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.     

2型糖尿病家系非糖尿病正常体重一级亲属脂联素水平5年随访

目的探讨2型糖尿病患者非糖尿病正常体重一级亲属脂联素水平变化及脂联素与胰岛素敏感性和颈动脉内膜中层厚度(IMT)之间的关系.方法入选2型糖尿病非糖尿病正常体重一级亲属53名和对照组37名,入组时检测了脂联素、血脂、血糖、血压及空腹胰岛素水平.用高频B超检测IMT及内皮依赖性血管舒张功能(EDVD).采用稳态模式(HOMA)评价胰岛素抵抗(HOMA-IR)和评价胰岛β细胞功能(HOMA-β).一级亲属组29名和对照组20名完成了5年随访.结果基线时一级亲属组血浆脂联素水平明显低于对照组[(10.06±5.79)对(14.43±7.91)mg/L,P<0.05].5年后一级亲属组脂联素水平降低24.0%(P<0.05),对照组脂联素水平降低36.7%(P<0.05).一级亲属组脂联素与腰臀比(r=-0.397)、空腹血糖(r=-0.373)、IMT(r=-0.372)和HOMA-IR(r=-0.40)负相关(均P<0.05).校正相关因素后,多元逐步回归分析显示一级亲属组脂联素与年龄,高密度脂蛋白胆固醇(HDL-C),IMT独立相关.对照组脂联素与低密度脂蛋白胆周醇(LDL-C)和IMT独立相关.结论 5年后一级亲属组和对照组脂联素水平均明显降低,脂联素降低可能与IMT增加相关.     

Coincidence of high antiislet and antithyroid autoantibody titles in first-degree relatives of patients with type 1 diabetes.

An association between thyroid and islet autoantibodies has been reported for patients with type 1 diabetes and their first-degree relatives. However no general agreement on this association has been reached since several studies reported controversial data. In the present study, sera from 429 healthy first-degree relatives of type 1 diabetic patients have been examined for the presence of thyroid and islet autoantibodies. Autoantibodies against glutamate decarboxylase (GAD65Ab) and tyrosine-phosphatase IA-2 (IA-2/ICA512Ab) have been detected by radioimmunoassay techniques with in vitro translated recombinant human 35S-autoantigens. The presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has been estimated by commercial radioimmunoassay kits. An increased frequency of TgAb was found in subjects who were positive for GAD65Ab (p=0.0257). However, no significant association between TPOAb and GAD65Ab or IA-2Ab or between TgAb and IA-2Ab could be established. These data indicate an increased rate of coincidence between TgAb and GAD65Ab in healthy first-degree relatives of type 1 diabetic patients. Accordingly a common genetic background leading to the appearance of both TgAb and GAD65Ab may be suggested.     

2型糖尿病患者一级亲属胰岛素抵抗干预结果

目的 对2型糖尿病患者有胰岛素抵抗(IR)一级亲属进行生活方式干预后,观察其胰岛β细胞功能及胰岛素敏感性的变化及IR改善情况.方法 将T2DM家系非DM但具有明显IR的一级亲属46人分为生活方式干预组与非干预组,定期观察各项指标,随访2年.结果 干预组经生活方式干预后BMI降低,2hPG、TG水平降低(P＜0.05),高胰岛素水平改善(P＜0.01),IR程度明显减轻(P＜0.01).结论 干预可以改善胰岛素敏感性,减轻IR,对减少糖尿病的发生,减少大血管并发症的形成具有积极的意义.     

Acute effects of dietary fat on inflammatory markers and gene expression in first-degree relatives of type 2 diabetes patients

BACKGROUND: Subjects with type 2 diabetes (T2D) and their relatives (REL) carry an increased risk of cardiovascular disease (CVD). Low-grade inflammation, an independent risk factor for CVD, is modifiable by diet. Subjects with T2D show elevated postprandial inflammatory responses to fat-rich meals, while information on postprandial inflammation in REL is sparse. AIM: To clarify whether medium-chain saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) have differential acute effects on low-grade inflammation in REL compared to controls (CON). METHODS: In randomized order, 17 REL and 17 CON ingested two fat-rich meals, with 72 energy percent from MUFA and 79 energy percent from mainly medium-chain SFA, respectively. Plasma high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), adiponectin, and leptin were measured at baseline, 15 min, 60 min, and 240 min postprandially. Muscle and adipose tissue biopsies were taken at baseline and 210 min after the test meal, and expression of selected genes was analyzed. RESULTS: Plasma IL-6 increased (p < 0.001) without difference between REL and CON and between the meals, whereas plasma adiponectin and plasma hs-CRP were unchanged during the 240 min observation period. Plasma leptin decreased slightly in response to medium-chain SFA in both groups, and to MUFA in REL. Several genes were differentially regulated in muscle and adipose tissue of REL and CON. CONCLUSIONS: MUFA and medium-chain SFA elicit similar postprandial circulating inflammatory responses in REL and CON. Medium-chain SFA seems more proinflammatory than MUFA, judged by the gene expression in muscle and adipose tissue of REL and CON.     

Lower beta-cell secretion in physically active first-degree relatives of type 2 diabetes patients

Regular physical activity may prevent or postpone type 2 diabetes, and is thought to be related to an increase of insulin sensitivity. We studied whether physically active, glucose-tolerant first-degree relatives of type 2 diabetes patients differ in glucose tolerance (oral glucose tolerance test [OGTT]) and insulin secretion (hyperglycemic glucose clamp) from less active first-degree relatives. A group of 37 relatives was split into 2 subgroups according to the sex-specific median of the sports index, assessed by a questionnaire, as the cutoff point. Blood glucose levels during the OGTT were lower in the highly active subgroup versus the less active counterparts (multivariate ANOVA [MANOVA], P = .011), but the plasma insulin levels were similar. First-phase secretion was not different in the highly active group versus the less active group, but second-phase secretion (average plasma insulin in the third hour) was significantly lower (P = .016). As expected, the insulin sensitivity index (ISI) was higher in the highly active subgroup (P= .011). Subdivision into subgroups with high or low maximal O2 consumption (VO2max) resulted in similar differences, but these were not significant. In a group of 21 controls, the results resembled the values in the relatives but were less often statistically significant. In conclusion, regular physical activity not only is associated with increased insulin sensitivity but also downregulates the pancreatic beta cell. This downregulation may provide an extra mechanism by which physical activity diminishes the development of type 2 diabetes.     

1型糖尿病一级亲属GADA、IA-2A与IAA联合检测的价值

目的 采用放射配体法检测118例1型糖尿病一级亲属的谷氨酸脱羧酶抗体(GA-DA)、蛋白酪氨酸磷酸酶抗体(IA-2A)、胰岛素自身抗体(IAA)，发现三种抗体单独检出率与欧美高加索人接近，联合检测阳性率优于单一抗体检测。     

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。     

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, G?teborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.     

Impaired endothelial function and insulin action in first-degree relatives of patients with type 2 diabetes mellitus

First-degree relatives (FDR) of patients with type 2 diabetes mellitus are at increased risk of developing type 2 diabetes mellitus. We studied if endothelial dysfunction of the resistance vessels is present and may coexist with metabolic insulin resistance in FDR. Male FDR (n = 13; 26 ± 1 years; body mass index, 25 ± 1 kg m² [mean ± SEM]) and matched control subjects (CON) (n = 22; 25 ± 1 years; body mass index, 24 ± 1 kg m²) were studied by hyperinsulinemic (40 mU min⁻¹⋅m⁻²) isoglycemic clamp combined with brachial arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography upon stimulation with systemic hyperinsulinemia (291 ± 11 pmol/L, pooled data from both groups) and upon intraarterial infusion of adenosine (ADN) and acetylcholine (ACH) ± hyperinsulinemia. Forearm blood flow response to ADN and ACH was less in FDR vs CON (P < .05); systemic hyperinsulinemia added to the FBF effect of ADN in CON (P < .05) but not in FDR. In addition, FDR demonstrated impaired FBF to hyperinsulinemia (2.1 ± 0.2 vs 4.0 ± 0.6 mL 100 mL⁻¹ min⁻¹) in FDR and CON, respectively (P < .05). Both M-value (5.0 ± 0.7 vs 7.0 ± 0.5 mg min⁻¹ kg⁻¹) and forearm glucose clearance (0.6 ± 0.1 vs 1.4 ± 0.4 mL 100 mL⁻¹⋅min⁻¹) were diminished in FDR compared with CON (all P < .05). FDR demonstrated endothelial dysfunction of the resistance vessels in addition to impaired insulin-stimulated increase in bulk flow. Moreover, FDR demonstrated whole-body insulin resistance as well as decreased basal and insulin-stimulated forearm glucose uptake. It remains to be established whether FDR also demonstrate impaired insulin-stimulated microvascular function.     

2型糖尿病一级亲与非一级亲冠状动脉病变程度的比较

两组的冠心病确诊率及Gensini评分亦无显著差异.结论 2型糖尿病一级亲在发生糖尿病前即表现出胰岛素敏感性降低,冠心病发生率升高和冠状动脉病变程度的加重,提示糖尿病一级亲不仅是冠心病的高危人群,而且有必要在早期就进行冠心病的筛查和预防.     

2型糖尿病患者一级亲属胰岛素抵抗与体重关系的研究

目的探讨2型糖尿病一级亲属胰岛素抵抗与体重的关系。方法2007年10月至2008年10月就诊于中国医科大学附属盛京医院的沈阳地区2型糖尿病患者,经知情同意后,选择其一级亲属(父母、同胞、子女)25例,根据75gOGTT试验分为正常糖耐量(FNGT)组、糖耐量减低(FIGT)组,另外选取性别、年龄与之相匹配,无糖尿病家族史的正常糖耐量12名为对照(NC)组,以正糖高胰岛素钳夹试验求得葡萄糖输注速率(GIR),比较3组间胰岛素敏感性的差异。结果FIGT组、FNGT组、NC组BMI依次为27.28±0.68、25.99±0.98和24.12±0.71,FIGT组明显高于NC组(P0.01),与FNGT组相比差异无统计学意义(P=0.11);FIGT组和FNGT组葡萄糖输注率分别为5.20±0.38和6.38±0.79,均明显低于NC组(9.83±0.86)(P0.01);葡萄糖输注率与BMI的相关系数为0.477(P0.01);多元逐步回归分析显示,BMI、糖尿病家族史均为影响胰岛素抵抗的显著因素(校正r2分别为0.39和0.21,P0.01)。结论2型糖尿病一级亲属不论血糖是否正常均存在胰岛素抵抗,此抵抗和家族史显著相关,独立于肥胖之外。     

2型糖尿病家系中患者与一级亲属血脂异常紊乱的研究

目的 探讨2型糖尿病（T2DM）家系人群中患者与一级亲属血脂紊乱异常类型、聚集程度的差异及血脂紊乱的影响因素。方法 对351例T2DM患者和300例非糖尿病一级亲属按血脂指标异常的项目数分为5组，并将血脂紊乱分为8种类型。比较家系两组人群异常血脂指标聚集性和血脂紊乱类型。在糖尿病患者中以血脂正常者为对照组，用Logistic回归分析年龄、体脂等和血脂的关系。结果 家系两组人群中的血脂紊乱类型的差异无统计学意义（x^2=4．294，P=0．7451），但患者组血脂紊乱的比例高于未患糖尿病亲属组（72．6％vs．57．7％，x^2=16．123，P=0．0000）。多因素分析发现年龄与TG的升高和HDL的降低有关，腰臀比的增大与TG有关[Exp（B）=1．799，P=0．012]。结论 糖尿病患者中存在异常血脂指标的聚集，但患者与其亲属的血脂紊乱类型相似。糖尿病患者腹部体脂的增加与总胆固醇水平有关。     

1型糖尿病一级亲属胰岛自身抗体与HLA-DQ基因型的关系

目的探讨1型糖尿病一级亲属谷氨酸脱羧酶抗体（GADA）、蛋白酪氨酸磷酸酶抗体（IA-2A）、胰岛素自身抗体（IAA）与HLA—DQ基因型之间的关系。方法横断面、病例对照研究。采用放射配体法检测351例糖耐量正常的1型糖尿病一级亲属与376名正常对照者GADA、IA-2A与IAA。其中156例自身免疫1型糖尿病一级亲属与278名正常对照采用PCR-直接测序法明确HLA-DQ基因型。结果（1）与正常对照比较，1型糖尿病一级亲属DQA1＊03、DQB1＊0303、＊0401等位基因与DQA1＊03-DQBl＊0303、DQA1＊05-DQB1＊0201、DQA1＊03-DQB1＊0401单体型频率增高（均P〈0．05或P〈0．01），而DQA1＊0601、＊0201和DQB1＊0301、＊0602等位基因与DQA1＊0102-DQB1＊0602单体型频率减少（均P〈0．05或P〈0．01）。（2）与1型糖尿病患者比较，1型糖尿病一级亲属DQA1＊03等位基因频率减少（45．8％vs54．5％，P〈0．05）。（3）携带DQA1＊03-DQB1＊0303单体型者，GADA、IA-2A与IAA任一自身抗体阳性率高于不携带此单体型者（23．0％们8．6％，P〈0．05）。结论携带DQA1＊03-DQB1＊0303单体型的一级亲属，GADA、IA-2A与IAA任一自身抗体检出率最高。     

LADA和2型糖尿病一级亲属胰岛β细胞功能的变化

目的 探讨成人隐匿性自身免疫性糖尿病（LADA）和2型糖尿病（T2DM）一级亲属胰岛β细胞功能的变化。方法 对24例健康对照（NC）、28例谷氨酸脱羧酶抗体（GAD-Ab）阳性LADA一级亲属、14例羧基肽酶H抗体（CPH—Ab）阳性LADA一级亲属，15例T2DM一级亲属行纳格列奈-OGTT，比较其反映B细胞功能的相关指标。结果 ①GAD-Ab阳性LADA一级亲属的胰岛素释放峰值、30min时的△I／△G、IRR、MVI、AUCIns较NC组降低（P〈0．05～0．01）；其HOMA—IR高于NC组（P〈0．05）；②T2DM一级亲属组的HOMA—IR高于NC组（P〈0．05）；③LADA一级亲属组中抗体阳性者的胰岛素释放峰值、30min时的△I／△G、IRR及MVI较阴性者降低更明显；后者的HOMA—IR大于NC组（P〈0．05）。结论 LADA一级亲属存在明显的早期相胰岛分泌与储备功能减退及IR，其中抗体阳性者以胰岛分泌功能缺陷为主伴IR，抗体阴性者以IR为主伴胰岛分泌功能缺陷；T2DM一级亲属存在明显的IR。     

2 型糖尿病患者一级亲属脂联素测定及其意义

观察胰岛素抵抗程度、脂联素及肿瘤坏死因子α（TNF-α）在2型糖尿病的非糖尿病一级亲属和无糖尿病家族史的对照之间的区别，发现一级亲属较对照组的HOMA-IR为高，但两组间脂联素、TNF-α水平差异无统计学意义。多元逐步回归分析显示BMI是影响脂联素的独立因子。     

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.     

Insulin action and secretion in healthy Hispanic-Mexican first-degree relatives of subjects with type 2 diabetes.

The aim of this study was to assess the early insulin secretion and insulin action of healthy non-diabetic Hispanic-Mexican subjects with and without family history of Type 2 diabetes (FHD). One hundred and twenty non-relative subjects were compared against 115 first-degree relatives of individuals with Type 2 diabetes. To assign the subjects to the correspondent group, the FHD was carefully ascertained by clinical examination of the participants' parents. Age and gender were matched criteria. Incomplete or unclear data about FHD, previous diagnosis of diabetes or chronic diseases were exclusion criteria. Subjects in both groups were required to have fasting glucose <6.1 mmol/l, and 2-h PG<7.7 mmol/l. Insulin action and secretion were estimated by HOMA (homeostasis model insulin analysis resistance index) and insulinogenic index, respectively. Logistic regression analysis showed an independent relationship between BMI and insulin resistance (HOMA score >5.0) (odds ratio, OR, 1.42, p=0.03), and between FHD and insulin resistance (OR 1.27, p=0.04). On the other hand, there was a strong and independent relationship between FHD and high early insulin secretion (insulinogenic index >0.72) (OR 1.64, p=0.01) but not between BMI and high early insulin secretion (OR 0.93, p=0.3). Healthy Mexican first-degree relatives of subjects with Type 2 diabetes show an independent relationship between FHD and both high early insulin response and decreased insulin action, whereas BMI was only related to insulin resistance.