The Leu7Pro polymorphism of preproNPY is associated with decreased insulin secretion, delayed ghrelin suppression, and increased cardiovascular responsiveness to norepinephrine during oral glucose tolerance test

CONTEXT: Neuropeptide Y (NPY) plays a role in angiogenesis, cardiovascular regulation, and hormone secretion. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY is associated with vascular diseases and has an impact on hormone levels in healthy subjects. OBJECTIVE: The current study investigated the role of the Leu7Pro polymorphism in metabolic and cardiovascular autonomic regulation. DESIGN AND SUBJECTS: A 5-h oral glucose tolerance test was performed on 27 healthy volunteers representing two preproNPY genotypes (Leu7/Pro7 and Leu7/Leu7) matched for age, sex, body mass index and physical activity. MAIN OUTCOME MEASURES: Simultaneously we performed cardiovascular autonomic function tests and plasma measurements of sympathetic transmitters, glucose, insulin, and ghrelin. RESULTS: The subjects with Leu7/Pro7 genotype had decreased plasma NPY, norepinephrine (NE), and insulin concentrations and insulin to glucose ratios. The suppression of ghrelin concentrations after glucose ingestion was delayed in these subjects. They also had increased heart rate variability indices and baroreflex sensitivity. However, they displayed significant negative association of NE concentration with variability of low-frequency R-R-intervals and with baroreflex sensitivity. CONCLUSIONS: The Leu7Pro polymorphism of preproNPY is related to decreased level of basal sympathetic activity, decreased insulin secretion, and delayed ghrelin suppression during oral glucose tolerance test. The increased responsiveness of autonomic functions to NE associated with the polymorphism may be connected to increased cardiovascular vulnerability.     

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.     

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.     

Insulin secretion after short- and long-term low-grade free fatty acid infusion in men with increased risk of developing type 2 diabetes

We studied the effect of a low-grade short- and long-term 20% Intralipid infusion (0.4 mL(-1) x kg(-1) x h(-1)) on insulin secretion and insulin action in 15 elderly obese men; 7 glucose intolerant first-degree relatives of type 2 diabetic patients (impaired glucose tolerance [IGT] relatives) and 8 healthy controls of similar age and body mass index (BMI). Intravenous glucose tolerance test (IVGTT) and a graded glucose infusion (dose-response test [DORE]) were performed to determine first phase insulin response and to explore the dose response relationship between glucose concentration and insulin secretion rates (ISR). ISR were calculated by deconvolution of plasma C-peptide concentrations. Insulin action was determined by performing a 120-minute hyperinsulinemic euglycemic clamp. All tests were performed 3 times, preceded by 0, 2, or 24 hours Intralipid infusion. Disposition indices (DI) were calculated for the IVGTT. Insulin action was reduced 25% after 2 and 24 hours Intralipid infusion in both groups. In IGT relatives, the beta-cell responsiveness to glucose (measured during DORE) decreased after 2 and 24 hours Intralipid infusion (P=.02), whereas first phase insulin response (measured during IVGTT) decreased after 24 hours Intralipid infusion. Insulin secretion measured during DORE and IVGTT was not affected by Intralipid infusion in controls. DI decreased after 2 and 24 hours Intralipid infusion in the total study population. In conclusion, insulin resistance induced by low-grade short- and long-term Intralipid infusion is not balanced by an adequate compensatory increase in insulin secretion in IGT relatives or in matched controls. IGT relatives appear to be more sensitive to the deleterious effects of low-grade fat infusion on insulin secretion than normal glucose tolerant control subjects.     

Exenatide 对高脂诱导胰岛素抵抗大鼠胰岛素敏感性及糖脂代谢的影响

目的 探讨Exenatide对高脂诱导胰岛素抵抗大鼠胰岛β细胞功能、胰岛素敏感性及糖脂代谢的影响. 方法 高脂诱导胰岛素抵抗大鼠给予Exenatide 6周后,采用静脉葡萄糖耐量(IVGTT)和胰岛素耐量(ITT)试验以及扩展胰岛素钳夹技术测定胰岛素敏感性和糖脂代谢,并观察血浆脂联素水平的变化.结果 高脂大鼠(HF)经Exenatide处理后,Lee′s指数、空腹血浆游离脂肪酸(FFA)、甘油三酯、胆固醇明显降低(均P＜0.01);IVGTT和ITT明显改善,胰岛素分泌水平增高,高剂量组(HFH)较低剂量组(HFL)上述指标改善更为明显.同时,HFH组血浆脂联素水平也明显升高(P＜0.01).在钳夹稳态时,HF组与对照组(NC)相比,血浆FFA、胰岛素水平均明显升高(均P＜0.01),葡萄糖输注率(GIR)、葡萄糖清除率(GRd)明显降低(均P＜0.01),且胰岛素对肝糖输出(HGP)的抑制作用明显障碍(仅抑制26%).经Exenatide(2 μg/kg)处理以后,血浆FFA、胰岛素水平则明显降低(均P＜0.01),GRd、GIR明显升高(均P＜0.01),胰岛素对HGP的抑制作用明显增强(抑制72%).结论 对高脂喂养大鼠用Exenatide预处理可能通过促进β细胞胰岛素分泌和上调血浆脂联素水平,改善糖脂代谢而使机体胰岛素敏感性增加.     

Improvement in glucose tolerance as a result of enhanced insulin sensitivity during electroacupuncture in spontaneously diabetic Goto-Kakizaki rats

We studied whether electroacupuncture (EA) applied on the abdomen improved glucose tolerance in the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes mellitus. Male GK rats and nondiabetic Wistar rats were studied under pentobarbital anesthesia. Blood samples were drawn from the ventral tail artery during the fasting stage and after a glucose load (0.5 g/kg). Electroacupuncture (15 Hz, 10 mA) was performed for 90 minutes during both the fasting and intravenous glucose tolerance test (IVGTT) periods. A hyperinsulinemic euglycemic clamp was also carried out to assess glucose uptake during EA. A significant decrease in fasting blood glucose and an increase in plasma insulin levels were observed during the fasting period in GK rats treated with EA. Blood glucose levels after glucose load were also significantly lower in GK rats treated with EA compared with controls. The homeostasis model assessment index during IVGTT indicated an improvement in insulin sensitivity in GK rats treated with EA, whereas glucose infusion rate during hyperinsulinemic clamp was increased significantly during EA. The present study demonstrated that EA improved hyperglycemia in the fasting stage with a marked increase in plasma insulin levels. Electroacupuncture also restored impaired glucose tolerance during an IVGTT in GK rats by enhancing insulin sensitivity.     

Plasma neuropeptide Y in impaired glucose tolerance

Neuropeptide Y (NPY) has been shown to be associated with insulin resistance, since central administration of the peptide induces muscular insulin resistance. NPY also occurs in pancreatic nerves and inhibits insulin secretion. In this study, we examined the plasma NPY levels in 10 women, aged 57–59 years, with impaired glucose tolerance (IGT), which is often accompanied by a combination of reduced insulin sensitivity and impaired insulin secretion. They were 145±4.1 pmol/l compared with 143±4.3 pmol/l in 10 age-matched women with normal glucose tolerance (NGT) (NS). Furthermore, the plasma NPY did not correlate with fasting glucose or insulin levels, the 2-h glucose value after a 75 g oral glucose challenge or insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique. This suggests that plasma NPY is not altered in IGT.     

Impact of the Leu7Pro polymorphism of preproNPY on diurnal NPY and hormone secretion in type 2 diabetes.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that plays a role in e.g. circulation, hormone release and angiogenesis. Earlier studies have shown that the Leucine 7 to Proline 7 (Leu7Pro) polymorphism of preproNPY is associated with increased risk for vascular complications in type 2 diabetes. The mechanism for this maybe altered transmitter and hormone levels or altered cardiovascular functions, which have been observed in healthy subjects having the Leu7Pro polymorphism. The current study was undertaken to explore if the Leu7Pro polymorphism has an impact on these functions in subjects with type 2 diabetes. Diurnal measurements were performed for Finnish Caucasian type 2 diabetes patients of two preproNPY genotypes (matched by sex, age, BMI, duration of diabetes and HbA1c) in resting position to prevent sympathetic stimulation. Standard meals were offered during the 24-hour study period. Nine subjects with the Leu7Pro polymorphism and ten subjects without this polymorphism were studied. Plasma concentrations of NPY, glucose, insulin, cortisol, prolactin and leptin were measured by taking blood samples at 20 time points (from 8 a.m. to 8 a.m.). Heart rate and blood pressure were measured at the same time points. The results show that NPY concentrations were similar in both preproNPY genotypes. Glucose, insulin, cortisol and leptin concentrations as well as heart rate and blood pressure were also similar. However, a significant difference between genotypes was found in the association of NPY concentrations with cortisol concentrations (p for difference=0.002). Also a statistically significant negative association of plasma NPY levels with plasma glucose levels was found in both genotypes. Since no impact of preproNPY genotype on mean NPY or hormone levels were detected in subjects with type 2 diabetes, the mechanisms for the increased risk for diabetic complications in the subjects with the Leu7Pro polymorphism need to be further explored.     

Skeletal muscle magnesium content is correlated with plasma glucose concentration in patients with essential hypertension treated with lisinopril or bendrofluazide

The association between change in glucose metabolism and change in skeletal muscle magnesium (Mg) concentration induced by antihypertensive treatment was evaluated in 37 patients with essential hypertension randomly treated with either lisinopril or bendrofluazide. Before and after 6 months of treatment, skeletal muscle biopsies were performed, glucose tolerance was determined by oral (OGTT) and intravenous glucose tolerance tests (IVGTT), and insulin sensitivity was assessed by the hyperinsulinemic euglycemic clamp technique. An inverse relationship was found between the treatment-induced change in fasting plasma glucose concentration and change in skeletal muscle Mg concentration (r = -0.39, P < .05). However, there was no significant correlation between skeletal muscle Mg content and either insulin sensitivity measured by the hyperinsulinemic euglycemic clamp test or glucose tolerance evaluated by IVGTT and OGTT. In conclusion, an increased circulating glucose concentration was correlated with a decreased Mg concentration in skeletal muscle during antihypertensive treatment. However, the Mg concentration in skeletal muscle did not significantly predict the insulin sensitivity or glucose tolerance.     

Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY.

The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of NPY is associated with high blood lipid concentrations and accelerated rate of atherosclerosis as well as diabetic retinopathy. Also, healthy subjects with this polymorphism have increased NPY secretion during sympathetic stimulation. Because NPY may regulate GH release and ghrelin may regulate NPY formation, we studied the effects of the Leu7/Pro7 genotype on GH, ghrelin, and IGF-I secretion during standardized cycle-ergometer exercise. Furthermore, we studied the effect of the Leu7/Pro7 genotype on diurnal GH secretion in rest in a separate study. The subjects with Leu7/Pro7 genotype had 54% higher maximal increases in the plasma GH concentrations than the controls during exercise. There were no significant differences in the ghrelin or IGF-I concentrations during exercise among the groups. Furthermore, there were no differences in diurnal GH secretion between the genotypes. The results indicate that the prepro-NPY genotype has an influence on GH response during exercise in humans. The clinical significance of this finding is not known, and further studies are needed to evaluate whether the observed change in GH secretion during exercise could play a role in promoting diseases.     

A simple method for quantitation of insulin sensitivity and insulin release from an intravenous glucose tolerance test.

Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)     

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

Aims/hypothesis

WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion.

Methods

A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40?±?13 years, BMI 28.9?±?8.2 kg/m² [mean ± SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n?=?319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n?=?102).

Results

rs10010131 was associated with reduced OGTT-derived insulin secretion (p?=?0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p?=?0.007 and p?=?0.04, respectively).

Conclusions/interpretation

A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.     

On the interplay beween insulin secretion and sensitivity as determinants of glucose tolerance

Both insulin secretion and sensitivity have been claimed to be the main characteristics in the determination of future detoriation in glucose tolerance. In this cross-sectional study insulin secretion and insulin sensiturity were determined in 228 subjects with varying degrees of glucose tolerance. Insulin secretion was measured in an intravenous glucose tolerance test (IVGTT) and insulin sensitivity by the hyperinsulinaemic euglycaemic clamp test. Both the early insulin response in the IVGTT (increment) and the glucose disposal rate in the clamp test (M-value) were found to be related hyperbolically to fasting glucose (r=–0.63 and –0.66, respectively; bothP<0.0001) and in a second-order polynomial manner to the glucose disappearence rate (k-value) in the IVGTT (r=0.53 and 0.48, respectively; bothP<0.0001). Multiple regression analysis showed the insulin increment in the IVGTT and theM-value in the clamp test to be equally important determinants of glucose tolerance, together explaining about 50% of the variation in fasting glucose and thek-value in the IVGTT. In conclusion, in this cross-sectional study insulin secretion and sensitivity studied over a broad range of glucose tolerance were found to be of amost equal importance in the determination of glucose tolerance. However, low levels of insulin increment in the IVGTT were more often associated with glucose intolerance than was a low insulin sensitivity.     

Changes in diurnal sympathoadrenal balance and pituitary hormone secretion in subjects with Leu7Pro polymorphism in the prepro-neuropeptide Y

Neuropeptide Y (NPY) is an important neurotransmitter in the central and peripheral nervous systems. It has a regulatory role in cardiovascular and metabolic functions and control of hormone release. The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of prepro-NPY is associated with increased blood lipid levels, accelerated atherosclerosis, and diabetic retinopathy. This study elucidated the role of this polymorphism in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. The two study groups comprised individuals with different genotype, but they were matched for age and body mass index. Subjects with the Leu7Pro polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with Leu7Pro polymorphism. Furthermore, these subjects had significantly lower prolactin concentrations in plasma. Systolic and diastolic blood pressure, serum free fatty acid and plasma leptin, ACTH, cortisol, LH, FSH, TSH, free thyroxin, and melatonin concentrations were similar during the 24-h period, compared with controls. These results show that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.     

Inhibition of the rise in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-deficient adults.

To test the hypothesis that GH-induced insulin resistance is mediated by an increase in FFA levels we assessed insulin sensitivity after inhibiting the increase in FFA by a nicotine acid derivative, Acipimox, in nine GH-deficient adults receiving GH replacement therapy. The patients received in a double blind fashion either Acipimox (500 mg) or placebo before a 2-h euglycemic (plasma glucose, 5.5 +/- 0.2 mmol/liter) hyperinsulinemic (serum insulin, 28.7 +/- 6.3 mU/liter) clamp in combination with indirect calorimetry and infusion of [3-(3)H]glucose. Acipimox decreased fasting FFA by 88% (P = 0.012) and basal lipid oxidation by 39% (P = 0.015) compared with placebo. In addition, the insulin-stimulated lipid oxidation was 31% (P = 0.0077) lower during Acipimox than during placebo. Acipimox increased insulin-stimulated total glucose uptake by 36% (P = 0.021) compared with placebo, which mainly was due to a 47% (P = 0.015) increase in glucose oxidation. GH induced insulin resistance is partially prevented by inhibition of lipolysis by Acipimox.     

TNF—α诱导的胰岛素抵抗小鼠胰岛素敏感性及糖脂代谢的变化

目的探讨TNF-α诱导的胰岛素抵抗（IR）小鼠胰岛素敏感性及糖脂代谢的变化。方法23只健康雄性C57BL／6J小鼠随机分为4组：高剂量（H）组、中剂量（M）组、低剂量（L）组分别给予腹腔注射6、3、1μg·kg^-1·d^-1的TNF-α，正常对照（NC）组注射等体积的生理盐水，共7天。采用静脉葡萄糖耐量试验（IVGTT）和3-[^3H]葡萄糖为示踪剂的扩展胰岛素钳夹技术，评价小鼠胰岛素敏感性和糖脂代谢的变化。结果TNF-α处理后，小鼠FBG、血浆胰岛素（Ins）和FFA水平均增高，且H组明显高于NC、M和L组。IVGTT结果显示H组糖耐量减低，Ins释放水平明显高于其他组。在胰岛素钳夹术中，H组基础葡萄糖清除率（GDR）和肝糖输出率（HGP）明显高于NC组（P＜50.01）。在钳夹稳态时，H组血浆Ins水平明显高于NC组（P＜0.01），Ins对FFA的抑制作用较NC组明显降低（P＜0.01），H组葡萄糖输注率（GIR）明显低于NC组（P＜0.01）；钳夹稳态时小鼠GDR明显增加，但H组GDR的增加仍明显低于NC组（P＜0.01）；钳夹结束时，NC组HGP被完全抑制，而H组仅被抑制59％。结论高剂量TNF-α（6μg·kg^-1·d^-1）处理可导致小鼠糖脂代谢紊乱以及肝和外周组织的球。     

Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial

Aims/hypothesis

The combined IVGTT–hyperinsulinaemic–euglycaemic clamp (Botnia clamp) allows the assessment of insulin secretion and sensitivity in one experiment. It remains unclear whether this clamp yields results comparable with those of the standard hyperinsulinaemic–euglycaemic clamp (SHEC) in diabetes patients. We hypothesised that the IVGTT induces responses affecting insulin sensitivity assessment.

Methods

Of 22 randomised diet- or metformin-treated patients with well-controlled type 2 diabetes, 19 randomly underwent a Botnia clamp and an SHEC, spaced by 2 weeks, in one clinical research centre in a crossover study. The main outcomes were whole-body and hepatic insulin sensitivity as measured by the clamp and [6,6-²H₂]glucose. Substrate utilisation was assessed from indirect calorimetry and beta cell function from insulin dynamics during IVGTT.

Results

The values of whole-body insulin sensitivity obtained from Botnia clamp and SHEC were correlated (r?=?0.87, p??1 min^?1 (Botnia and SHEC, p??1 min^?1 (p?NEFA (r?=??0.60, p?r?=??0.16, p?=?0.52) or hepatic insulin sensitivity between IVGTT and placebo before the clamps correlated with individual variations of insulin sensitivity.

Conclusions/interpretation

The Botnia clamp provides similar estimates of insulin sensitivity as SHEC in patients with type 2 diabetes, but changes in NEFA during IVGTT may affect insulin sensitivity and thereby the discrimination between insulin-sensitive and insulin-resistant individuals. Trial registration: ClinicalTrials.gov NCT01397279 Funding: The study was funded by the Ministry of Science and Research of the State of North Rhine-Westphalia and the German Federal Ministry of Health, and supported in part by grants from the Federal Ministry for Research to the Centers for Diabetes Research, Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases and the Schmutzler-Stiftung.     

Associations between circulating free fatty acids, visceral adipose tissue accumulation, and insulin sensitivity in postmenopausal women

The aims of the study were to evaluate the contribution of visceral adipose tissue (AT) accumulation and insulin sensitivity to the determination of circulating free fatty acid (FFA) concentrations measured during a 2-hour euglycemic-hyperinsulinemic clamp and to verify whether elevated FFAs are associated with other components of the metabolic syndrome in postmenopausal women. This cross-sectional study included 115 postmenopausal women (46-68 years old). Visceral AT was estimated by computed tomography. Insulin sensitivity was assessed by a 2-hour euglycemic-hyperinsulinemic clamp. Free fatty acid concentration was measured in the fasting state and every 30 minutes during the clamp. Fasting plasma glucose and 2-hour plasma glucose were measured by an oral glucose tolerance test. Visceral AT was associated positively and insulin sensitivity negatively with FFA area under the curve (AUC) measured during the clamp. Women with high visceral AT accumulation and low insulin sensitivity had higher FFA AUC than women with high visceral AT accumulation and high insulin sensitivity or women with low visceral AT combined with either low or high insulin sensitivity. Free fatty acid AUC was positively associated with triglyceride (r = 0.25, P < .05), fasting plasma glucose (r = 0.26, P < .01), 2-hour plasma glucose (r = 0.27, P < .01), and diastolic blood pressure (r = 0.21, P < .05) independently of visceral AT and insulin sensitivity. In postmenopausal women, the presence of both high visceral AT and low insulin sensitivity is needed to observe an elevated FFA AUC. Moreover, FFA AUC is associated with some components of the metabolic syndrome, independently of visceral AT and insulin sensitivity.     

New insulin sensitivity index from the oral glucose tolerance test

A new insulin sensitivity index was devised on the basis of an autoregressive model and its validity was investigated. Using data from the 75-g oral glucose tolerance test (OGTT), 115 subjects were divided into 3 groups: 40 with normal glucose tolerance, 34 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus. The new insulin sensitivity index: oral glucose insulin sensitivity index (GSI) was calculated from five sets of plasma glucose and insulin levels obtained at 0, 30, 60, 90 and 120 min during OGTT using a formula based on an autoregressive model. Forty-three of the 115 subjects were examined for insulin sensitivity index (ISI) by euglycemic hyperinsulinemic clamp. GSI decreased in the order of normal glucose tolerance group>impaired glucose tolerance group>diabetic group. There was a significant correlation between GSI and the ISI derived from euglycemic hyperinsulinemic clamp study data in all 43 subjects who underwent both tests (r=0.72; P<0.0001). The ISI calculated by previous methods poorly correlated with the ISIs obtained by euglycemic hyperinsulinemic clamp study. In conclusion, this new insulin sensitivity index based on the data obtained from OGTT using an autoregressive model is comparable to an insulin sensitivity index by euglycemic hyperinsulinemic clamp technique and may be superior to previous indexes that have been devised to determine insulin sensitivity from OGTT data.     

利拉鲁肽对RNAi介导的脂联素基因抑制ApoE基因敲除小鼠糖脂代谢的影响

目的 探讨利拉鲁肽对脂联素基因表达缺陷的ApoE基因敲除(ApoE-/-)小鼠糖脂代谢的影响.方法 采用静脉葡萄糖耐量试验(IVGTT)评价利拉鲁肽的量效关系.利用扩展高胰岛素钳夹技术评价各组小鼠糖脂代谢和胰岛素敏感性变化.结果 在IVGTT中,利拉鲁肽1 mg/kg组,糖负荷后5、15和30 min血糖值均明显低于其它剂量组(均P＜0.01),而血浆胰岛素水平在5、15 min均明显高于其他3组(均P＜0.01).联合注射利拉鲁肽和脂联素RNAi腺病毒组体重、空腹血糖、血浆游离脂肪酸、总胆固醇、甘油三酯、血浆胰岛素和低密度脂蛋白胆固醇(LDL-C)水平显著低于脂联素RNAi腺病毒组(P＜0.05或P＜0.01),而高密度脂蛋白胆固醇(HDL-C)则明显高于脂联素RNAi组(P＜0.05).钳夹稳态时,脂联素RNAi组血浆胰岛素明显高于利拉鲁肽组(P＜0.01),游离脂肪酸、总胆固醇、甘油三酯虽被抑制,但仍明显高于利拉鲁肽组(P＜0.05).利拉鲁肽组葡萄糖输注率(GIR)则明显高于脂联素RNAi组(P＜0.01).钳夹结束时,脂联素RNAi组葡萄糖清除率(GRd)明显低于利拉鲁肽组(P＜0.01),而肝糖输出率则明显高于利拉鲁肽组(P＜0.01).结论 长期的利拉鲁肽干预上调了脂联素基因表达缺陷ApoE-/-小鼠血浆脂联素水平,并改善了其胰岛素抵抗.