Dietary weight loss in insulin-resistant non-obese humans: Metabolic benefits and relationship to adipose cell size.

BACKGROUND AND AIMS: Overweight and obesity increase risk for diabetes and cardiovascular disease, largely through development of insulin resistance. Benefits of dietary weight loss are documented for obese individuals with insulin resistance. Similar benefits have not been shown in overweight individuals. We sought to quantify whether dietary weight loss improves metabolic risk profile in overweight insulin-resistant individuals, and evaluated potential mediators between weight loss and metabolic response. METHODS AND RESULTS: Healthy volunteers with BMI 25-29.9 kg/m2 underwent detailed metabolic phenotyping including insulin-mediated-glucose disposal, fasting/daylong glucose, insulin, triglycerides, FFA, and cholesterol. Subcutaneous fat biopsies were performed for measurement of adipose cell size. After 14 weeks of hypocaloric diet and 2 weeks of weight maintenance, cardiometabolic measures and biopsies were repeated. Changes in weight, % body fat, waist circumference, adipose cell size and FFA were evaluated as predictors of change in insulin resistance. Weight loss (4.3 kg) yielded significant improvements in insulin resistance and all cardiovascular risk markers except glucose, HDL-C, and LDL-C. Improvement in insulin sensitivity was greater among those with <2 vs >2 cardiovascular risk factors at baseline. Decrease in adipose cell size and waist circumference, but not weight or body fat, independently predicted improvement in insulin resistance. CONCLUSIONS: Weight loss yields metabolic health benefits in insulin-resistant overweight adults, even in the absence of classic cardiovascular risk factors. Weight loss-related improvement in insulin sensitivity may be mediated through changes in adipose cell size and/or central distribution of body fat. The insulin-resistant subgroup of overweight individuals should be identified and targeted for dietary weight loss. CLINICAL TRIALS IDENTIFIER: NCT00186459.

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.

Inflammation in subcutaneous adipose tissue: relationship to adipose cell size.

AIMS/HYPOTHESIS: Inflammation is associated with increased body mass and purportedly with increased size of adipose cells. We sought to determine whether increased size of adipose cells is associated with localised inflammation in weight-stable, moderately obese humans. METHODS: We recruited 49 healthy, moderately obese individuals for quantification of insulin resistance (modified insulin suppression test) and subcutaneous abdominal adipose tissue biopsy. Cell size distribution was analysed with a multisizer device and inflammatory gene expression with real-time PCR. Correlations between inflammatory gene expression and cell size variables, with adjustment for sex and insulin resistance, were calculated. RESULTS: Adipose cells were bimodally distributed, with 47% in a 'large' cell population and the remainder in a 'small' cell population. The median diameter of the large adipose cells was not associated with expression of inflammatory genes. Rather, the fraction of small adipose cells was consistently associated with inflammatory gene expression, independently of sex, insulin resistance and BMI. This association was more pronounced in insulin-resistant than insulin-sensitive individuals. Insulin resistance also independently predicted expression of inflammatory genes. CONCLUSIONS/INTERPRETATION: This study demonstrates that among moderately obese, weight-stable individuals an increased proportion of small adipose cells is associated with inflammation in subcutaneous adipose tissue, whereas size of mature adipose cells is not. The observed association between small adipose cells and inflammation may reflect impaired adipogenesis and/or terminal differentiation. However, it is unclear whether this is a cause or consequence of inflammation. This question and whether small vs large adipose cells contribute differently to inflammation in adipose tissue are topics for future research. TRIAL REGISTRATION: ClinicalTrials.gov NCT00285844.

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 is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women.

AIMS/HYPOTHESIS: We have previously described differences in adipose cell size distribution and expression of genes related to adipocyte differentiation in subcutaneous abdominal fat obtained from insulin-sensitive (IS) and -resistant (IR) persons, matched for degree of moderate obesity. To determine whether other biological properties also differ between IR and IS obese individuals, we quantified markers of inflammatory activity in adipose tissue from overweight IR and IS individuals. METHODS: Subcutaneous abdominal tissue was obtained from moderately obese women, divided into IR (n = 14) and IS (n = 19) subgroups by determining their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Inflammatory activity was assessed by comparing expression of nine relevant genes and by immunohistochemical quantification of CD45- and CD68-containing cells. RESULTS: SSPG concentrations were approximately threefold higher in IR than in IS individuals. Expression levels of CD68, EMR1, IL8, IL6 and MCP/CCL2 mRNAs were modestly but significantly increased (p < 0.05) in IR compared with IS participants. Results of immunohistochemical staining were consistent with gene expression data, demonstrating modest differences between IR and IS individuals. Crown-like structures, in which macrophages surround single adipocytes, were rarely seen in tissue from either subgroup. CONCLUSIONS/INTERPRETATION: A modest increase in inflammatory activity was seen in subcutaneous adipose tissue from IR compared with equally obese IS individuals. Together with previous evidence of impaired adipose cell differentiation in IR vs equally obese individuals, it appears that at least two biological processes in subcutaneous adipose tissue characterize the insulin-resistant state independent of obesity per se.

Persistence of improvement in insulin sensitivity following a dietary weight loss programme.

AIM: Short-term dietary weight loss can improve insulin resistance but long-term studies are lacking. We sought to quantify the degree to which maintenance of weight loss after a short-term dietary intervention was associated with persistent metabolic benefits. METHODS: Fifty-seven insulin-resistant obese subjects had insulin-mediated glucose disposal quantified through the steady-state plasma glucose (SSPG) test, and associated metabolic risk markers quantified at baseline, after a 16-week dietary weight loss intervention, and in 25 subjects, at follow-up of 28.8 +/- 13 months. Changes in metabolic variables over time were analysed and correlation with weight loss ascertained. Those with greatest vs. least long-term SSPG response (responders vs. non-responders) were compared. Multivariate analysis was performed for predictors of persistent SSPG response. RESULTS: At follow-up, the 25 subjects who returned for metabolic testing had, on average, maintained their weight loss. Insulin-mediated glucose disposal remained significantly improved vs. baseline, as did plasma triglyceride and HDL cholesterol (HDL-C) concentrations, and improvement correlated with total amount of weight lost. Comparison of SSPG responders to non-responders showed no difference in amount of weight lost and SSPG change during the 16-week dietary intervention; however, SSPG non-responders regained 2.6% of weight lost, whereas responders lost an additional 1.5% at follow-up (p < 0.05 vs. non-responders). Non-responders had baseline characteristics consistent with more severe insulin resistance, including higher fasting plasma glucose (p = 0.03). Long-term SSPG change was independently predicted by both total weight loss (p = 0.005) and baseline fasting plasma glucose (p = 0.007). CONCLUSIONS: Improvement in insulin sensitivity is maintained for 2-3 years following dietary weight loss if weight is not regained. Triglyceride and HDL-C concentrations also remain improved over time, consistent with improvement in insulin sensitivity. Fasting glucose and weight regain predict less long-term response in insulin sensitivity. These results highlight the potential long-term benefits of weight loss and importance of preventing weight regain among high-risk individuals.

Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and insulin resistance in healthy nondiabetic volunteers.

BACKGROUND: This study was initiated to compare the adherence to cultured endothelial cells of mononuclear cells isolated from normotensive and hypertensive individuals. METHODS AND RESULTS: Mononuclear cell binding to endothelium was greater in patients with hypertension (32+/-1 versus 25+/-2; P<0.001) than in normal volunteers. There was a significant relationship (r=0.42, P<0. 01) between mononuclear cell binding and mean arterial pressure, independent of differences in age, sex, and body mass index. A significant relationship also existed between insulin resistance (estimated by the steady-state plasma glucose concentration during the insulin suppression test) and mononuclear cell binding in both the normotensive (r=0.86, P<0.001) and hypertensive (r=0.74, P<0. 001) groups. Furthermore, multiple regression analysis demonstrated an independent relationship (P<0.001) between mononuclear cell binding and both steady-state plasma glucose and hypertensive status. CONCLUSIONS: These results indicate that both hypertension and insulin resistance lead to changes in mononuclear cells that increase their adherence to cultured endothelial cells.

Multiple valve operation for advanced valvular heart disease: results and risk factors in 513 patients.

To assess the results and incremental risk factors affecting outcome after multiple-valve operation in the early blood cardioplegia era of cardiac surgery, follow-up data (mean +/- SD 3.1 +/- 2 years) were obtained on 97% of 513 patients (mean age +/- SD 58.8 +/- 10.5 years) who underwent a multiple-valve procedure between June 1976 and August 1985. Preoperatively 41% of patients were in New York Heart Association functional class III and 54% in class IV. Three groups accounted for 98.6% of the patients: 57.7% had an aortic and mitral valve procedure, 29% had a mitral and tricuspid valve procedure and 11.9% had a triple-valve procedure. The overall hospital mortality rate was 12.5% and overall 5-year survival rate was 67.1%. Hazard function analysis for all deaths revealed systolic pulmonary artery pressure (p less than 0.0001), age (p = 0.005), triple valve procedure (p less than 0.005), concomitant coronary bypass operation (p less than 0.005) and prior cardiac surgery (p less than 0.002) as the significant incremental risk factors predicting decreased survival in the early hazard phase; diabetes (p less than 0.005) predicted decreased survival in the late hazard phase. Postoperatively the condition of 80% of the patients improved to functional class I or II; only 0.6% remained in functional class IV. The 5-year rate of freedom from late combined valve-related morbidity was 81.7% and that of freedom from late combined valve-related morbidity and mortality was 71.7%. These results demonstrate excellent clinical improvement and late survival after multiple valve operation in patients with advanced valvular heart disease, justifying aggressive surgical therapy in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbohydrate-induced hypertriglyceridemia: an insight into the link between plasma insulin and triglyceride concentrations.

This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.

The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers.

This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.

Fasting remnant lipoprotein cholesterol and triglyceride concentrations are elevated in nondiabetic, insulin-resistant, female volunteers.

This study was initiated to test the hypothesis that plasma concentrations of remnant lipoproteins would be higher after an overnight fast in insulin-resistant compared to insulin-sensitive volunteers. Forty-three healthy nonobese women were studied, divided into insulin-resistant (n = 21) and insulin-sensitive (n = 22) groups on the basis of their steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide acetate, insulin, and glucose. Under these conditions, steady state plasma insulin concentrations are similar in all subjects (approximately 60 microU/mL), and the higher the SSPG concentrations, the more insulin resistant the individual. By selection, mean (+/-SEM) SSPG concentrations were significantly higher (P < 0.001) in the insulin-resistant group (210 +/- 7 vs. 78 +/- 3 mg/dL). In addition, the insulin-resistant group had higher triglycerides (198 +/- 27 vs. 101 +/- 12 mg/dL; P < 0.005) and lower high density lipoprotein cholesterol (48 +/- 4 vs. 60 +/- 4 mg/dL; P < 0.05) concentrations. Finally, insulin resistance was associated with higher remnant lipoprotein particle concentrations of cholesterol (7.2 +/- 0.8 vs. 4.4 +/- 0.3; P < 0.005) and triglycerides (22.2 +/- 3.4 vs. 8.5 +/- 1.0; P < 0.001). All of these differences were seen despite the fact that the two groups were similar in terms of age and body mass index. These results identify additional abnormalities in lipoprotein metabolism that may contribute to the increased risk of coronary heart disease seen in insulin-resistant, nondiabetic subjects (syndrome X).

Effect of insulin resistance on postprandial elevations of remnant lipoprotein concentrations in postmenopausal women.

BACKGROUND: Questions remain as to why postmenopausal women are at a higher risk of coronary artery disease (CAD) than are premenopausal women. Studies have shown that plasma concentrations of remnant lipoproteins (RLPs) are elevated in patients with CAD and that increases in plasma RLP concentrations may be related to variations in insulin-mediated glucose disposal. OBJECTIVE: We sought to evaluate the possibility that postprandial accumulation of plasma RLPs will be accentuated in insulin-resistant, postmenopausal women. DESIGN: Postmenopausal women were divided into insulin-sensitive (n = 15) and insulin-resistant (n = 15) groups according to their steady state plasma glucose concentrations in response to a 180-min infusion of octreotide, insulin, and glucose. Plasma insulin, triacylglycerol, and RLP-cholesterol concentrations were measured either hourly (insulin) or every 2 h (triacylglycerol and RLP cholesterol) for 8 h, before and after breakfast (0800) and lunch (1200). RESULTS: By selection, insulin-resistant women had higher steady state plasma glucose concentrations than did insulin-sensitive women (10.8 +/- 0.5 compared with 4.1 +/- 5 mmol/L, respectively; P < 0.001), associated with higher fasting triacylglycerol (1.58 +/- 0.04 compared with 1.00 +/- 0.03 mmol/L; P = 0.01) and lower HDL-cholesterol (1.06 +/- 0.08 compared with 1.34 +/- 0.05; P = 0.01) concentrations. In addition, measurements of daylong concentrations of insulin, triacylglycerol, and RLP cholesterol were also significantly greater in insulin-resistant than in insulin-sensitive women (P < 0.001). CONCLUSIONS: Postprandial accumulation of RLPs is accentuated in insulin-resistant, postmenopausal women. This may contribute to the increased risk of CAD in these individuals.

High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk.

In this study we compared the effects of variations in dietary fat and carbohydrate (CHO) content on concentrations of triglyceride-rich lipoproteins in 8, healthy, nondiabetic volunteers. The diets contained, as a percentage of total calories, either 60% CHO, 25% fat, and 15% protein, or 40% CHO, 45% fat, and 15% protein. They were consumed in random order for 2 weeks, with a 2-week washout period in between. Measurements were obtained at the end of each dietary period of plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, remnant lipoprotein (RLP) cholesterol, and RLP triglyceride concentrations, both after an overnight fast and throughout an 8-hour period (8 A.M. to 4 P.M.) in response to breakfast and lunch. The 60% CHO diet resulted in higher (mean +/- SEM) fasting plasma triglycerides (206 +/- 50 vs 113 +/- 19 mg/dl, p = 0.03), RLP cholesterol (15 +/- 6 vs 6 +/- 1 mg/dl, p = 0.005), RLP triglyceride (56 +/- 25 vs 16 +/- 3 mg/dl, p = 0.003), and lower HDL cholesterol (39 +/- 3 vs 44 +/- 3 mg/dl, p = 0.003) concentrations, without any change in LDL cholesterol concentration. Furthermore, the changes in plasma triglyceride, RLP cholesterol, and RLP triglyceride persisted throughout the day in response to breakfast and lunch. These results indicate that the effects of lowfat diets on lipoprotein metabolism are not limited to higher fasting plasma triglyceride and lower HDL cholesterol concentrations, but also include a persistent elevation in RLPs. Given the atherogenic potential of these changes in lipoprotein metabolism, it seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO.

Insulin regulation of plasma free fatty acid concentrations is abnormal in healthy subjects with muscle insulin resistance.

This study evaluated the ability of insulin to regulate free fatty acid (FFA) concentrations in healthy nondiabetic subjects selected to be either insulin-resistant or -sensitive on the basis of insulin-mediated glucose disposal by muscle. Comparisons of steady-state plasma glucose (SSPG), insulin (SSPI), and FFA concentrations were made at the end of 3 infusion periods: (1) under basal insulin conditions (approximately 10 microU/mL), (2) in response to isoproterenol-induced stimulation of lipolysis at the same basal insulin concentration, and (3) following inhibition of isoproterenol-induced lipolysis by a 2-fold increase in the insulin concentration. The results showed that steady-state FFA concentrations were significantly higher under basal conditions (360 +/- 73 v 158 +/- 36 microEq/L, P = .02), in response to isoproterenol-induced lipolysis (809 +/- 92 v433 +/- 65 microEq/L, P = .005), and following insulin inhibition of isoproterenol-induced lipolysis (309 +/- 65 v 159 +/- 37 microEq/L, P = .06). These differences were found despite the fact that SSPG concentrations were also higher in insulin-resistant individuals during all 3 infusion periods. These results demonstrate that the ability of insulin to regulate plasma FFA concentrations is impaired in healthy subjects with muscle insulin resistance, indicating that insulin-resistant individuals share defects in the ability of insulin to stimulate muscle glucose disposal and to inhibit adipose tissue lipolysis.

Relationship between insulin resistance, weight loss, and coronary heart disease risk in healthy, obese women.

Several popular books have recently been published stating that being insulin-resistant favors weight gain and/or prevents weight loss. Because this view seems to have gained widespread support in the general population, we thought it important to perform the current study testing the hypothesis that differences in insulin-mediated glucose disposal do not affect weight loss in response to calorie-restricted diets. For this purpose, we studied the change in weight and risk factors for coronary heart disease (CHD) in healthy women volunteers, defined as being obese on the basis of a body mass index (BMI) greater than 30.0 kg/m(2). The insulin suppression test was used to stratify obese women at baseline into insulin-resistant and insulin-sensitive subgroups on the basis of their steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of octreotide, exogenous insulin, and glucose. They were then instructed on a calorie-restricted diet plus sibutraminine (15 mg/day) for a total period of 4 months. Baseline measurements also included determination of fasting lipid and lipoprotein concentrations, and hourly (8 AM to 4 PM) determinations of plasma glucose and insulin concentrations before and after breakfast and lunch. Twenty-four women completed the 4-month period of calorie restriction: 13 classified as insulin-resistant (SSPG = 219 +/- 7 mg/dL) and 11 as insulin-sensitive (SSPG = 69 +/- 6 mg/dL). The insulin-resistant group also had higher (P =.03) plasma triglyceride (TG) concentrations and a higher ratio of total to high-density lipoprotein (HDL) cholesterol concentration (P =.02) at baseline. Both groups lost a significant amount of weight during the study, and there was no difference between the weight loss in the insulin-resistant (8.6 +/- 1.3 kg) and insulin-sensitive (7.9 +/- 1.4 kg) groups. Weight loss in the insulin-resistant group was also associated with a significant decrease in SSPG concentration (219 +/- 7 to 144 +/- 14 mg/dL), associated with significantly lower fasting TG concentrations (P <.001) and day-long concentrations of plasma glucose and insulin (P <.005). None of these variables changed in the insulin-sensitive group. These results indicate that: (1) CHD risk factors in obese women vary as a function of being insulin-resistant or insulin-sensitive; (2) dramatic variations in insulin-mediated glucose disposal do not modulate weight loss in response to calorie-restricted diets, and (3) weight loss is effective in reducing CHD risk in insulin-resistant, obese women. Given these data, it seems obvious that attempts to reduce CHD risk factors by weight loss should focus on obese individuals who are also insulin-resistant.

Metabolic changes following sibutramine-assisted weight loss in obese individuals: role of plasma free fatty acids in the insulin resistance of obesity.

The relationship between insulin-mediated glucose disposal and daylong free fatty acid (FFA) concentrations before and after sibutramine-assisted weight loss was investigated in 24 healthy, normotensive, nondiabetic, obese women (body mass index [BMI] >30.0 kg/m(2)). The 24 volunteers were defined as being insulin-resistant (IR) or insulin-sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration in response to a 180-minute continuous intravenous infusion of octreotide, insulin, and glucose. The mean (+/- SEM) SSPG concentrations were significantly higher (P <.001) in the IR group (219 +/- 7 v 69 +/- 6 mg/dL) at baseline. The IR group also had significantly higher plasma glucose (P =.002), insulin (P <.001), and FFA (P =.02) concentrations measured at hourly intervals from 8 AM to 4 PM, before and after breakfast (8 AM) and lunch (noon). Weight loss in response to an energy-restricted diet for 4 months and sibutramine (15 mg/d) was comparable in the 2 experimental groups (8.6 +/- 1.3 v 7.9 +/- 1.4 kg). SSPG concentrations decreased significantly (P <.001) following weight loss (219 +/- 7 to 144 +/- mg/dL) in the IR group, but there was no change in the SSPG of the IS group (69 +/- 6 to 73 +/- 7 mg/dL. The improvement in insulin sensitivity in the IR group after weight loss was associated with a significant decline in daylong plasma glucose (P >.001) and insulin (P =.02) concentrations, without a weight-loss-associated decrease in daylong plasma FFA responses. In contrast, there was no significant change in plasma glucose, insulin, and FFA concentrations following weight loss in the IS group. These results indicate that daylong FFA concentrations vary substantially in obese individuals as a function of whether they are IR or IS. Furthermore the observation that the IR group was more insulin-sensitive after weight loss, associated with lower daylong insulin concentrations in the absence of a significant decrease in circulating FFA concentrations, suggests that resistance to insulin-mediated glucose disposal in obese individuals cannot be entirely due to high FFA levels.

Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes.

This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.

Insulin resistance, dietary cholesterol, and cholesterol concentration in postmenopausal women.

Questions remain concerning the effect of variations in cholesterol intake on plasma cholesterol concentration, as well as on the role of factors modulating the metabolic impact of this dietary intervention. To define the impact of wide variations in dietary cholesterol intake on plasma total and low-density lipoprotein (LDL) cholesterol concentrations, as well as testing the hypothesis that resistance to insulin-mediated glucose disposal would accentuate the increase in plasma total and LDL cholesterol concentrations in response to a given increment in dietary cholesterol intake, we performed a prospective, randomized study comparing diets varying in cholesterol content in 65 healthy, postmenopausal women, 31 defined as insulin-resistant and 34 as insulin-sensitive. The changes in total and LDL cholesterol in response to increments in dietary cholesterol of up to approximately 800 mg/day were modest in magnitude, without evidence of a statistically significant diet-induced increase in cholesterol concentration, or of any difference in the responses of insulin-resistant as compared with insulin-sensitive women. These results indicate that relatively large increments in dietary cholesterol intake had little effect on total or LDL cholesterol concentrations in healthy, postmenopausal women, irrespective of whether they were insulin-resistant or insulin-sensitive.

Multiple aneurysms of the coronary arteries in a patient with systemic aneurysmal disease.

A case of multiple coronary artery aneurysms in a patient with an abdominal aortic aneurysm and bilateral popliteal artery aneurysms is reported. As diagnosis and treatment of coronary artery disease become more aggressive, a higher incidence of detection of coronary artery aneurysms in conjunction with peripheral vascular lesions is likely. The role of coronary sinus cardioplegia in minimizing the risk of embolization from the coronary aneurysms during surgical repair is emphasized.

Effects of graded reductions in internal mammary artery bypass flow on left ventricular function.

This study investigated the controversial relationship between reduction in internal mammary artery (IMA) graft blood flow and left ventricular function in a canine model. Ten dogs underwent IMA grafting to the left anterior descending coronary artery. The left anterior descending coronary artery proximal to the IMA graft was intermittently occluded while IMA flow was mechanically controlled for 5-minute periods to produce four IMA flow groups representing 100%, 75%, 50%, and 25% of unoccluded IMA graft blood flow. As a control, the left ventricle was reperfused with native left anterior descending coronary artery flow between each IMA graft flow period to allow return to steady state. Sonomicrometry was used to obtain stroke work end-diastolic dimension relationship data for regional and global left ventricular function for each of the four flow groups. The global pressure recruitable work area relationship showed a significant rightward shift at 25% of unoccluded IMA flow, whereas the regional pressure recruitable work area relationship shifted at 50% of unoccluded IMA flow. Thus, regional myocardial function is more sensitive to reductions in IMA blood flow than is global left ventricular performance, and there is a significant IMA flow reserve for global left ventricular function.