Comparison of two surrogate estimates of insulin resistance to predict cardiovascular disease in apparently healthy individuals.

BACKGROUND AND AIMS: Insulin resistance is associated with a cluster of abnormalities that increase cardiovascular disease (CVD). Several indices have been proposed to identify individuals who are insulin resistant, and thereby at increased CVD risk. The aim of this study was to compare the abilities of 3 indices to accomplish that goal: 1) plasma triglyceride × glucose index (TG × G); 2) plasma triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C); and 3) Metabolic Syndrome (MetS). METHODS AND RESULTS: In a population sample of 723 individuals (486 women and 237 men, 50 ± 16 and 51 ± 16 years old, respectively), baseline demographic and metabolic variables known to increase CVD risk and incident CVD were compared among individuals defined as high vs. low risk by: TG × G; TG/HDL-C; or MetS. CVD risk profiles appeared comparable in high risk subjects, irrespective of criteria. Crude incidence of CVD events was increased in high risk subjects: 12.2 vs. 5.3% subjects/10 years, p = 0.005 defined by TG/HDL-C; 13.4 vs. 5.3% subjects/10 years, p = 0.002 defined by TG × G; and 13.4% vs. 4.5% of subjects/10 years, p < 0.001 in subjects with the MetS. The area under the ROC curves to predict CVD were similar, 0.66 vs. 0.67 for TG/HDL-C and TG × G, respectively. However, when adjusted by age, sex and multiple covariates, hazard ratios for incident CVD were significantly increased in high risk patients classified by either TG/HDL-C ratio (2.18, p = 0.021) or MetS (1.93, p = 0.037), but not by TG × G index (1.72, p = 0.087). CONCLUSION: Although the 3 indices identify CVD risk comparably, the TG × G index seems somewhat less effective at predicting CVD.

Use of the triglyceride/high-density lipoprotein cholesterol ratio to identify cardiometabolic risk: impact of obesity?

There is evidence that the plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) identifies insulin resistance and increased cardiometabolic risk and outcome in apparently healthy individuals. Since use of the TG/HDL-C ratio to accomplish this task in persons over a wide range of adiposity has not been studied, the ability of previously defined sex-specific TG/HDL-C cut-points to identify increased cardiometabolic risk was evaluated in apparently healthy normal weight, overweight, and obese individuals. Data were analyzed from a population-based study of apparently healthy men (n=416) and women (n=893), subdivided into categories by body mass index (BMI, kg/m2): normal weight (BMI 20.0-24.9), overweight (BMI 25.0-29.9) and obese (BMI 30.0-34.9). The adiposity groups were further stratified on the basis of their TG/HDL-C ratio into groups defined as being either at 'high risk' versus 'low risk' of cardiometabolic disease. Multiple cardiometabolic risk factors were compared between these subgroups, as was their degree of insulin resistance assessed by fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. The proportion of high-risk individuals varied with BMI category, ranging from 14% (normal weight) to 36% (obese). However, within each BMI category high-risk individuals had a significantly more adverse cardiometabolic risk profile. Finally, the adjusted OR of being insulin resistant was significantly greater in those with a high TG/HDL-C ratio in the normal (3.02), overweight (2.86), and obese (2.51) groups. Thus, irrespective of differences in BMI, the TG/HDL-C ratio identified apparently healthy persons with a more adverse cardiometabolic risk profile associated with an increased prevalence of insulin resistance.

Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic.

AIMS: There is general acceptance that the physiological relationship between insulin sensitivity and insulin secretion is hyperbolic. This conclusion has evolved from studies in which one test assessed both variables, and changes in plasma insulin concentration were used as a surrogate measure for insulin secretion rate. The aim of this study was to see if a hyperbolic relationship would also emerge when separate and direct measures were used to quantify both insulin sensitivity and insulin secretion rate. METHODS: Steady-state plasma glucose (SSPG) was determined in 146 individuals without diabetes using the insulin suppression test, with 1/SSPG used to quantify insulin sensitivity. The graded-glucose infusion test was used to quantify insulin secretion rate. Plasma glucose and insulin concentrations obtained during an oral glucose tolerance test (OGTT) were used to calculate surrogate estimates of insulin action and insulin secretion rate. A hyperbolic relationship was assumed if the ß coefficient was near -1 using the following model: log (insulin secretion measure) = constant + ß × log (insulin sensitivity measure). RESULTS: OGTT calculations of insulin sensitivity (Matsuda) and plasma insulin response [ratio of insulin/glucose area-under-the-curve (AUC) or insulin total AUC] provided the expected hyperbolic relationship [ß = -0.95, 95% CI (-1.09, -0.82); -1.06 (-1.14, -0.98)]. Direct measurements of insulin sensitivity and insulin secretion rate did not yield the same curvilinear relationship [ß = -1.97 (-3.19, -1.36)]. CONCLUSIONS: These findings demonstrate that the physiological relationship between insulin sensitivity and insulin secretion rate is not necessarily hyperbolic, but will vary with the method(s) by which it is determined.

Effect of liraglutide administration and a calorie-restricted diet on lipoprotein profile in overweight/obese persons with prediabetes.

BACKGROUND AND AIMS: To evaluate the effects of 14 weeks of liraglutide plus modest caloric restriction on lipid/lipoprotein metabolism in overweight/obese persons with prediabetes. METHODS AND RESULTS: Volunteers with prediabetes followed a calorie-restricted diet (-500 Kcal/day) plus liraglutide (n = 23) or placebo (n = 27) for 14 weeks. The groups were similar in age (58 ± 7 vs. 58 ± 8 years) and body mass index (31.9 ± 2.8 vs. 31.9 ± 3.5 kg/m(2)). A comprehensive lipid/lipoprotein profile was obtained before and after intervention using vertical auto profile (VAP). Weight loss was greater in the liraglutide group than in the placebo group (6.9 vs. 3.3 kg, p < 0.001), as was the fall in fasting plasma glucose concentration (9.9 mg/dL vs. 0.3 mg/dL, p < 0.001). VAP analysis revealed multiple improvements in lipid/lipoprotein metabolism in liraglutide-treated compared with placebo-treated volunteers, including decreases in concentrations of total cholesterol, low-density lipoprotein cholesterol and several of its subclasses, triglyceride, and non-high-density cholesterol. The liraglutide-treated group also had a significant shift away from small, dense low-density lipoprotein-particles, as well as decreases in apolipoprotein B concentration and ratio of apolipoprotein B/apolipoprotein A-1. There were no significant changes in the lipoprotein profile in the placebo-treated group. CONCLUSION: Treatment with liraglutide plus modest calorie restriction led to enhanced weight loss, a decrease in fasting plasma glucose concentration, and improvement in multiple aspects of lipid/lipoprotein metabolism associated with increased cardiovascular disease (CVD) risk. The significant clinical benefit associated with liraglutide-assisted weight loss in a group at high risk for CVD - obese/overweight individuals with prediabetes - as seen in our pilot study, suggests that this approach deserves further study.

Identifying cardiovascular disease risk and outcome: use of the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio versus metabolic syndrome criteria.

BACKGROUND: Metabolic syndrome (MetS) has been shown to predict both risk and CVD events. We have identified sex-specific values for the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio associated with an unfavourable cardio-metabolic risk profile, but it is not known whether it also predicts CVD outcome. METHODS: To quantify risk for CVD outcomes associated with a high TG/HDL-C ratio and to compare this risk with that predicted using MetS, a population longitudinal prospective observational study was performed in Rauch City, Buenos Aires, Argentina. In 2003 surveys were performed on a population random sample of 926 inhabitants. In 2012, 527 women and 269 men were surveyed again in search of new CVD events. The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. MAIN OUTCOME: The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. RESULTS: The number of subjects deemed at 'high' CVD risk on the basis of an elevated TG/HDL-C ratio (30%) or having the MetS (35%) was relatively comparable. The unadjusted hazard risk was significantly increased when comparing 'high' versus 'low' risk groups no matter which criteria was used, although it was somewhat higher in those with the MetS (HR = 3.17, 95% CI:1.79-5.60 vs. 2.16, 95% CI:1.24-3.75). However, this difference essentially disappeared when adjusted for sex and age (HR = 2.09, 95% CI:1.18-3.72 vs. 2.01, 95% CI:1.14-3.50 for MetS and TG/HDL-C respectively). CONCLUSIONS: An elevated TG/HDL-C ratio appears to be just as effective as the MetS diagnosis in predicting the development of CVD.

Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome?

BACKGROUND AND AIMS: The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. METHODS AND RESULTS: Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥ 4.14 and ≥ 4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥ 4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. CONCLUSION: While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.

The metabolic syndrome: time to get off the merry-go-round?

The diagnostic category of the metabolic syndrome (MetS) has received considerable attention over the last decade, and prestigious organizations continue to strive for its incorporation into medical practice. This review has three goals: (i) summarize the history of the several attempts to define a diagnostic category designated as the MetS; (ii) question the aetiological role of abdominal obesity in the development of the other components of the MetS; and (iii) evaluate a diagnosis of the MetS as an effective way to identify apparently healthy individuals at increased risk to develop cardiovascular disease (CVD) or type 2 diabetes (2DM). The most important conclusion is that the MetS seems to be less effective in this population than the Framingham Risk Score in predicting CVD, and no better, if not worse, than fasting plasma glucose concentrations in predicting 2DM.

Adiposity indices in the prediction of metabolic abnormalities associated with cardiovascular disease in non-diabetic adults.

BACKGROUND AND AIMS: The prevalence of insulin resistance and cardiovascular disease (CVD) increases with degree of obesity. Whether measurements of generalized and abdominal obesity differ in the ability to predict changes associated with increased CVD risk is widely debated. We compared the prevalence of metabolic abnormalities in 275 women and 204 men stratified by categories of body mass index (BMI) and waist circumference (WC), and assessed the ability of these adiposity indices in combination with metabolic risk variables to predict insulin resistance. METHODS AND RESULTS: Healthy, non-diabetic volunteers underwent measurements of BMI, WC, blood pressure, fasting plasma glucose (FPG), lipoprotein concentrations, and direct quantification of insulin-mediated glucose uptake. Insulin resistance was defined as the top tertile of steady-state plasma glucose (SSPG) concentrations. BMI and WC were highly correlated (P < 0.001) in both women and men. Abnormal SSPG and triglyceride concentrations were associated with increasing adiposity by either index in both genders. Among women, abnormal FPG and high density lipoprotein cholesterol (HDL-C) concentrations were associated with increasing BMI and WC. In men, abnormal HDL-C was associated with increasing BMI only. Elevated systolic blood pressure (SBP) was associated with increasing BMI in both genders. The odds of insulin resistance were greatest in women with elevated FPG and triglycerides (4.5-fold). In men, the best predictors were BMI and SBP, and WC and HDL-C (3-fold). CONCLUSION: BMI is at least comparable to WC in stratifying individuals for prevalence of metabolic abnormalities associated with increased CVD risk and predicting insulin resistance.

Pioglitazone increases the proportion of small cells in human abdominal subcutaneous adipose tissue.

Rodent and in vitro studies suggest that thiazolidinediones promote adipogenesis but there are few studies in humans to corroborate these findings. The purpose of this study was to determine whether pioglitazone stimulates adipogenesis in vivo and whether this process relates to improved insulin sensitivity. To test this hypothesis, 12 overweight/obese nondiabetic, insulin-resistant individuals underwent biopsy of abdominal subcutaneous adipose tissue at baseline and after 12 weeks of pioglitazone treatment. Cell size distribution was determined via the Multisizer technique. Insulin sensitivity was quantified at baseline and postpioglitazone by the modified insulin suppression test. Regional fat depots were quantified by computed tomography (CT). Insulin resistance (steady-state plasma insulin and glucose (SSPG)) decreased following pioglitazone (P < 0.001). There was an increase in the ratio of small-to-large cells (1.16 +/- 0.44 vs. 1.52 +/- 0.66, P = 0.03), as well as a 25% increase in the absolute number of small cells (P = 0.03). The distribution of large cell diameters widened (P = 0.009), but diameter did not increase in the case of small cells. The increase in proportion of small cells was associated with the degree to which insulin resistance improved (r = -0.72, P = 0.012). Visceral abdominal fat decreased (P = 0.04), and subcutaneous abdominal (P = 0.03) and femoral fat (P = 0.004) increased significantly. Changes in fat volume were not associated with SSPG change. These findings demonstrate a clear effect of pioglitazone on human subcutaneous adipose cells, suggestive of adipogenesis in abdominal subcutaneous adipose tissue, as well as redistribution of fat from visceral to subcutaneous depots, highlighting a potential mechanism of action for thiazolidinediones. These findings support the hypothesis that defects in subcutaneous fat storage may underlie obesity-associated insulin resistance.

Pioglitazone decreases postprandial accumulation of remnant lipoproteins in insulin-resistant smokers.

BACKGROUND: Fasting hypertriglyceridaemia has been reported to occur commonly in cigarette smokers and is thought to increase cardiovascular disease (CVD) risk in these individuals. More recently, it has been suggested that an increase in non-fasting triglycerides, rather than fasting hypertriglyceridaemia, is an independent CVD risk factor. METHODS: In this study, we divided 24 smokers into insulin-resistant (IR) and insulin-sensitive (IS) groups by determining their steady-state plasma glucose concentrations during the insulin suppression test and compared fasting and daylong postprandial accumulation of total triglycerides and remnant lipoprotein (RLP) concentrations, before and after 3 months of pioglitazone (PIO) administration. RESULTS: The two groups were similar in age, body mass index, race and gender distribution, but differed dramatically in insulin sensitivity. Baseline fasting and postprandial triglyceride, RLP cholesterol and RLP triglyceride concentrations were significantly higher in the IR smokers (p=0.01 to <0.01). Insulin resistance [corrected] and both fasting and postprandial triglyceride and RLP triglyceride levels decreased significantly (p=0.05 to 0.01) [corrected] in PIO-treated IR smokers, without any significant increase in weight instead of insulin sensitivity and both fasting and postprandial triglyceride and RLP triglyceride levels decreased significantly (p = 0.05 to, 0.01) in PIO-treated IR smokers, without any significant increase in weight. [corrected] CONCLUSIONS: The postprandial accumulation of RLP particles is increased in the IR subset of smokers and is likely to contribute to the increased CVD risk in these individuals. Furthermore, PIO administration provides a possible therapeutic approach to decreasing postprandial lipaemia and CVD risk in IR smokers who are unwilling or unable to stop smoking.

Insulin resistance in pulmonary arterial hypertension.

Although obesity, dyslipidemia and insulin resistance (IR) are well known risk factors for systemic cardiovascular disease, their impact on pulmonary arterial hypertension (PAH) is unknown. The present authors' previous studies indicate that IR may be a risk factor for PAH. The current study has investigated the prevalence of IR in PAH and explored its relationship with disease severity. Clinical data and fasting blood samples were evaluated in 81 nondiabetic PAH females. In total, 967 National Health and Nutrition Examination Surveys (NHANES) females served as controls. The fasting triglyceride to high-density lipoprotein cholesterol ratio was used as a surrogate of insulin sensitivity. While body mass index was similar in NHANES versus PAH females (28.6 versus 28.7 kg.m(-2)), PAH females were more likely to have IR (45.7 versus 21.5%) and less likely to be insulin sensitive (IS; 43.2 versus 57.8%). PAH females mostly (82.7%) had New York Heart Association (NYHA) class II and III symptoms. Aetiology, NYHA class, 6-min walk-distance and haemodynamics did not differ between IR and IS PAH groups. However, the presence of IR and a higher NYHA class was associated with poorer 6-months event-free survival (58 versus 79%). Insulin resistance appears to be more common in pulmonary arterial hypertension females than in the general population, and may be a novel risk factor or disease modifier that might impact on survival.

Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats.

INTRODUCTION AND AIMS: Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT-3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary-induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT-3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats. RESULTS: ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC(50) values for forskolin-stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 +/- 60 microM) compared with SD rats (332 +/- 38 microM). EC(50) values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol-stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 +/- 23 microM) compared with SD rats (343 +/- 27 microM). Insulin inhibited lipolysis in adipocytes from SD rats with an IC(50) value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC(50) values for CVT-3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT-3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT-3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT-3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A(1) receptors relative to beta-actin expression in adipocytes from SD (0.98 +/- 0.2) and ZDF rats (0.99 +/- 0.3). CONCLUSION: The antilipolytic effects of CVT-3619 appear to be independent of insulin resistance and animal model.

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis.

AIMS/HYPOTHESIS: The biological mechanism by which obesity predisposes to insulin resistance is unclear. One hypothesis is that larger adipose cells disturb metabolism via increased lipolysis. While studies have demonstrated that cell size increases in proportion to BMI, it has not been clearly shown that adipose cell size, independent of BMI, is associated with insulin resistance. The aim of this study was to test this widely held assumption by comparing adipose cell size distribution in 28 equally obese, otherwise healthy individuals who represented extreme ends of the spectrum of insulin sensitivity, as defined by the modified insulin suppression test. SUBJECTS AND METHODS: Subcutaneous periumbilical adipose tissue biopsy samples were fixed in osmium tetroxide and passed through the Beckman Coulter Multisizer to obtain cell size distributions. Insulin sensitivity was quantified by the modified insulin suppression test. Quantitative real-time PCR for adipose cell differentiation genes was performed for 11 subjects. RESULTS: All individuals exhibited a bimodal cell size distribution. Contrary to expectations, the mean diameter of the larger cells was not significantly different between the insulin-sensitive and insulin-resistant individuals. Moreover, insulin resistance was associated with a higher ratio of small to large cells (1.66 +/- 1.03 vs 0.94 +/- 0.50, p = 0.01). Similar cell size distributions were observed for isolated adipose cells. The real-time PCR results showed two- to threefold lower expression of genes encoding markers of adipose cell differentiation (peroxisome proliferator-activated receptor gamma1 [PPARgamma1], PPARgamma2, GLUT4, adiponectin, sterol receptor element binding protein 1c) in insulin-resistant compared with insulin-sensitive individuals. CONCLUSIONS/INTERPRETATION: These results suggest that after controlling for obesity, insulin resistance is associated with an expanded population of small adipose cells and decreased expression of differentiation markers, suggesting that impairment in adipose cell differentiation may contribute to obesity-associated insulin resistance.

ADMA is independently related to flow-mediated vasodilation in subjects at low cardiovascular risk.

BACKGROUND: Increased plasma concentrations of asymmetric dimethylarginine (ADMA) contribute to impair endothelial function in patients with established cardiovascular disease (CVD) and/or individuals with clinical syndromes known to increase CVD. However, the impact of ADMA on endothelial function in apparently healthy individuals has not been determined. MATERIALS AND METHODS: To address this issue, we measured endothelial-dependent vasodilatation in response to forearm ischaemia (flow-mediated vasodilatation, FMD) in 111 non-smoking, healthy volunteers with low CVD risk by the Framingham risk equation. Measurements were also made of multiple anthropometric, metabolic, and dynamic variables related to FMD. l-arginine and its methylated derivates (ADMA and SDMA) were quantified by high-liquid pressure chromatography. RESULTS: After adjustment by gender, lower values for FMD were significantly associated with increases in plasma ADMA concentrations (anova linear trend by FMD tertiles, P < 0.05) as well as in brachial artery diameter (partial r = -0.352, P = 0.001), body mass index (-0.337, P = 0.001), fasting insulin (-0.368, P < 0.001) and high-sensitivity C-reactive protein (-0.283, P = 0.007) plasma concentrations, and with decreased HDL cholesterol (0.233, P = 0.026). Multiple linear regression analysis indicated that the only statistically significant predictors of FMD were brachial artery diameter (P < 0.001), ADMA (P < 0.05) and fasting plasma insulin (P < 0.001) concentrations. CONCLUSIONS: In conclusion, a significant relationship between increases in plasma ADMA concentration and lower values of FMD is not limited to patients with clinical syndromes related to CVD, but can also be seen in healthy subjects at low global CVD risk.

The relationship between insulin resistance and dyslipidaemia in cigarette smokers.

AIM: Considerable evidence shows that cigarette smokers tend to have the dyslipidemic pattern of high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations, a highly atherogenic lipoprotein profile also typical of the insulin-resistant state even in the absence of cigarette smoking. However, because cigarette smokers are frequently insulin resistant, it is unclear if this dyslipidaemia is secondary to smoking, per se, or simply to the fact that smokers tend to be insulin resistant. The present study was initiated to determine whether this dyslipidaemia prevalent in cigarette smokers and characteristic of insulin-resistant individuals is a function of cigarette smoking or of insulin resistance. METHODS: As measured using vertical auto profile-II methodology, the lipid and lipoprotein concentrations were compared in 34 cigarette smokers divided into insulin-sensitive and insulin-resistant subgroups. The two groups were similar in age and body mass index, differing only in their insulin-mediated glucose uptake as quantified by the steady-state plasma glucose concentration determined during the insulin suppression test. RESULTS: While levels of TG and very low-density lipoprotein cholesterol (VLDL-C) were significantly elevated in insulin-resistant cigarette smokers, total cholesterol (C), low-density lipoprotein cholesterol (LDL-C), narrow-density (ND) LDL-C, intermediate-density lipoprotein-C (IDL-C), HDL-C and non-HDL-C were not different in the two groups. The insulin-resistant smokers also had a preponderance of small, dense LDL particles, while the reverse was true of the insulin-sensitive cigarette smokers. CONCLUSIONS: These data suggest that the dyslipidaemia previously attributed to smoking occurs primarily in those smokers who are also insulin resistant.

Insulin resistance, the insulin resistance syndrome, and cardiovascular disease.

Insulin-mediated glucose disposal varies widely in apparently healthy human beings, and the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes increase risk of cardiovascular disease (CVD), and in 1988, this cluster of related abnormalities was designated as comprising a syndrome (X). Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome. In addition to the identification of additional clinical syndromes related to insulin resistance/hyperinsulinemia, a number of new risk factors have been recognized that would increase CVD risk in these individuals. Thus, in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension. The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to try to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful.