Elevated intact proinsulin levels are indicative of Beta-cell dysfunction, insulin resistance, and cardiovascular risk: impact of the antidiabetic agent pioglitazone

Background:

Insulin resistance (IR) and deterioration of beta-cell secretion are main features in the development of type 2 diabetes, which is reflected in increasing serum intact proinsulin levels in later disease stage. Introduction of stable assays that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products has resulted in the finding that serum intact proinsulin values can serve as a direct marker for beta-cell dysfunction, are a highly specific indicator of IR, and can predict cardiovascular risk.

Method:

Determination of fasting intact proinsulin may be used to monitor and optimize antidiabetic therapeutic approaches. Our study group has been involved in a variety of clinical studies investigating drug effects on beta-cell secretory capacity, IR, and intact proinsulin levels. One focus was on the impact of insulin-sensitizing therapy with pioglitazone on the pancreatic beta-cell load.

Results:

Treatment with pioglitazone resulted in significant decreases in elevated proinsulin levels in type 2 diabetes patients. This effect was independent from glycemic control.

Conclusions:

Measurement of fasting intact proinsulin values allows a staging of beta-cell dysfunction and evaluation of IR, thus providing an interesting diagnostic tool for both selection of appropriate therapy and monitoring of treatment success.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R² = 56.2 %) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R² = 40.1 %). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the β-cell function both in men and women. © 1998 John Wiley & Sons, Ltd.     

Prediction of incident hypertension and arterial stiffness using the non–insulin‐based metabolic score for insulin resistance (METS‐IR) index

Hypertension is associated with insulin resistance (IR), metabolic syndrome (MS), and arterial stiffness. Non–insulin‐based IR indexes were developed as tools for metabolic screening. Here, we aimed to evaluate the novel non–insulin‐based Metabolic Score for IR (METS‐IR) index for the prediction of incident hypertension and arterial stiffness evaluated using pulse wave velocity (PWV) analysis, compared with other non–insulin‐based IR indexes. We evaluated two populations, a cross‐sectional evaluation of high‐risk individuals (n = 305) with a wide range of metabolic comorbidities and dyslipidemia in whom PWV measurement was performed and a 3‐year prospective cohort of normotensive individuals (N = 6850). We observed a positive correlation between METS‐IR and PWV in the cross‐sectional cohort, which was higher compared with other non–insulin‐based fasting IR indexes; furthermore, PWV values >75th percentile were associated with the upper tercile of METS‐IR values. In the prospective cohort, we observed an increased risk for incident hypertension for the upper METS‐IR tercile (METS‐IR ≥ 46.42; HR: 1.81, 95% CI: 1.41‐2.34), adjusted for known cardiovascular risk factors, and observed that METS‐IR had greater increases in the predictive capacity for hypertension along with SBP and the Framingham Hypertension Risk Prediction Model compared with other non–insulin‐based IR indexes. Therefore, METS‐IR is a novel non–insulin‐based IR index which correlates with arterial stiffness and is a predictor of incident hypertension, complementary to previously validated risk prediction models.     

High serum insulin,insulin resistance and their associations with cardiovascular risk factors The Northern Sweden MONICA population study

Abstract. Objectives. To estimate the prevalence of insulin resistance and high serum insulin levels and to investigate their relationship to other cardiovascular risk factors. Design. Cross-sectional cardiovascular risk factor survey. Setting. Northern Sweden. Subjects. A subsample of the population-based Northern Sweden MONICA Study. This subsample underwent an oral glucose tolerance test after an overnight fast, and consisted of 354 men and 404 women in the 25–64-year age range. Main outcome measures. Delineation of low insulin sensitivity and high serum insulin by the diagnostic test technique, prevalence of these variables and their associations with cardiovascular risk factors. Results. The participants were classified into four subgroups by an insulin sensitivity index and fasting serum insulin. The combination of low insulin sensitivity and high serum insulin was present in 17% of the male and in 18% of the female 25–64-year-old population. In both sexes this combination was closely associated (P < 0.001) with body mass index, waist-hip ratio, blood pressure and serum triglycerides, and correlated inversely with serum HDL cholesterol (P < 0.001). When high serum insulin was present as an isolated entity it was as closely associated with other cardiovascular risk factors such as isolated low insulin sensitivity, except that impaired glucose tolerance occurred exclusively in the group with isolated low insulin sensitivity. Conclusions. The combination of insulin resistance and high insulin levels is associated with a marked clustering of cardiovascular risk factors and is present in one-sixth of the middle-aged population in the north of Sweden.     

An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study.

AIMS: To investigate the effect of treatment with pioglitazone on beta-cell function and insulin sensitivity in Type 2 diabetes. METHODS: Thirty subjects with diet-controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment. RESULTS: All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA-%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg(-1) min(-1) vs. +3.2 (2.9) l kg(-1) min(-1), respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA-%B increased with pioglitazone, +11.5% (4.8) vs. -2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta-cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, -0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA(1c) of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS). CONCLUSIONS: Basal beta-cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta-cells are under less stress.     

Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients

Objective: We examined the effects of rosiglitazone treatment on profiles of adipocytokines levels, postprandial insulin and glucose excursion, lipids levels, comparing with those of pioglitazone treatment in patients with type 2 diabetes mellitus (T2DM). Methods: Changes in body weight, haemoglobin A_1c (HbA_1c), glucose/insulin/C‐peptide/free fatty acid (FFA) during 75 g oral glucose tolerance test (OGTT), HDL‐/LDL‐cholesterol, triglyceride (TG) and adipocytokines [tumour necrosis factor (TNF)‐α, leptin and adiponectin] were measured in T2DM patients treated with rosiglitazone, 8 mg/day (n = 35), or pioglitazone, 45 mg/day (n = 21), for 3 months. Results: After rosiglitazone or pioglitazone treatment, HbA_1c (8.6–7.2 vs. 8.3–6.9%, rosiglitazone vs. pioglitazone), fasting plasma glucose (190–144 vs. 178–140 mg/dl), fasting FFA (729–595 vs. 641–526 μEq/l), mean plasma glucose‐OGTT (292–229 vs. 285–233 mg/dl) and mean FFA‐OGTT (580–430 vs. 488–377 μEq/l) decreased similarly and all were statistically significant (p < 0.01). The insulinogenic index (ΔI_0–120/ΔG_0–120) (0.19–0.30 vs. 0.17–0.26) and Matsuda index of insulin sensitivity (2.0–3.1 and 2.7–4.3) increased (p < 0.01) similarly, despite increase in body weight (85–88 vs. 81–84 kg). TNF‐α (3.8–3.4 vs. 5.2–4.5 pg/ml) decreased (p < 0.05) and adiponectin (6.3–17.8 vs. 7.1–16.4 μg/ml) increased (p < 0.01), while leptin did not change following either treatment. After rosiglitazone treatment, plasma HDL‐cholesterol (34–38 mg/dl) and LDL‐cholesterol (103–120 mg/dl) increased (p < 0.01), while TGs (177–167 mg/dl) did not change significantly. After pioglitazone treatment, plasma HDL‐cholesterol (34–37 mg/dl) increased (p < 0.05), while LDL‐cholesterol (104–105 mg/dl) did not change and TGs (153–106 mg/dl) decreased (p < 0.01). Conclusions: Rosiglitazone and pioglitazone have similar beneficial effects on glycaemic control insulin sensitivity, insulin secretion and plasma adipocytokine levels. However, pioglitazone has a more beneficial effect on the plasma lipid profile than rosiglitazone.     

Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.

AIMS: This study compared the effects of 52 weeks' treatment with pioglitazone, a thiazolidinedione that reduces insulin resistance, and glibenclamide, on insulin sensitivity, glycaemic control, and lipids in patients with Type 2 diabetes. METHODS: Patients with Type 2 diabetes were randomized to receive either pioglitazone (initially 30 mg QD, n = 91) or micronized glibenclamide (initially 1.75 mg QD, n = 109) as monotherapy. Doses were titrated (to 45 mg for pioglitazone and 10.5 mg for glibenclamide) to achieve glycaemic targets during the next 12 weeks: fasting blood glucose of < or = 7 mmol/l and 1-h postprandial blood glucose of < or = 10 mmol/l. Patients were maintained on the titrated dose for 40 weeks. RESULTS: Pioglitazone significantly increased insulin sensitivity compared with glibenclamide, as assessed by homeostasis model assessment (17.0% vs. -13.0%; P < 0.001), quantitative insulin sensitivity check index (0.011 vs. -0.007; P < 0.001) and fasting serum insulin (-1.3 pmol/l vs. 23.8 pmol/l; P = 0.007). The glibenclamide group had significantly lower HbA1c than the pioglitazone group after 12 weeks of therapy (7.8% vs. 8.3%, P = 0.015), but significantly higher HbA1c after 52 weeks of therapy (7.8% vs. 7.2%, P = 0.001). Pioglitazone significantly (vs. glibenclamide) increased mean HDL-C (P < 0.001), decreased mean triglycerides (P = 0.019), and decreased mean atherogenic index of plasma (AIP; P = 0.001) and mean total cholesterol/HDL-C (P = 0.004), without significantly elevating mean total cholesterol or mean LDL-C compared with glibenclamide. CONCLUSIONS These data suggest that the effects of pioglitazone are more sustained than those of glibenclamide for improving insulin sensitivity in patients with Type 2 diabetes, and that 52 weeks' treatment with pioglitazone has favourable effects on glycaemic control and lipoprotein profile.     

预防性应用吡格列酮改善胰岛素抵抗的脂肪内分泌机制

目的探讨吡格列酮改善胰岛素抵抗过程中脂肪内分泌功能的改变。方法45只W istar雄性大鼠随机分为对照组、胰岛素抵抗组和吡格列酮组。胰岛素抵抗动物模型成功建立后,分析各组抵抗素、脂联素和脂联素受体的表达。结果与胰岛素抵抗组比较,吡格列酮组大鼠的体质量、空腹血糖、游离脂肪酸差异不明显,但胰岛素、胰岛素抵抗指数、葡萄糖耐量和胰岛素耐量明显改善（P〈0.01）,脂联素表达明显增高（P〈0.05）。结论脂肪内分泌功能紊乱在高脂诱导胰岛素抵抗的发生中起着重要的作用,预防性应用吡格列酮可明显延缓大鼠胰岛素抵抗的发生,改善脂肪内分泌功能。     

吡格列酮和胰岛素对内皮祖细胞增殖和凋亡及分泌一氧化氮的影响

目的观察吡格列酮和胰岛素对大鼠骨髓内皮祖细胞(EPCs)的增殖能力、凋亡及分泌NO能力的影响,并探讨其机制。方法取正常SD大鼠32只,随机分为吡格列酮组和非吡格列酮组,各16只,分别给予吡格列酮和生理盐水灌胃预处理。喂养10天后,断颈处死,密度梯度离心法取骨髓单个核细胞,在M199培养液中培养扩增EPCs并进行鉴定。贴壁细胞培养4天后,将吡格列酮组EPCs消化后进一步分为两组,分别给予胰岛素(1nmol/L)或空白干预,非吡格列酮组EPCs处理同吡格列酮组EPCs。24h后检测NO水平,3天后检测凋亡情况,7天后检测细胞增殖能力。结果吡格列酮预处理能提高EPCs数量(P<0.01),吡格列酮预处理和(或)体外给予胰岛素干预组EPCs与未处理组细胞相比EPCs增殖能力提高(P<0.01),凋亡程度降低(P<0.05),培养上清中NO浓度增加(P<0.05)。结论体内吡格列酮预处理与体外胰岛素干预均能促进EPCs增殖,抑制EPCs凋亡,并促进EPCs分泌NO,且两种药物联合应用具有协同作用。     

A diabetes risk score helps identify metabolic syndrome and cardiovascular risk in Indians - the Chennai Urban Rural Epidemiology Study (CURES-38)

AIMS: The aims of the study were to compare the recently evolved Indian Diabetes Risk Score (IDRS), in subjects with different grades of glucose intolerance and to evaluate its usefulness as an indicator of cardiovascular risk in Asian Indians, a high risk group for diabetes and coronary artery disease (CAD). METHODS: The data for the present study were obtained from the Phase 3 (n = 2350, response rate: 90.4%) of the Chennai Urban Rural Epidemiology Study, a population-based study done in Chennai, the largest city in southern India. IDRS was developed based on multiple logistic regression analysis using four simple parameters namely age, abdominal obesity, family history of type 2 diabetes and physical activity. In all subjects, family history of diabetes was obtained, and details on physical activity were assessed using a validated questionnaire. Subjects with an IDRS of <30 was categorized as low risk, 30-50 as medium risk and those with > or =60 as high risk for diabetes. Biochemical and anthropometric measurements were done using standardized procedures. Minnesota coding was used to grade 12-lead electrocardiogram. RESULTS: The mean IDRS increased significantly with worsening glucose intolerance [normal glucose tolerance (NGT) subjects: 48 +/- 17, impaired glucose tolerance (IGT): 57 +/- 16, newly diagnosed diabetics (NDD): 61 +/- 15 and known diabetics (KD): 68 +/- 12; p for trend <0.001]. Among NGT group, the prevalence of cardiovascular risk factors increased progressively in low-, medium- to high-risk score groups; hypertension: 9.4, 22.1 and 38.2% (p for trend: < 0.001), hypertriglyceridemia: 8.8, 19.9 and 25.3% (p for trend: < 0.001), hypercholesterolemia: 7.2, 20.3 and 34.9% (p for trend: < 0.001) and metabolic syndrome: 1.8, 14.6 and 30.3% (p for trend: < 0.001), respectively. The prevalence of CAD was also significantly higher in individuals with high risk compared with those with low risk (p = 0.030) and the medium risk (p = 0.050) in the NGT group. CONCLUSIONS: The results suggest that in Asian Indians, (i) the diabetes risk score increases with increasing glucose intolerance, and (ii) it can serve as an effective indicator of metabolic syndrome and cardiovascular risk even among subjects with NGT.     

高动物蛋白饮食对高血压患者血管功能及心血管危险因素的影响

目的 调查高血压患者的生活方式,了解高动物蛋白饮食对血管功能和颈动脉内膜中层厚度等心血管危险因素的影响。方法 在我院心血管门诊选取符合纳入标准的高血压患者88例,通过问卷调查方式获取参与者的一般生活方式,检测肱动脉血流介导的血管舒张功能（FMD）和肱踝脉搏波传导速度,同时收集患者颈动脉内膜中层厚度（IMT）等一般临床资料,分析高动物蛋白饮食与血管功能及颈动脉内膜中层厚度等心血管危险因素的相关性。结果 男性52例,女性36例,年龄中位数42 (38, 53)岁。平均动脉压中位数106 (97, 112) mmHg,最高平均动脉压中位数123 (116, 132) mmHg。FMD中位数5.1 (3.8, 7.3)%,IMT中位数0.9 (0.8, 1.2) mm。在日常饮食中,偏向于高动物蛋白饮食的39例,比较均衡的36例;高动物蛋白饮食与FMD显著负相关,与IMT显著正相关;而且,动物蛋白摄入量较大的受试者倾向于存在更大的心血管风险。结论 高血压患者在接受有效降压治疗的同时,应采取健康的生活方式,均衡饮食,避免过高的动物蛋白摄入量,可能有助于降低心血管疾病风险。     

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow‐mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT). Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age‐ and sex‐matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA‐IR). A randomised double‐blind placebo‐controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated. Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium‐independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo. Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.     

Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study

AIM: To determine the effects of pioglitazone treatment combined with insulin on glucose and lipid metabolism in patients with type 2 diabetes. METHODS: In a multicentre, double-blind study, 690 patients [body mass index, 33.19 kg/m2 +/- 5.47; haemoglobin A1c (A1C), 9.78 +/- 1.51; mean duration, 12.9 years] with diabetes poorly controlled with a stable insulin dose (> 30 U/day for > or =30 days) were randomly allocated to pioglitazone 30 or 45 mg once daily for 24 weeks. RESULTS: In the pioglitazone 30- and 45-mg groups, respectively, 71 and 70% of patients completed the study. At 24 weeks, statistically significant, dose-dependent mean decreases from baseline were seen in the pioglitazone 30- and 45-mg groups for A1C (-1.17 and -1.46%, respectively) and fasting plasma glucose (-31.9 and -45.8 mg/dl, respectively). Insulin dosage also decreased significantly (-4.5 and -7.3 U, respectively; p < or = 0.05) from baseline. Decreases in triglycerides [pioglitazone 45 mg: -5.9% (p < or = 0.05)], very low-density lipoprotein cholesterol [pioglitazone 45 mg: -6.2% (p < or = 0.05)] and free fatty acids [-0.94 (p < or = 0.05) and -2.13 (p < 0.0001) mg/dl, respectively] and increases in high-density lipoprotein cholesterol (9.7 and 13.0%, respectively; p < 0.0001) also were observed from baseline. Small but significant increases in total and low-density lipoprotein cholesterol (p < 0.01) from baseline were observed. Mean weight gain was 2.9 and 3.4 kg in the respective groups; lower limb oedema was reported in 13 and 12% of patients, respectively. The incidences of oedema, weight gain and heart failure were not higher than anticipated in this population. No evidence of hepatotoxicity or clinically significant elevations in liver function test parameters was seen. CONCLUSIONS: In patients with poorly controlled type 2 diabetes, addition of pioglitazone to insulin significantly improved glycaemic control, had a positive effect on important components of the lipid profile in a dose-dependent manner and was generally well tolerated.     

Effect of pioglitazone and ramipril on biomarkers of low-grade inflammation and vascular function in nondiabetic patients with increased cardiovascular risk and an activated inflammation: results from the PIOace study

Aims

This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk.

Methods and Results

Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m², duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (−0.89 ± 1.98 mg/liter; -25%) and PIRA (−0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (−29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (−40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase-9: -48 ± 127 (−12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (−13%), p < .05 for RAM vs PIO or PIRA in all cases].

Conclusions

Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials.     

Insulin secretion and action in different stages of glucose tolerance in Asian Indians.

AIMS: To evaluate the sequence of changes in insulin secretion and action in different stages of glucose tolerance and the effect of obesity on insulin profile in South Indian adults. Blood samples from 260 consecutive cases with no known history of diabetes were collected. Plasma insulin levels were measured during a 75-g oral glucose tolerance test. Insulin resistance (IR) was calculated, using the homeostasis model assessment (HOMA). An index of insulin secretion was derived as the ratio of incremental insulin at 30 min divided by 30 minute plasma glucose (delta I/G). RESULTS: Normoglycaemia was present in 164, impaired glucose tolerance (IGT) in 60 and diabetes in 36 subjects. Fasting and 2 h insulin secretion showed bell shaped curves with increasing plasma glucose. The peak values corresponded to the cut-off values used for the diagnosis of clinical diabetes. IR was higher in obese than in nonobese, nondiabetic subjects but the effect of obesity on IR was not found in subjects with diabetes. IGT was associated with higher IR, but not with evidence of a beta-cell defect. CONCLUSIONS: Evaluation of insulin resistance and beta-cell function in different stages of glucose tolerance indicate that insulin resistance is manifested in the early stage of glucose intolerance in South Indians, i.e. IGT. A beta-cell defect was mostly found in people with diabetes. The beta-cell defect is more common in diabetes among the nonobese.     

The white blood cell count: its relationship to plasma insulin and other cardiovascular risk factors in healthy male individuals

Targher G, Seidell JC, Tonoli M, Muggeo M, De Sandre G, Cigolini M (Division of Endocrinology and Metabolic Diseases, Institute of Clinical Medicine, University of Verona, Italy; and Department of Chronic Diseases and Environmental Epidemiology-RIVM, Bilthoven, The Netherlands). The white blood cell count: relationship to plasma insulin and other cardiovascular risk factors in healthy males. J Intern Med 1996; 239: 435–41. Objectives. To evaluate the relationships of total and differential white blood cell (WBC) count to the components of the so-called insulin resistance syndrome. Subjects and design. The study population consisted of a random sample of 90 38-year-old healthy men with normal glucose tolerance. Interventions. A 75 g oral glucose tolerance test was performed in all participants. Main outcome measures. Total and differential WBC count, lipids, blood pressure, plasma glucose, C-peptide and insulin (at fasting and 2 h after glucose load). Results. Total WBC count correlated consistently with plasma 2-h glucose (r=0.38; P<0.001), fasting and 2-h postload insulin (r=0.26 and r=0.33; P<0.01–0.001, respectively) and C-peptide (r=0.28 and r=0.32; P<0.01–0.001) concentrations. Smokers had significantly higher total leukocytes (P<0.01), neutrophils and lymphocytes than nonsmokers. Furthermore, total WBC count correlated positively with body mass index, blood pressure, plasma triglycerides, fibrinogen, and negatively with HDL cholesterol concentration. As differential WBC count, most variables correlated essentially to neutrophils and/or lymphocytes, whereas plasma insulin and C-peptide concentrations correlated essentially to lymphocytes and monocytes, but not to neutrophils. In a multiple linear regression analysis, only 2-h plasma glucose (P<0.01) and fibrinogen (P<0.05) were positive predictors of total WBC count after adjusting for all potentially confounding variables. Conclusions. The results indicate that increased, albeit normal, WBC count associates with the cluster of metabolic and haemodynamic disorders typical of the insulin resistance syndrome, and suggest that increased WBC count may be yet another component of this syndrome.     

Effects of intranasal insulin on endogenous glucose production in insulin‐resistant men

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single‐blind, crossover study. Overweight or obese insulin‐resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m², homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30‐minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin‐resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin‐sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP.