Steady-state Plasma Glucose Concentrations Research Articles

Isolated Impaired Fasting Glucose and Peripheral Insulin Sensitivity

In a recent consensus statement, the American Diabetes Association (ADA) concluded that individuals with impaired fasting glucose (IFG) have "normal muscle insulin sensitivity." To subject this conclusion to further validation, we evaluated the relationship between glucose tolerance categories and peripheral insulin sensitivity in a large nondiabetic population. Insulin sensitivity was directly quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 nondiabetic individuals divided into four groups: normal glucose tolerance (NGT, n = 318), isolated IFG (n = 63), isolated impaired glucose tolerance (IGT, n = 33), and combined IFG and IGT (IFG/IGT, n = 32). Insulin sensitivity was significantly different in all three groups with pre-diabetes (IFG, IGT, IFG/IGT) as compared with NGT (P < 0.05). Using tertiles of SSPG concentration in the NGT group as operational definitions of insulin resistance (highest tertile) and insulin sensitivity (lowest tertile), there was considerable heterogeneity within the pre-diabetic groups. Thus, 57% of IFG individuals were insulin resistant, and 13% were insulin sensitive. The IFG/IGT group was most homogeneous, with 94% classified as insulin resistant and only 3% as insulin sensitive. Peripheral insulin sensitivity varies considerably in nondiabetic individuals, with IFG individuals showing the most heterogeneity within the pre-diabetes group. We believe that this heterogeneity in insulin sensitivity, and the relatively few patients in whom insulin sensitivity has been measured directly in the past, explain the discrepancy between our findings and those of the recent ADA consensus statement.

Lipoprotein abnormalities are associated with insulin resistance in South Asian Indian women

South Asian Indians are at increased risk of coronary heart disease (CHD), possibly related to dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations. The importance of differences in insulin resistance as compared to abdominal obesity in the development of this atherogenic lipoprotein profile is not clear, and the current cross-sectional study was initiated to examine this issue. Consequently, we defined the relationship between differences in insulin-mediated glucose uptake (IMGU), abdominal obesity, and various measures of lipoprotein metabolism known to increase CHD risk in 52 apparently healthy women of South Asian Indian ancestry. IMGU was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test and abdominal obesity was assessed by measurement of waist circumference (WC), and the population was divided into tertiles on the basis of their SSPG results. Results indicated that although there were significant differences in SSPG, TG, and HDL-C values, there were no differences in age, blood pressure, total cholesterol, low-density lipoprotein cholesterol, body mass index, or WC between the highest and lowest tertiles. SSPG concentrations were significantly correlated with both log TG ( r = 0.44, P = .001) and HDL-C ( r = −0.44, P < .001) concentration, whereas TG and HDL-C concentrations were not significantly related to WC. Furthermore, the relationships between SSPG concentration and TG and HDL-C remained significant when adjusted for age and WC. Finally, a more extensive lipoprotein analysis indicated that the most insulin resistant tertile had higher TG concentrations, lower concentrations of HDL-C and HDL-C subclasses, and smaller and denser low-density lipoprotein particles than the most insulin sensitive tertile, despite the 2 groups not being different in age, BMI, or WC. These results indicate that a highly atherogenic lipoprotein profile seen in South Asian Indian women is significantly associated with insulin resistance independent of differences in WC.

Serum Alanine Aminotransferase Levels Decrease Further With Carbohydrate Than Fat Restriction in Insulin-Resistant Adults

Although weight loss interventions have been shown to reduce steatosis in nonalcoholic fatty liver disease (NAFLD), the impact of dietary macronutrient composition is unknown. We assessed the effect on serum alanine aminotransferase (ALT) concentrations of two hypocaloric diets varying in amounts of carbohydrate and fat in obese insulin-resistant individuals, a population at high risk for NAFLD. Post hoc analysis of ALT concentrations was performed in 52 obese subjects with normal baseline values and insulin resistance, as quantified by the steady-state plasma glucose (SSPG) test, who were randomized to hypocaloric diets containing either 60% carbohydrate/25% fat or 40% carbohydrate/45% fat (15% protein) for 16 weeks. The primary end point was change in ALT, which was evaluated according to diet, weight loss, SSPG, and daylong insulin concentrations. Although both diets resulted in significant decreases in weight and SSPG, daylong insulin, and serum ALT concentrations, the 40% carbohydrate diet resulted in greater decreases in SSPG (P < 0.04), circulating insulin (P < 0.01), and ALT (9.5 +/- 9.4 vs. 4.2 +/- 8.3 units/l; P < 0.04) concentrations. ALT changes correlated with improvement in insulin sensitivity (P = 0.04) and daylong insulin (P < 0.01). Individuals with ALT concentrations above the proposed upper limits experienced significant declines in ALT, unlike those with lower ALT levels. In a population at high risk for NAFLD, a hypocaloric diet moderately lower in carbohydrate decreased serum ALT concentrations to a greater degree than a higher-carbohydrate/low-fat diet, despite equal weight loss. This may result from a relatively greater decline in daylong insulin concentrations. Further research with histological end points is needed to further explore this finding.

TheAPOB-516C/T polymorphism is associated with differences in insulin sensitivity in healthy males during the consumption of diets with different fat content

Several apo B polymorphic sites have been studied for their potential use as markers for CHD in the population and for potential gene-diet interactions. Our aim was to determine whether the presence of the -516C/T polymorphism in the APOB gene promoter modifies insulin sensitivity to dietary fat. We studied fifty-nine healthy volunteers (thirty men and twenty-nine women, thirty-six homozygotes for the -516C allele (C/C) (nineteen males and seventeen females) and twenty-three heterozygotes for the -516T allele (C/T) (eleven males and twelve females)). Subjects consumed three diets during the feeding study, 4 weeks each: an SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate (CHO)-rich diet (30 % fat, 55 % CHO) or a MUFA-rich diet (38 % fat, 22 % MUFA) following a randomised cross-over design. For each diet, we investigated peripheral insulin sensitivity with the insulin suppression test. Male carriers of the -516T allele showed a significantly greater decrease in steady-state plasma glucose concentrations when changing from the SFA-rich diet (9.18 (sd 1.35) mmol/l) to the MUFA (6.55 (sd 0.74) mmol/l) or the CHO (6.31 (sd 0.93) mmol/l) diets than did those who were homozygous for the C allele (P = 0.040). Furthermore, C/T subjects presented higher plasma NEFA values after consumption of the SFA diet compared with the MUFA and CHO diets (P = 0.001). This effect was not observed in females (P = 0.908). Our findings show that male carriers of the -516T allele, C/T, have a significant increase in insulin resistance after consumption of all diets, but the difference is more exaggerated after the SFA diet compared with the MUFA- and CHO-rich diets.

Comparison of Body Mass Index Versus Waist Circumference With the Metabolic Changes That Increase the Risk of Cardiovascular Disease in Insulin-Resistant Individuals

This study compared the abilities of body mass index (BMI) and waist circumference (WC) to identify resistance to insulin-mediated glucose uptake and related metabolic abnormalities in 261 apparently healthy patients. Insulin resistance and associated metabolic abnormalities occur more commonly in the overweight/obese, and these changes increase the risk of cardiovascular disease (CVD). Determining either their BMI or WC can identify patients more likely to experience the adverse effects of excess adiposity on CVD risk, and the relative clinical utility of these measurements is not clear. Therefore, insulin-mediated glucose uptake was quantified in 261 apparently healthy adults by determining the steady-state plasma glucose concentrations during the insulin suppression test; the higher the concentration, the greater the defect in insulin action. The fasting plasma glucose, triglyceride, and total, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations were also measured, and the associations between these variables and the measurements of BMI and WC were determined. The greater the degree of adiposity, the higher the steady-state plasma glucose, fasting plasma glucose, and triglyceride concentrations, irrespective of the index of adiposity used. However, increases in the total and low-density lipoprotein cholesterol and decreases in the high-density lipoprotein cholesterol concentrations were only seen in those with higher BMI values. In conclusion, because BMI performed at least as well as WC in identifying differences in insulin sensitivity and multiple CVD risk factors, either estimate can be used to identify patients at increased CVD risk.

The relationship between insulin resistance and dyslipidaemia in cigarette smokers

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. 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. 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. These data suggest that the dyslipidaemia previously attributed to smoking occurs primarily in those smokers who are also insulin resistant.

Plasma Asymmetric Dimethylarginine Concentrations Are Elevated in Obese Insulin-Resistant Women and Fall with Weight Loss

Plasma asymmetric dimethylarginine (ADMA) concentrations are higher in apparently healthy, insulin-resistant (IR) individuals and decrease in response to thiazolidenedione treatment. The objective of the study was to determine whether ADMA concentrations would also fall when insulin sensitivity is enhanced with weight loss in obese individuals. DESIGN/SETTING/PATIENTS/INTERVENTION: Twenty obese women classified as IR or insulin sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration during the insulin suppression test underwent 12 wk of dietary weight loss. Plasma glucose, insulin, and ADMA were measured at baseline and after weight loss; change in insulin resistance was quantified by repeating the SSPG after the dietary intervention. Although weight loss was similar in the two groups, significant improvements in SSPG, glucose, and insulin concentrations were confined to the IR group. Baseline plasma ADMA concentrations (mean +/- sd) were higher in IR subjects (1.69 +/- 0.44 vs. 1.18 +/- 0.45 micromol/liter, P = 0.02) and decreased to 1.20 +/- 0.22 micromol/liter (P < 0.001) with weight loss. In contrast, ADMA levels did not change with a similar extent of weight loss in the IS group. Plasma ADMA levels are higher in obese, IR women than in equally obese, IS women and decrease in response to weight loss when associated with enhancement of insulin sensitivity.

Body mass index and waist circumference both contribute to differences in insulin-mediated glucose disposal in nondiabetic adults

Overweight and obese individuals are more likely to be insulin resistant and at increased risk of adverse clinical outcomes. Questions remain as to whether waist circumference (WC) or body mass index (BMI) most effectively identifies insulin-resistant individuals. This study quantified insulin-mediated glucose uptake (IMGU) in 330 apparently healthy volunteers and compared the relation between this value and measurements of WC and BMI. IMGU was quantified via determination of the steady-state plasma glucose (SSPG) concentration during the insulin-suppression test. Differences in SSPG concentrations due to variations in WC within a given BMI category, as well as those due to differences in BMI within a given WC classification, were then compared. BMI and WC correlated with each other (r = 0.78, P < 0.001) and equally with SSPG concentrations (r = 0.58 and 0.57, respectively; P < 0.001). When stratified by BMI, abdominally obese subjects within the overweight BMI category had higher SSPG concentrations than did those with a normal WC (P < 0.05). When classified by WC, subjects in the overweight BMI category had greater SSPG concentrations than did subjects in the normal BMI category within the normal WC category (P < 0.01), as did subjects in the obese BMI category in comparison with subjects in the overweight BMI category within the obese WC category (P < 0.01). The more overweight or obese a person, the greater the degree of insulin resistance; differences in adiposity accounted for approximately one-third of the variation in IMGU, irrespective of the index used. Furthermore, there was no difference in the relation between the degree of insulin resistance and either index of adiposity.

The Apolipoprotein E Gene Promoter (−219G/T) Polymorphism Determines Insulin Sensitivity in Response to Dietary Fat in Healthy Young Adults

Insulin sensitivity (IS) is determined by genetic and environmental factors, including diet. The apoE gene promoter -219G/T polymorphism is associated with coronary heart disease and increased postprandial triacylglycerol-rich lipoprotein concentration, circumstances related to insulin resistance. Thus, our aim was to determine whether this polymorphism modified the IS response to dietary fat in healthy young adults. Volunteers (n = 43) with the apoE3/E3 genotype (8 GG, 25 GT and 10 TT) completed 3 dietary periods, each lasting 4 wk. They first consumed a SFA-rich diet [38% fat (% of energy in the total diet), 20% SFA (% of energy in the total diet)], and then, in a randomized, crossover design, a carbohydrate (CHO)-rich diet (30% fat, 55% CHO) or a monounsaturated fatty acid (MUFA)-rich diet (38% fat, 22% MUFA). After each diet period, we investigated peripheral IS using the insulin suppression test. The steady-state plasma glucose (SSPG) concentration was lower (P < 0.05) in GG subjects than in GT and TT individuals, regardless of the diet consumed. Significant diet x genotype interactions were found for SSPG and plasma nonesterified FFA (NEFA) concentrations. Thus, the shift from the SFA-rich diet to the MUFA- or CHO-rich diets decreased (P < 0.05) the SSPG and NEFA concentrations in GG and GT, but not in TT subjects. In conclusion, carriers of the -219T allele are less insulin sensitive than GG individuals. Furthermore, only carriers of the -219G allele have improved IS when MUFA- or CHO-rich diets are consumed instead of a SFA-rich diet.

Body mass index and waist circumference correlate to the same degree with insulin-mediated glucose uptake

To compare the relationship between insulin-mediated glucose uptake (IMGU) and excess adiposity as determined by measurement of either body mass index (BMI) or waist circumference (WC), IMGU was quantified by determining the steady-state plasma glucose (SSPG) concentration with the insulin suppression test and the relationship between the SSPG concentration and BMI or WC evaluated in a study of 208 healthy individuals (128 women/80 men). The results indicated that BMI and WC were correlated ( P < .001) to a similar degree in both men ( r = 0.90) and women ( r = 0.86). Steady-state plasma glucose and both indices of excess adiposity were also significantly correlated ( P < .001) to an essentially identical extent in men ( r values of 0.71 vs 0.70) and women ( r values of 0.54 vs 0.53). When the population was divided into tertiles on the basis of SSPG concentrations, 96% of those in the most insulin-resistant tertile were identified as being overweight/obese by BMI criteria and 84% as abdominally obese by WC criteria. However, a substantial number of those in the most insulin-sensitive tertile also demonstrated excess adiposity as defined by either BMI (45%) or WC (33%). To summarize, (1) BMI and WC correlate closely within an individual and equally well with IMGU, and (2) BMI is as effective as WC in identifying insulin-resistant individuals.

Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals

Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means +/- SE from 13.5 +/- 0.62 to 9.8 +/- 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P = 0.008) during the insulin suppression test and by 21% (P = 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR.

The Ala54Thr polymorphism of the fatty acid–binding protein 2 gene is associated with a change in insulin sensitivity after a change in the type of dietary fat

Background: Insulin resistance, a condition associated with type 2 diabetes, results from the interaction of environmental and genetic factors. Objective: We examined the influence of the intestinal fatty acid-binding protein 2 (FABP2) Ala54Thr polymorphism on insulin sensitivity. Design: Fifty-nine healthy young subjects (28 were Ala54/Ala54, 27 were Ala54/Thr54, and 4 were Thr54/Thr54) completed 3 diets, each of which lasted 4 wk. The first diet, which all subjects consumed, was a high-saturated fatty acid (SFA) diet (38% of energy as fat and 20% of energy as SFAs). The second and third diets were administered according to a randomized crossover design, and they consisted of a low-fat and high-carbohydrate diet (CHO diet; 28% of energy from fat and <10% of energy from SFAs) and a high-monounsaturated fatty acid (MUFA) diet (called the Mediterranean diet; 38% of energy from fat and 22% of energy from MUFAs). All food and drinks were prepared and provided in the research kitchen. We determined in vivo insulin resistance by using the insulin suppression test with somatostatin. Results: Steady state plasma glucose concentrations were significantly higher in Ala54Thr subjects after the SFA diet than after the CHO diet or the Mediterranean diet. The plasma free fatty acid concentrations in these subjects were significantly lower after the CHO and Mediterranean diets than after the SFA diet. However, no significant differences between the 3 diets were observed in the Ala54 allele homozygotes. Conclusion: Insulin sensitivity decreased in subjects with the Thr54 allele of the FABP2 polymorphism when SFAs were replaced by MUFAs and carbohydrates.

Is There a Simple Way to Identify Insulin-Resistant Individuals at Increased Risk of Cardiovascular Disease?

The goal of this study was to evaluate the ability of various routine measures of lipoprotein metabolism to identify patients who were insulin resistant and dyslipidemic, and therefore, at increased risk of cardiovascular disease. For this purpose, insulin resistance was quantified by determining the steady-state plasma glucose concentration during the insulin suppression test in 449 apparently healthy patients. The low-density lipoprotein (LDL) particle diameter and subclass phenotype were measured by gradient gel electrophoresis in 1,135 patients. Pearson's correlation coefficients and receiver-operating characteristic curves were used to evaluate measures of lipoprotein metabolism as potential markers of insulin resistance and LDL phenotype. The results indicated that the ratio of the plasma concentrations of triglyceride to high-density lipoprotein cholesterol was the best predictor of insulin resistance and LDL particle diameter. The optimal triglyceride/high-density lipoprotein cholesterol ratio for predicting insulin resistance and LDL phenotype was 3.5 mg/dl; a value that identified insulin-resistant patients with a sensitivity and specificity comparable to the criteria currently proposed to diagnose the metabolic syndrome. The sensitivity and specificity were even greater for identification of patients with small, dense, LDL particles. In conclusion, a plasma triglyceride/high-density lipoprotein cholesterol concentration ratio > or =3.5 provides a simple means of identifying insulin-resistant, dyslipidemic patients who are likely to be at increased risk of cardiovascular disease.

The −514 C/T polymorphism in the hepatic lipase gene promoter is associated with insulin sensitivity in a healthy young population

Impaired insulin action has been associated with diabetes, dyslipidemia and atherosclerotic vascular disease. The expression of insulin resistance results from the interaction of environmental and genetic factors. Human hepatic lipase (HL) is a lipolytic enzyme that plays a role in the metabolism of several lipoproteins, while insulin up-regulates the activity of HL via insulin-responsive elements in the HL promoter. We have examined the influence of -514 C/T polymorphism in the hepatic lipase gene promoter on insulin sensitivity in 59 healthy young subjects (30 males and 29 females). The volunteers were subjected to three dietary periods, each lasting four weeks. During the first period all subjects consumed a saturated fat (SFA)-enriched diet with 38% as fat (20% SFA, 12% monounsaturated fatty acids (MUFA) and 6% polyunsaturated fatty acids (PUFA)). In the second and third dietary periods, a randomized crossover design was used, consisting of a low fat, high carbohydrate diet (CHO diet) (< 10% SFA, 12% MUFA and 6% PUFA) and a high-MUFA, or Mediterranean diet, with < 10% SFA, 22% MUFA and 6% PUFA. We determined the in vivo insulin resistance using the insulin suppression test with somatostatin. Steady-state plasma glucose (SSPG) concentrations (a measure of insulin sensitivity) were significantly higher in men carriers of the -514T allele after the consumption of the SFA diet than after the CHO diet and the Mediterranean diet. This effect was not observed in women. Moreover, there were no significant differences in insulin sensitivity after the three diets in men and women with the CC genotype. In summary, our results show an improvement in insulin sensitivity in men with the -514T allele of the HL promoter polymorphism, when MUFA and carbohydrates are consumed instead of SFA fat.

Relationship between several surrogate estimates of insulin sensitivity in non-diabetic patients with coronary artery disease.

Insulin resistance plays an important role in the pathogenesis of coronary artery disease (CAD). Thus, there is a need for accurate and accessible tools for measurement of insulin sensitivity in patients with this disease. This study explored the relationship between several surrogate estimates of insulin sensitivity in non-diabetic patients with angiographic evidence of CAD. The study population consisted of 1363 non-diabetic subjects with angiography results which revealed evidence of CAD in 660 and no evidence of CAD in 703 subjects. After overnight fasting, blood samples were drawn for determination of glucose and insulin concentrations in order to determine the homeostasis model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). In addition, steady-state plasma glucose (SSPG) concentrations obtained from insulin suppression tests were carried out in 54 subjects with and 194 subjects without CAD. The correlation of QUICKI with other surrogate estimates of insulin sensitivity in obese and non-obese subjects was also evaluated. The QUICKI correlated significantly with other methods for estimating insulin sensitivity in the CAD and non-CAD groups. The QUICKI also had a closer correlation with SSPG and log fasting plasma insulin (log FPI) in subjects with CAD (r = -0.573 and -0.869, respectively) than HOMA-IR (r = 0.508 and 0.777, respectively). QUICKI had a closer correlation with SSPG in the obese subjects than in the non-obese subjects, irrespective of the presence of CAD. The QUICKI was more closely related with SSPG, insulin area, and log FPI than other measurements of insulin sensitivity. These findings suggest that the QUICKI may provide a convenient, efficient method to measure insulin sensitivity in non-diabetic patients with CAD.

Comparative effects of rosuvastatin and gemfibrozil on glucose, insulin, and lipid metabolism in insulin-resistant, nondiabetic patients with combined dyslipidemia

To evaluate the pharmacologic intervention most likely to decrease cardiovascular disease risk in insulin-resistant patients with combined dyslipidemia, 39 patients with this abnormality were assessed before and after 3 months of treatment with gemfibrozil (1,200 mg/day) or rosuvastatin (40 mg/day) with regard to: (1) steady-state plasma glucose concentration at the end of a 180-minute infusion of octreotide, insulin, and glucose; (2) fasting lipid, lipoprotein, and apolipoprotein concentrations; and (3) daylong glucose, insulin, triglyceride, and remnant lipoprotein cholesterol concentrations in response to breakfast and lunch. The 2 groups were similar at baseline in age, gender, body mass index and in measurements of carbohydrate and lipoprotein metabolism. Neither gemfibrozil nor rosuvastatin enhanced insulin sensitivity or lowered daylong glucose and insulin concentrations in insulin-resistant patients with combined dyslipidemia, but both drugs significantly decreased fasting triglyceride concentrations. However, only rosuvastatin treatment significantly (p <0.05 to <0.001) reduced fasting low-density lipoprotein cholesterol, apolipoprotein B-100, apolipoprotein C-III, apolipoprotein C-III:B particles, the apolipoprotein B-100:apolipoprotein A-I ratio, and increased apolipoprotein A-I (p <0.05). The degree of improvement in fasting and postprandial remnant lipoprotein cholesterol concentrations was significantly greater (p <0.05) in rosuvastatin-treated patients, and this difference in the relative effectiveness of the drugs was also true of the decrease in non-high-density lipoprotein cholesterol concentrations.

Impact of degree of obesity on surrogate estimates of insulin resistance.

To evaluate the role of adiposity in the relationship between specific and surrogate estimates of insulin-mediated glucose uptake (IMGU) in a large nondiabetic population. Healthy volunteers were classified by BMI into normal weight (<25.0 kg/m(2), n = 208), overweight (25.0-29.9 kg/m(2), n = 168), and obese (>or=30.0 kg/m(2), n = 109) groups. We then assessed how differences in BMI affect the correlation between steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, glucose, and insulin (a specific measure of IMGU) and five surrogate estimates: fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve for insulin in response to oral glucose (I-AUC). Correlation coefficients (r values) between SSPG and surrogate measures of IMGU were all significant (P < 0.05), but the magnitude varied between BMI groups: normal weight: fasting plasma glucose 0.20, fasting plasma insulin 0.33, HOMA-IR 0.36, QUICKI -0.33, and I-AUC 0.69; overweight: fasting plasma glucose 0.19, fasting plasma insulin 0.55, HOMA-IR 0.55, QUICKI -0.54, and I-AUC 0.72; and obese: fasting plasma glucose 0.40, fasting plasma insulin 0.56, HOMA-IR 0.60, QUICKI -0.61, and I-AUC 0.69. The relationship between direct and surrogate estimates of IMGU varies with BMI, with the weakest correlations seen in the normal-weight group and the strongest in the obese group. In general, I-AUC is the most useful surrogate estimate of IMGU in all weight groups. Fasting plasma insulin, HOMA-IR, and QUICKI provide comparable information about IMGU. Surrogate estimates of IMGU based on fasting insulin and glucose account for no more than 13% of the variability in insulin action in the normal-weight group, 30% in the overweight group, and 37% in the obese group.

Plasma Ghrelin Concentrations Are Decreased in Insulin-Resistant Obese Adults Relative to Equally Obese Insulin-Sensitive Controls

Ghrelin, an orexigenic hormone that may play a role in body weight regulation, is reduced in states of obesity. Because obesity is associated with insulin resistance and compensatory hyperinsulinemia, we determined whether these metabolic characteristics were independently associated with suppressed ghrelin concentrations. To investigate this hypothesis, using steady-state plasma glucose concentrations, we identified 20 insulin-resistant (IR) and 20 insulin-sensitive (IS) individuals who were equally obese. The mean body mass indexes were 32.5 +/- 0.4 and 32.0 +/- 0.4 kg/m(2) for the IR and IS groups, respectively. Fasting insulin concentrations were 19.5 and 7.4 micro U/ml (P < 0.001), respectively. Ghrelin concentrations were suppressed in the IR group (252 +/- 19 pg/ml) relative to the IS group (412 +/- 35 pg/ml; P < 0.001). Ghrelin correlated inversely with both insulin resistance (r = -0.64; P < 0.001) and fasting insulin concentration (r = -0.58; P < 0.001). Multivariate analysis confirmed that both insulin resistance and hyperinsulinemia independently predicted low ghrelin concentrations. Our results demonstrate that in obese individuals, insulin resistance and hyperinsulinemia are inversely associated with ghrelin concentrations. Thus, insulin resistance or related metabolic abnormalities may constitute part of a feedback mechanism by which body weight is regulated in humans.

Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals

Obese individuals tend to be both insulin resistant and at increased risk to develop cardiovascular disease (CVD). Given the increased prevalence of obesity in the US population, we thought it important to define the relationship between degree of obesity and insulin-mediated glucose disposal in the population at large, as well as the relationship between obesity, insulin resistance, and CVD risk in these individuals. To do this we quantified insulin-mediated glucose disposal in 465 healthy volunteers by determining the steady-state plasma glucose (SSPG) concentrations at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Adiposity was estimated by body mass index (BMI) and the relationship between BMI and SSPG defined. In addition, a series of CVD risk factors were measured, including blood pressure, plasma glucose, and insulin concentrations, before and after 75 g of oral glucose, and fasting plasma lipid and lipoprotein concentrations. The results indicated that SSPG concentration and BMI were significantly correlated ( r = 0.54, P > .001), and 36% of individuals in the most insulin-resistant tertile were obese (BMI ≥ 30.0 kg/m 2). However, 16% of those in the most insulin-resistant tertile were of normal weight (BMI < 25.0 kg/m 2). Although CVD risk factors were accentuated in general with progressive increases in either BMI or SSPG concentration, important differences were noted. Thus, the higher the SSPG concentration, the more the increase in plasma glucose, insulin, and triglyceride (TG) concentrations, whereas the greater the BMI, the higher the low-density lipoprotein concentration. Furthermore, while CVD risk factors increased significantly with each tertile of insulin resistance, significant differences in CVD risk were only apparent when the lowest BMI tertile was compared with the other 2, with the values in the middle and upper BMI differing from each other. These results show that while BMI and insulin resistance are related, they are not synonymous, and that they make independent and different contributions to increasing CVD risk.

Plasma adiponectin concentrations do not increase in association with moderate weight loss in insulin-resistant, obese women

Plasma adiponectin concentrations were measured before and after moderate weight loss in 20 obese women, divided at baseline into insulin-resistant (IR) and insulin-sensitive (IS) subgroups on the basis of their steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of octreotide, glucose, and insulin. The groups were similar in age and body weight and lost comparable amounts of weight (8 to 9 kg) during the weight loss period. Fasting plasma insulin and SSPG concentrations were significantly higher ( P < .001) and adiponectin concentrations somewhat lower ( P = .10) in the IR group ( P < .001) at baseline. Both SSPG and plasma insulin concentrations decreased in IR subjects ( P < .001), but did not change in IS individuals. Adiponectin concentrations did not change with weight loss in either group. Thus, neither weight loss, per se, nor enhanced insulin sensitivity resulted in a change in plasma adiponectin concentrations.