diabetes (25 men and 25 women) aged 20–60 years and 30 control of similar age. All cases were taken from SRM Medical College Hospital and Research Centre, Chennai. All the cases were analyzed for HOMA_IR, QUICKI, IR ratio, fasting glucose, insulin (ELISA), lipid profile and alanine aminotransferase. Student's ‘t’ test was applied for statistical analysis.ResultThe data show the significance of insulin resistance (HOMA_IR) (2.76 ± 1.46, 1.35 ± 0.8, p < 0.001) in the first degree relatives of type 2 diabetes mellitus when compared with controls respectively and increased level fasting plasma insulin (12.28 ± 6.16, 6.12 ± 3.04, p < 0.001). In the lipid profile the total cholesterol and TAG are significant. No statistical significance was found in ALT (24.8 ± 9.84, 20.08 ± 11.02).ConclusionResults of the study conclude that there is a high prevalence of insulin resistance in the first degree relatives of type 2 diabetes mellitus. ALT levels in the first degree relatives of type 2 diabetes mellitus had increased levels of insulin resistance, the pathogenesis suggesting increase in ALT levels as seen in insulin resistance condition. In our study, ALT was not statistically significant.     

2型糖尿病的非糖尿病一级亲属血浆纤溶受损

目的　探讨 2型糖尿病 (T2DM )及T2DM的非糖尿病一级亲属 (FDRs)血浆纤溶酶原激活物抑制物 1 (PAI 1 )的变化及其影响因素。方法　测定 31例正常人、57例一级亲属、35例T2DM患者的血浆PAI 1水平 ;采用方差分析、逐步多元直线回归分析。结果　 (1 )HOMA胰岛素抵抗 (HOMA IR)在对照组、FDRs、T2DM组逐渐升高 ,胰岛功能 (HOMA β)逐渐下降 ,且有显著差异 (P <0 0 5) ,T2DM组HbA1c显著高于对照组和FDRs(P <0 0 1 )。 (2 )FDRs和T2DM组血浆PAI 1水平显著低于对照组 (P <0 0 5)。结论　T2DM及非糖尿病的T2DM一级亲属胰岛素敏感指数下降 ,纤溶受损 ,且与肥胖、血脂水平呈正相关。     

2型糖尿病家系一级亲属同胞腰臀股围的变化

目的：研究2型糖尿病家系一级亲属同胞糖代谢异常及糖耐量正常者的腰、臀、股围变化及其意义。方法：在560个临床表现为2型糖尿病的家系中，去除1型糖尿病、线粒体糖尿病和收集标本数少的家系后，得406个2型糖尿病家系，将其家系一级亲属同胞成员分为正常糖耐量组（NGT组，425例）、糖耐量减退组（IGT组，79例）、糖尿病组（DM组，694例），并以同胞配偶中的无糖尿病家族史的正常糖耐量者作为对照组（C组，429例），比较各组间腰、臀、股围及其各个比值的6个参数的差异。结果：DM组腰围、腰臀比、腰股比、臀股比高于C组，臀围、股围低于C组（腰围P＝0．0059，余均＜0．001）。NGT组腰臀比，腰股比大于C组（P分别显0．0009，0．0045），股围小于C组（P＝0．0321），均有显著差异。腰围、腰臀比、腰股比在X组、NGT组、IGT组、DM组有逐渐增高趋势，臀围、股围在四组有逐渐减低趋势。去除用胰岛素治疗，或体重指数＜20kg/m^2或空腹血糖＞14mmol/L者比较6个参数在4组中的差异，显示上述变化趋势更显著。结论：糖代谢异常患者，随着糖代谢异常的加重，其体脂有重新分布，逐渐向中心性肥胖发展的趋势。即腹围渐大，臀围，尤其是股围有逐渐相对缩小的趋势。值得注意的是2型糖尿病家系同胞一级亲属中的糖耐量正常者已不同于群体中的糖代谢正常者，开始出现此种变化趋势，可能与遗传因素有关。     

A study on the types of diabetes mellitus in first degree relatives of diabetic patients

The genetic characteristics of the diabetic types have been assessed by following up their frequency in first degree relatives of some non-selected diabetic patients, registered at eight different centers of the country. Out of 1,003 non-diabetic controls only 46 (4.6%) had 52 diabetic relatives, 65.4% of type 2 (non-insulin-dependent). Comparatively, out of the 704 patients, 172 (24.4%) had 229 diabetic first degree relatives, 72.5 of type 2. Out of 231 type 1 (insulin-dependent) diabetic patients, 29 (12.6%) had 34 diabetic relatives, 55.9% of type 1. Out of 300 type 2 patients, 99 (33.0%) had 121 diabetic relatives, 84.0% of type 2. The other 173 diabetic patients presented an "intermediary" type of the disease (needing insulin many years after onset). Forty-four (25.4%) of them had 64 diabetic relatives, 67.2% of type 2, 20.3% of type 1 and 12.5% with "intermediary" diabetes. The five times higher frequency of diabetes in patients' relatives versus controls is pointed out. Type 2 diabetic relatives predominated. The proportion of probands with diabetic relatives increased from 4.6% in non-diabetics to 12.6% in type 1, to 25.4% in "intermediary" diabetes and to 33.0% in type 2. The heredity of type 1 prevailed in type 1 and that of type 2 in type 2 and in "intermediary" diabetes. The fact that "intermediary" diabetes tends towards type 1 (insulin-dependent) as therapy and towards type 2 (non-insulin-dependent) as heredity might be an argument supporting the controversy on the diabetic syndrome classification.     

2型糖尿病非糖尿病一级亲属中肥胖患者血浆内脂素水平

检测了2型糖尿病一级亲属、单纯肥胖和健康对照者内脂素（visfatin）、内皮依赖性血管舒张功能、颈总动脉内膜中层厚度，并用MRI评价内脏脂肪和皮下脂肪面积。结果提示2型糖尿病一级亲属中肥胖患者和单纯肥胖患者内脂素水平高于2型糖尿病一级亲属非肥胖者和健康对照组，并且内脂素与空腹血糖呈独立负相关。     

Proportional proinsulin responses in first-degree relatives of patients with type 2 diabetes mellitus

Elevated fasting proinsulin immunoreactive material (PIM) has previously been found in patients with type 2 (non-insulin-dependent) diabetes mellitus. It is not known whether this is a genetic trait or whether it is related to the manifestation of type 2 diabetes. Neither is it clear whether the raised fasting insulin immunoreactivity previously observed in first-degree relatives of patients with type 2 diabetes is due to raised PIM. Furthermore, it has not been investigated whether first-degree relatives have altered PIM responses to different secretagogoues. To study this, PIM, insulin and C-peptide were measured in patients with type 2 diabetes, in their first-degree relatives and in healthy control subjects in the fasting state and in relatives and controls during a hyperglycemic clamp. At the end of the hyperglycemic clamp, 0.5 mg of glucagon was given intravenously to stress the beta cells further. Fasting PIM concentrations were significantly higher in patients with type 2 diabetes (P<0.05). These patients did not have significantly elevated fasting insulin levels when corrected for PIM. In the relatives, fasting insulin concentrations were elevated but PIM levels were normal suggesting that the increase in fasting insulin concentrations reflected an increase in true insulin. The incremental PIM, insulin and C-peptide responses to glucose and glucagon in the relatives were not different from those in the controls. We conclude that elevated fasting PIM levels in patients with type 2 diabetes seem not to be a genetic trait. First-degree relatives of patients with type 2 diabetes are truly hyperinsulinemic in the fasting state, and they have proportional PIM, insulin and C-peptide responses to glucose and glucagon.     

Different pathophysiology of impaired glucose tolerance in first-degree relatives of individuals with type 2 diabetes mellitus

To assess whether an increased genetic predisposition for type 2 diabetes mellitus (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an oral glucose tolerance test and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) who had normal glucose homeostasis and no first-degree T2DM relative (n = 133), IGT with a first-degree T2DM relative (IGT/FH+, n = 74), or IGT without a first-degree T2DM relative (IGT/FH−, n = 50). Compared with those with normal glucose homeostasis, first- and second-phase plasma insulin responses were reduced approximately 45% and 30%, respectively (both P < .001), in IGT/FH+, whereas insulin sensitivity was only approximately 20% reduced (P = .011). In contrast, in IGT/FH−, first-phase plasma insulin responses were only approximately 20% reduced (P = .016), second-phase plasma insulin responses were not reduced, but insulin sensitivity was approximately 40% reduced (P < .001). The IGT/FH+ group differed significantly from the IGT/FH− group by having 25% to 30% lower first-phase plasma insulin responses (P = .026) and 25% to 30% greater insulin sensitivity (P = .027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first-phase plasma insulin responses were approximately 30% lower in IGT/FH+ with a BMI of at least 27 kg/m² (P = .018) but similar in IGT/FH+ with a BMI less than 27 kg/m² compared with the corresponding IGT/FH− subgroups. We conclude that, in IGT, an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.     

动态监测新诊断2型糖尿病患者的血糖水平

目的　动态监测新诊断2型糖尿病(T2DM)患者血糖漂移的细节及波动趋势。　方法　采用动态血糖监测系统(CGMS)对40 例新诊断、未经干预治疗的T2DM患者进行连续71(43~90)小时的血糖监测。　结果　CGMS所测的血糖值与血浆血糖值及指端血糖值均呈显著正相关(r=0.92, r=0.93, P均<0.001)。患者一天中血糖较高的时间段为早餐后2 h及中、晚餐后3 h。6 am~< 11 am是血糖高峰最集中(52.5%)的时间段,而62.5%的血糖低谷值出现在1 am~ <6 am。血糖>7 8 及11.1 mmol/L所占的时间百分比分别为96(37~100)%和62(8~100)%。血糖>7.8 及11.1 mmol/L的时间百分比与HbA1c(9.8%±1.9%)均呈显著正相关(r=0.74, r=0.76,P均<0 001)。　结论　动态血糖监测能较详细地显示T2DM患者血糖水平波动的特征,对拟定更为合理的治疗方案提供临床依据。     

Perturbation of erythrocyte antioxidant barrier, lipid peroxidation and protein carbonylation in non-diabetic first degree relatives of patients with type 2 diabetes

OBJECTIVE: Oxidative stress plays an important role in the pathogenesis of type 2 diabetes. But it is still discussed whether oxidative stress precedes or merely reflects diabetic complications. The present study was carried out to search for the possibility of oxidative stress among the first degree relatives of patients with type 2 diabetes, as they are more prone to develop type 2 diabetes. METHODS: This study has been conducted on 30 first degree relatives of patients with type 2 diabetes and 34 healthy subjects without any known family history of diabetes. Whole blood glutathione, plasma malondialdehyde (MDA), protein carbonylation, fasting glucose levels and the activities of anti-oxidant enzymes glutathione peroxidase, catalase and glutathione S-transferase were measured. RESULTS: The antioxidant enzyme glutathione peroxidase, plasma MDA and protein carbonyl levels were significantly elevated in the test group compared with controls. The glutathione levels were significantly decreased in the test group. CONCLUSION: This study reveals alteration of antioxidant status and oxidative stress among the first degree relatives of patients with type 2 diabetes.