Low adiponectin level in young normotensive men with a family history of essential hypertension.

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, nonobese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.     

A family history of Type 2 diabetes is associated with increased plasma levels of C-reactive protein in non-smoking healthy adult women.

AIMS: The aim of our study was to test whether a family history of Type 2 diabetes (FH) in women is associated with plasma C-reactive protein (CRP). METHODS: CRP plasma levels were measured in 162 women, aged 18-60 years; 95 had a positive family history of Type 2 diabetes in a parent or grandparent (FH+), and 67 gave no family history of this disease (FH-). Other measurements included: central fat accumulation, as evaluated by waist circumference; insulin resistance, as calculated by homeostatic model assessment (HOMAIR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. RESULTS: CRP plasma levels were significantly higher in FH+ than in FH- subjects. Moreover, CRP was independently associated with age, body mass index, waist circumference, HOMAIR, and FH. CONCLUSIONS: Our study, performed in a selected population of women free from well-known risk factors for atherothrombosis, demonstrates that subjects with a family history of Type 2 diabetes have higher CRP plasma levels than age- and BMI-matched controls with no family history. Our results show that a family history of Type 2 diabetes is an independent contributor of CRP concentrations, in addition to age, total fatness, central fat accumulation, and insulin resistance.     

Decreased tyrosine kinase activity in partially purified insulin receptors from muscle of young,non-obese first degree relatives of patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary Recently, we demonstrated insulin resistance due to reduced glucose storage in young relatives of Type 2 diabetic patients. To investigate whether this was associated with a defective insulin receptor kinase, we studied ten of these young (27±1 years old) non-obese glucose tolerant first degree relatives of patients with Type 2 diabetes and eight matched control subjects with no family history of diabetes. Insulin sensitivity was assessed by a hyperinsulinaemic, euglycaemic clamp. Insulin receptors were partially purified from muscle biopsies obtained in the basal and the insulin-stimulated state during the clamp. Insulin binding capacity was decreased by 28% in the relatives (p<0.05) in the basal biopsy. Tyrosine kinase activity in the receptor preparation was decreased by 50% in both basal and insulin-stimulated biopsies from the relatives. After stimulation with insulin in vitro, kinase activity was reduced in the relatives in basal (p<0.005) and insulin-stimulated (p<0.01) biopsies and also when expressed per insulin binding capacity (p0.05). Insulin stimulation of non-oxidative glucose metabolism correlated with in vitro insulin-stimulated tyrosine kinase activity (r=0.61, p<0.01) and also when expressed per binding capacity (r=0.53, p<0.025). We suggest that the marked defect in tyrosine kinase activity in partially purified insulin receptors from skeletal muscle is an early event in the development of insulin resistance and contributes to the pathophysiology of Type 2 diabetes.     

Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin-dependent) diabetic patients

Summary Insulin resistance is a common feature of Type 2 (non-insulin-dependent) diabetes mellitus. This defect in insulin-mediated glucose metabolism could result from a defect in either glucose oxidation or non-oxidative glucose disposal. To examine this question, euglycaemic insulin clamp studies were performed in 16 normal weight Type 2 and 11 age-matched control subjects. In Type 2 diabetic patients the fasting plasma glucose concentration, 8.39±0.50 mmol/l, was allowed to decline (over 54±6 min) to 5.33±0.11 mmol/l before starting the insulin clamp. Total body glucose uptake was significantly decreased in Type 2 diabetic patients vs control subjects (148±15 vs 264±25 mg/min · m², p<0.001). Both total glucose oxidation (59±6 vs 89±6 mg/min·m², p<0.005) and non-oxidative glucose disposal (89±15 vs 179±24 mg/min · m², p<0.005) were significantly reduced in the Type 2 diabetic patients. Basal glucose oxidation was also reduced in the Type 2 diabetic patients (22±3 vs 38±5 mg/min·m², p<0.01). In conclusion, during the postabsorptive state and under conditions of euglycaemic hyperinsulinaemia, impairment of glucose oxidation and non-oxidative glucose disposal both contribute to the insulin resistance observed in normal weight Type 2 diabetic patients. Since lipid oxidation was normal in this group of diabetic patients, excessive non-esterified fatty acid oxidation cannot explain the defects in glucose disposal.     

Metabolic rate and vascular function are reduced in women with a family history of type 2 diabetes mellitus

Metabolic and vascular abnormalities have been found in individuals with type 2 diabetes mellitus (T2D). Family history is often associated with increased risk of the development of T2D. We sought to determine if young, sedentary, insulin-sensitive individuals with a family history of T2D (FH+) have a reduced resting energy expenditure (REE) and vascular endothelial function compared with individuals who have no family history of T2D (FH-). The REE was determined in 18 FH+ individuals and 15 FH- individuals using indirect open-circuit calorimetry. Vascular endothelial function was measured via flow-mediated dilation (FMD) of the brachial artery. C-reactive protein and interleukin-6 were also measured to look at vascular inflammation. Body composition was measured via bioelectrical impedance analysis to determine fat-free mass and fat mass for each individual. Insulin resistance was calculated using the homeostasis model assessment equation and fasting insulin and glucose concentrations. Subjects (n = 42) were approximately 26 years old and had normal fasting serum insulin or glucose concentrations. The REE normalized for body weight (kilocalories per day per kilogram body weight) was significantly reduced in the FH+ women compared with FH- women (P < .001) but not in the men. The FMD was significantly reduced (34.3%) in the FH+ group compared with the FH- in women (P = .002). However, no between-group difference in FMD was present in male subjects (P = .376). Young, healthy, insulin-sensitive women with a family history of T2D have reduced whole-body metabolic rate and vascular endothelial function compared with those with no family history of disease. These differences in whole-body metabolic rate and vascular endothelial function were not present in male subjects.     

Family history of diabetes is a major determinant of endothelial function.

OBJECTIVES: We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND: Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. METHODS: Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH-). RESULTS: Although fasting glucose was higher in FH+ than FH- (5.3 +/- 0.1 mmol/l vs. 4.9 +/- 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 +/- 0.9% vs. 11.7 +/- 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH- (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04). CONCLUSIONS: Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.     

Family history of diabetes impacts on interactions between minimal model estimates of insulin sensitivity and glucose effectiveness

Aims/hypothesis: Insulin resistance and glucose effectiveness (S_G) are major determinants of glucose tolerance and independently predict the development of type 2 diabetes in individuals with a family history of disease. We examined the inter‐relationship between insulin sensitivity (S_I) and S_G in offspring of two parents with type 2 diabetes and in individuals with no family history of diabetes. Methods: Fifty non‐diabetic individuals, including 26 offspring of two type 2 diabetic parents (family history, FH+) and 24 with no family history of diabetes (FH?) similar in gender, age, ethnicity and body mass index (BMI) were studied. Each subject underwent a 100‐g oral glucose tolerance test (OGTT) and insulin modified frequently sampled intravenous glucose tolerance, analysed using the Bergman’s minimal model (MINMOD). Results: Thirteen subjects of the FH+ group and nine of the FH? group had impaired glucose tolerance (IGT). S_I and S_G were independent variables in the FH+ group, while they correlated highly with each other in the FH? group (r = 0.69, p = 0.0002). The relationship between S_I and S_G persisted when analysing the IGT and normal glucose tolerance subgroups separately, demonstrating that these associations were not because of differences in glycaemia. Consistently, S_G strongly correlated with additional measures of insulin resistance only in the FH? group, including fasting insulin (r = 0.56, p = 0.004), homeostasis model assessment of insulin resistance (r = 0.57 p = 0.003) and BMI (r = 0.66, p = 0.0004). Conclusions: These results demonstrate that familial factors impart important physiological differences in the inter‐relationship between insulin‐dependent and insulin‐independent glucose disposal, which may be important in modulating risk for development of disease.     

Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S(I)) and low insulin-independent glucose effectiveness (S(G)) predict the development of diabetes one to two decades later. To determine whether low S(I), low S(G,) or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During 25 +/- 6 years follow-up, comprising 2,758 person years, the FH- cohort (54 +/- 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S(I) and S(G) derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low S(I) and low S(G). The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S(I), i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S(I) and low S(G), both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.     

2型糖尿病患者非糖尿病一级亲属的胰岛素抵抗出现先于β细胞功能缺陷

目的 研究2型糖尿病患者非糖尿病一级亲属的胰岛素抵抗和胰岛β细胞功能的变化.方法 选取2型糖尿病患者一级亲属23名,其中糖耐量正常者10名(NGT组),糖耐量受损者13名(IGT组).以无糖尿病家族史的糖耐量正常者9名(NC组)为对照.应用高胰岛素-正葡萄糖钳夹技术和静脉葡萄糖耐量试验评估胰岛素抵抗和胰岛β细胞功能.结果 NGT组和IGT组的葡萄糖输注率(mg·kg-1·min-1)分别为(7.04±0.62)和(6.16±0.73),与NC组(10.22±0.93)相比明显降低(均P＜0.05).NGT组的第一时相胰岛素分泌量(对数转换)高于IGT组(3.87±0.24 vs 3.03±0.28,P＜0.05),NC组为(3.37±0.30).NGT组(1.43±0.22)与NC组(1.18±0.41)的葡萄糖处置指数(对数转换)明显高于IGT组(0.32±0.20,P＜0.01或P＜0.05),NC组与NGT组之间差异无统计学意义.结论 2型糖尿病患者非糖尿病一级亲属已经存在胰岛素抵抗,当胰岛素分泌不能代偿抵抗时开始出现糖耐量减退.     

Different aetiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects

Summary Insulin responses to intravenous glucose infusion and glucose utilization during hyperinsulinaemic euglycaemic clamp were determined in a large homogeneous group of 65-year-old male subjects. Twenty-eight had untreated Type 2 (non-insulin-dependent) diabetes mellitus and the remaining 44 control subjects had a normal glucose tolerance. Diabetic patients with abdominal obesity displayed peripheral insulin resistance in combination with defective insulin secretion, whereas non-obese diabetic patients showed only a secretory defect. Thus, Type 2 diabetes in obese and non-obese elderly male subjects may take two forms where the cause of hyperglycaemia differs.     

The Impact of a Family History of Type 2 Diabetes on Insulin Secretion and Insulin Sensitivity in Individuals With Varying Glucose Tolerance

IntroductionThis study was performed to investigate the impact of a family history of type 2 diabetes (T2DM) on insulin resistance and beta-cell dysfunction in populations with varying glucose tolerance.MethodsAmong the total of 142 participants, 73 subjects with no family history of T2DM (FH?) included 42 with normal glucose tolerance (NGT/FH?) and 31 with impaired glucose tolerance (IGT/FH?); and 69 first-degree relatives of patients with T2DM (FH+) included 36 with NGT (NGT/FH+) and 33 with IGT (IGT/FH+). Insulin resistance was evaluated by Insulin Sensitivity Index (ISI) based on the euglycemic hyperinsulinemic clamp. Islet beta-cell function was assessed by disposition index (DI) for the acute insulin response to glucose (AIRg) using intravenous glucose tolerance test. Metabolic data were compared between groups after adjustment for age, sex, body mass index and waist-to-hip ratio.ResultsThe NGT/FH+ group showed lower level of ISI (P = 0.023) than the NGT/FH? group, whereas no difference was found in AIRg or DI between these 2 subgroups. In the FH? individuals, both ISI and DI of the IGT/FH? group decreased compared with the NGT/FH? group (both P < 0.05). In the FH+ individuals, no difference was found in ISI between the IGT/FH+ and NGT/FH+ groups, whereas the IGT/FH+ group had a lower level of AIRg and DI than the NGT/FH+ group (both P < 0.0001).ConclusionsThis study showed that the pathophysiological changes were different between individuals with and without a family history of T2DM during the glucose tolerance aggravation.     

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.     

高血压遗传史与胰岛素抵抗，高血压的关联

目的 探讨高血压遗传史对第二、三代直系亲属血压水平,胰岛素抵抗及致动脉粥样硬化危险因素的影响。方法 对象为高血压家族史阳性病例187人,高血压家族史阴性99人及他们的配偶子女286家858人,指标包括血压、血糖、总胆固醇、甘油三脂、高密胆固醇、纤维蛋白原、胰岛素敏感指数。结果 调整年龄、性别影响后,高血压家族史阳性第二代高血压、血压正常者之胰岛素敏感指数相似,但均相当于高血压家族史阴性第二代非高血压的2／3。高血压家族史阳性的第二代高血压,血压正常者组的FSG、TC、TG、FB均高于而HDL－c低于后者。第三代子女间血压、TC、TG、FSG、HDL－c趋势与第二代结果相似,但胰岛素敏感指数仅为家族史阴性组的4／5。结论 高血压遗传因素可影响第二代及第三代子女,不管遗传或不遗传高血压,但毫无例外地遗传胰岛素抵抗及相关的代谢,表明胰岛素抵抗是高血压遗传因素的主要内容;胰岛素抵抗是否产生高血压尚必须有其他辅助条件或环境因素。     

Non-oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise

Whole-body glucose utilization consists of mitochondrial glucose oxidation and non-oxidative glycogen synthesis. We examined whether reduction of both non-oxidative glucose disposal and glucose oxidation contributes to insulin resistance in type 2 diabetes. We also examined the effects of exercise on these two components. Whole-body glucose disposal rate (GDR, mg/kg/min) was evaluated in 37 type 2 diabetic (T2DM) and 17 non-diabetic (non-DM) subjects as the mean of glucose infusion rate during steady state in the euglycaemic–hyperinsulinaemic clamp study. Glucose oxidation rates were assessed by indirect calorimetry, and non-oxidative GDR was calculated by subtracting glucose oxidation rate from GDR. Intramyocellular lipid (IMCL) content of the soleus muscle was measured using ¹H-magnetic resonance spectroscopy. In 10 T2DM subjects, the changes in oxidative and non-oxidative glucose disposal during clamp were examined after 3-month exercise intervention. GDR (2.93 ± 1.55 vs. 4.55 ± 1.83, p = 0.001) and non-oxidative GDR (1.45 ± 1.52 vs. 3.01 ± 1.87, p = 0.002) were significantly lower in T2DM than in non-DM subjects. Glucose oxidation rate was comparable in the two groups, and inversely correlated with IMCL (n = 15, r =−0.565, p = 0.028). GDR (2.28 ± 1.67 to 4.63 ± 2.42, p = 0.021) and non-oxidative GDR (0.72 ± 1.27 to 2.26 ± 1.91, p = 0.047) were increased after exercise intervention, although the change in glucose oxidation rate was not significant. In summary, reduction of non-oxidative glucose disposal may contribute to decreased whole-body glucose utilization. In addition, exercise improves insulin resistance mainly by increasing non-oxidative glucose disposal in type 2 diabetes.     

左旋精氨酸刺激试验评价遗传背景对正常糖耐量者和初诊糖尿病患者胰岛β细胞功能的影响

目的 探讨遗传背景对左旋精氨酸(L-ARG)刺激后胰岛β细胞第一时相分泌功能的影响.方法 检测201例L-ARG刺激前后胰岛素值,其中有家族史初诊2型糖尿病患者(FH+DM)61例、无家族史初诊2型糖尿病患者(FH-DM)55例、有家族史正常糖耐量者(FH+)31例、无家族史正常糖耐量者(FH-)54例.以HOMA胰岛素抵抗指数(HOMA-IR)评价胰岛素抵抗.结果 校正性别、年龄、BMI后,(1)糖尿病组(FH+DM和FH-DM)TC、TG、空腹血浆血糖(FPG)、糖负荷后2 h血糖、空腹胰岛素(Fins)、HOMA-IR明显高于糖耐量正常组(FH+和FH-),胰岛素峰值倍数明显低于糖耐量正常组,P<0.05;(2)4组胰岛素均2 min达分泌峰值,4 min开始下降;(3)FH+组胰岛素峰值倍数较FH-组下降20.8%,分别为7.27与9.18倍,P<0.05;(4)FH+DM组2 min胰岛素分泌峰值、HOMA-IR、患病年龄明显低于FH-DM组(P<0.05),两组峰值倍数分别为5.18与5.31倍,差异无统计学意义(P>0.05);(5)FH+DM组胰岛素峰值倍数较FH-组下降了 43.6%(P<0.05).结论 2型糖尿病早期,尽管胰岛素抵抗表现不显著,遗传背景却使胰岛β细胞第一时相分泌功能减退;而无遗传背景者,胰岛素抵抗使胰岛素第一时相分泌下降相对缓慢.     

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training

Aims/hypothesis Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. Materials and methods Anthropometric parameters and maximum volume of oxygen utilisation (VO_2max) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic–euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. Results Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO_2max increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. Conclusions/interpretation Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention. N. Burns and F. M. Finucane contributed equally to this work.     

The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents

Family history is an important predictor of the cardiovascular risk factor cluster associated with insulin resistance. The dyslipidemia associated with insulin resistance may contribute to elevated blood pressure (BP). This study was undertaken to further explore the link between family history, dyslipidemia, and BP regulation. Twenty-three lean normal volunteers with a negative family history (FH-, n = 11) or positive family history (FH+, n = 12) of hypertension were evaluated under baseline conditions and during a 4-h infusion of intralipid and heparin (acute hyperlipidemia). Fasting blood was drawn for lipids including nonesterified fatty acids (NEFA). After 2 and 4 h of intralipid and heparin, blood was drawn for NEFA. The BP was measured at baseline and every 30 min after starting the intralipid and heparin infusion. Baseline triglycerides and very low density lipoprotein cholesterol concentrations were higher in FH+ than FH- subjects (P < .05). However, NEFA increased similarly in both groups during the infusion of intralipid and heparin. The BP and heart rate increased with acute hyperlipidemia in all subjects combined (P < .05). Despite the similar increase of NEFA, mean BP, pulse pressure, and pressure-rate product increased significantly in FH+ subjects but not in FH- volunteers with acute hyperlipidemia. Although systolic BP increased in both groups, the increase was greater in FH+ than in FH- volunteers during acute hyperlipidemia (14 +/- 2 v 10 +/- 2 mm Hg, P < .05). These results suggest that higher plasma lipids combined with a greater pressor response to hyperlipidemia may contribute to the development of high BP in subjects with a family history of hypertension.     

Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from Type 2 diabetic patients

Aims/hypothesis p38 mitogen activated protein kinase (MAPK) is generally thought to facilitate signal transduction to genomic, rather than metabolic responses. However, recent evidence implicates a role for p38 MAPK in the regulation of glucose transport; a site of insulin resistance in Type 2 diabetes. Thus we determined p38 MAPK protein expression and phosphorylation in skeletal muscle from Type 2 diabetic patients and non-diabetic subjects.Methods In vitro effects of insulin (120 nmol/l) or AICAR (1 mmol/l) on p38 MAPK expression and phosphorylation were determined in skeletal muscle from non-diabetic (n=6) and Type 2 diabetic (n=9) subjects.Results p38 MAPK protein expression was similar between Type 2 diabetic patients and non-diabetic subjects. Insulin exposure increased p38 MAPK phosphorylation in non-diabetic, but not in Type 2 diabetic patients. In contrast, basal phosphorylation of p38 MAPK was increased in skeletal muscle from Type 2 diabetic patients.Conclusion/interpretation Insulin increases p38 MAPK phosphorylation in skeletal muscle from non-diabetic subjects, but not in Type 2 diabetic patients. However, basal p38 MAPK phosphorylation is increased in skeletal muscle from Type 2 diabetic patients. Thus, aberrant p38 MAPK signalling might contribute to the pathogenesis of insulin resistance.Abbreviations AICAR 5-aminoimidazole-4-carboxamide ribonucleoside - AMPK 5-AMP activated protein kinase - ERK 1/2 extracellular regulated kinase - GIR glucose infusion rate - IRS-1 insulin receptor substrate 1 - MAPK mitogen-activated protein kinase - PI phosphatidylinositol - VO_2max maximal oxygen uptake     

Metabolic characteristics of autoimmune diabetes mellitus in adults

Summary It is still a matter of debate whether patients who develop islet-cell antibody positive autoimmune diabetes during adulthood represent slowly evolving Type 1 (insulindependent) diabetes mellitus or a separate subgroup of Type 2 (non-insulin-dependent) diabetes. To address this question, we measured C-peptide response to a test meal, and energy metabolism in the basal state and during a euglycaemic, hyperinsulinaemic clamp in (1) 29 patients with Type 2 diabetes; (2) 10 patients with autoimmune diabetes developing after the age of 40 years; (3) 11 patients with Type 1 diabetes and (4) 15 non-diabetic control subjects. While C-peptide response to a test meal was lacking in Type 1 diabetes and nearly normal in Type 2 diabetes, the C-peptide response in autoimmune diabetes was markedly reduced. Patients with Type 2 diabetes, autoimmune diabetes and Type 1 diabetes showed a 47%, 45% and 42%, respectively, reduction in the rate of non-oxidative glucose metabolism compared with control subjects (p<0.05-0.01). Similarly, patients with Type 2 diabetes (+52%), autoimmune diabetes (+27%) and Type 1 diabetes (+33%) presented with an enhanced basal rate of hepatic glucose production, which was less suppressed by insulin compared with healthy control subjects (p<0.01). However, patients with autoimmune diabetes derived more energy from oxidation of glucose and proteins and less energy from oxidation of lipids than patients with either Type 1 or Type 2 diabetes (p<0.05-0.01). In conclusion, patients who develop autoimmune diabetes during adulthood share the defects in hepatic glucose production and in non-oxidative glucose metabolism with both Type 1 and Type 2 diabetes. Oxidative energy metabolism in autoimmune diabetes, however, differs from that observed in Type 1 and Type 2 diabetes. Given the metabolic characteristics of these patients, it seems justified to consider autoimmune diabetes in adults as a subgroup of diabetes developing in adult age.     

Acute hyperglycemia rapidly suppresses endothelium-dependent arterial dilation in first-degree relatives of type 2 diabetic patients.

OBJECTIVE: Previous studies showed that endothelium-dependent arterial dilation is impaired in first-degree relatives of type 2 diabetes in the fasting state. In the present study, we examined whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading in this cohort. PATIENTS AND METHODS: This study included 32 normal glucose tolerant subjects. Of them, 17 with a family history (FH) of type 2 diabetic parents (FH+) and 15 with no first-degree relative with diabetes or coronary artery disease (FH-). The examination of vascular function was performed in fasting state and repeated 1 and 2 hours after a 75-g oral glucose loading by high resolution ultrasound. RESULTS: Endothelium- dependent arterial dilation in FH+ group were significantly lower than those in FH- before and after oral glucose loading (5.12+/-0.61% vs 6.03+/-0.56%, fasting; 4.0+/-0.65% vs 5.70+/-0.42%, 1 h; 4.43+/-0.61% vs 5.82+/-0.67% 2 h, p<0.05 each). In FH+ group, endothelium-dependent arterial dilation decreased significantly at 60 min (4.0+/-0.65% vs 5.12+/-0.61%, p<0.01) and increased markedly from 60 min at 120 min (4.43+/-0.61% vs 4.0+/-0.65%, p<0.05), which was still significantly lower than baseline (4.43+/-0.61% vs 5.12+/-0.61%, p<0.01) . In FH- group, however, the arterial dilation did not differ significantly among the three time points (p 0.05). In multiple regression analysis, endothelium-dependent arterial dilation was significantly correlated to FH+(r=-0.302, p<0.01). In addition, endothelium-dependent arterial dilation showed a correlation with plasma glucose (r=-0.460, p<0.01) and TBARS (r=-0.382, p<0.01) during OGTT in FH+ subjects. CONCLUSION: Significant endothelial dysfunction is present in the fasting state, hyperglycemia in response to oral glucose loading rapidly suppresses endothelium-dependent arterial dilation in FH+ subjects, probably through increased production of oxygen-derived free radicals.