Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia.

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.

Associations between lipoprotein lipase gene polymorphisms and insulin resistance in coronary heart disease.

BACKGROUND: Lipoprotein lipase (LPL) is a crucial enzyme in plasma lipoprotein metabolism. Variants of the LPL gene (Pvu II and Hind III polymorphisms) may increase the risk of developing coronary heart disease (CHD) but their effect on insulin resistance remains unknown. The present study was conducted to examine whether DNA variations of the LPL gene were related to insulin resistance, carbohydrate and lipid risk factors for CHD in nondiabetic individuals. METHODS: Pvu II and Hind III allele status of the LPL gene and fasting plasma glucose, insulin and lipid values were determined in nondiabetic men with angiographically documented CHD (n = 102) and in a control group (n = 145). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance as measured by an insulin suppression test were also carried out in 46 (45%) of the patients with CHD and in 73 (50%) of the control individuals. RESULTS: The allele frequencies of LPL Pvu II and Hind III were not significantly different between the CHD patients and the controls. No association was found between Pvu II status and blood pressure, fasting plasma glucose, insulin, lipid levels or insulin resistance in patients with CHD. Nevertheless, compared with individuals with the Hind III H2H2 allele, CHD patients carrying the H1 allele (H1H1 + H1H2) were more insulin resistant, as indicated by higher steady state plasma glucose concentrations (253 +/- 87 vs 200 +/- 74 mg/dl, p = 0.032). CONCLUSIONS: We suggest that the LPL gene Hind III allele might be associated with insulin resistance in nondiabetic men with CHD. However, further studies with larger populations of both sexes will be required to confirm this finding.

Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes.

BACKGROUND: It has been shown that insulin resistance syndrome, including glucose intolerance, dyslipidemia, and hypertension, is frequently associated with coronary artery disease (CAD). However, their relative contributions and predictive power in the development of CAD are still unclear, particularly in persons without diabetes. METHOD: We examined these risk factors between 96 patients without diabetes but with angiographically documented CAD and 96 age-, sex-, and body mass index-matched healthy control subjects. Fasting plasma lipoprotein, glucose, and insulin concentrations in response to a 75-g oral glucose tolerance test were determined, and insulin sensitivity was measured by the insulin suppression test. RESULTS: Patients with CAD had significantly higher values of fasting glucose, glucose and insulin responses to oral glucose tolerance test, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride and decreased high-density lipoprotein (HDL) cholesterol concentrations compared with those of healthy people (P < 0.02-0.001). Although the steady-state plasma insulin values were similar in both groups, the steady-state plasma glucose (SSPG) concentrations were significantly higher in patients with CAD (12.2+/-0.4 versus 8.1+/-0.4 mmol/L, P < 0.001) compared with healthy subjects. When HDL < 0.9 mmol/L, LDL cholesterol > or = 4.1 mmol/L, triglyceride > or = 2.3 mmol/L, SSPG > or = 10.5 mmol/L, and presence of hypertension were defined as separate risk factors for CAD, significantly higher odds-ratio values were observed in patients with CAD compared with healthy people. From logistic multiple regression analysis, SSPG was the strongest risk, followed by lowered HDL cholesterol, elevated triglyceride and LDL cholesterol, and hypertension, to predict CAD. These 5 factors accounted for 36% of total risk for development of CAD in persons without diabetes. CONCLUSIONS: Patients without diabetes with CAD have abnormal glucose metabolism, hyperinsulinemia, and insulin resistance. Degree of insulin resistance (SSPG values), plasma lipid values, and history of hypertension together accounted for one third of all risk for CAD, although degree of insulin resistance was the strongest risk factor.

Lack of association between genetic variation in the beta3-adrenergic receptor gene and insulin resistance in patients with coronary heart disease.

The beta-adrenergic system plays a critical role in regulating lipolysis and thermogenesis. Recent studies have suggested that a missense Trp64Arg mutation in the beta3-adrenergic receptor gene is involved in visceral obesity and insulin resistance. We investigated the effect of this mutation on insulin resistance in patients with angiographically documented coronary heart disease ([CHD]n = 137) and normal subjects (n = 188). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance measured by the insulin suppression test, were determined in 58 (42%) patients with CHD and 121 (64%) controls. The genotype and allele frequency of the beta3-adrenergic receptor did not differ between patients with CHD and controls. The blood pressure, body mass index (BMI), waist to hip ratio, fasting plasma glucose, insulin, and lipid, and plasma glucose and insulin responses to the glucose load were relatively similar in subjects with and without the mutation in CHD and normal groups. The degree of insulin sensitivity, ie, the steady-state plasma glucose concentration, was not significantly different between subjects with and without the mutation in the CHD group (11.3 +/- 1.2, n = 11 v 11.9 +/- 0.6 mmol/L, n = 47, P = NS) and control group (8.4 +/- 0.7, n = 30 v 8.2 +/- 0.4 mmol/L, n = 91, P = NS). We conclude that Trp64Arg polymorphism of the beta3-adrenergic receptor gene does not likely play a major role in the development of CHD in the Chinese population. In addition, it appears to have no association with the insulin resistance syndrome in either CHD or non-CHD subjects.

Insulin resistance in patients with Klinefelter's syndrome and idiopathic gonadotropin deficiency.

Patients with Klinefelter's syndrome (KS) have hypergonadotropic hypogonadism and have a higher incidence of diabetes mellitus. Patients with idiopathic gonadotropin deficiency (IGD) also have hypogonadism but have no proven impaired glucose metabolism. Because high serum testosterone concentrations are thought to correlate with insulin resistance, we assessed the relationship of testosterone concentration with insulin resistance in patients with KS or IGD and normal subjects. Seven patients with KS, six with IGD, and seven normal individuals (controls) were enrolled. Insulin resistance was evaluated by two methods: the total area under the curve (AUC) and the incremental AUC of serum insulin concentrations in response to a 75-g oral glucose load, and the insulin suppression test. KS patients had significantly higher follicle-stimulating hormone and luteinizing hormone concentrations than the normal controls, while IGD patients did not. The plasma testosterone concentrations were significantly lower in both KS and IGD groups than in controls. The incremental AUC and total AUC were higher in both KS and IGD patients than in normal subjects. The steady-state plasma glucose concentrations of the KS and IGD groups were significantly higher than that of the normal group, while the steady-state plasma insulin concentrations were similar in all three groups. After log transformation, the plasma testosterone concentration was negatively related to steady-state plasma glucose concentration in all three groups (r = -0.58, p = 0.019). In conclusion, insulin resistance was consistently noted in patients with KS and IGD. Plasma testosterone concentration is inversely related to insulin resistance.

Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease.

BACKGROUND: Variants of the angiotensinogen gene may increase the risk of having arterial hypertension and coronary heart disease (CHD), but their effect on insulin resistance remains unknown. METHODS: We determined M235 and T174 allele status and fasting plasma glucose, insulin, and lipids values in nondiabetic men with CHD documented on angiography (n = 102) and in a control group (n = 145). Plasma glucose and insulin responses to 75 gm oral glucose tolerant test and insulin resistance as measured by an insulin suppression test were also carried out in 46 (45%) patients with CHD and in 73 (50%) members of a control group. RESULTS: We found no association between M235T status and blood pressure, fasting plasma glucose, insulin, most of the lipids values, and insulin resistance in patients with CHD and normal subjects. Nevertheless, compared with individuals with homozygotes T174, subjects with heterozygotes T174M were associated with greater glucose and insulin response to the oral glucose tolerance test and insulin resistance indicated by higher steady state plasma glucose concentrations in patients with CHD (14.7+/-0.9 vs 11.3+/-0.7 mmol/L, p < 0.04). Similar findings were found in the control group, with higher steady-state plasma glucose values in individuals with heterozygotes T174M than in those with homozygotes T174 (10.1+/-1.4 vs 7.7+/-0.4 mmol/L, p < 0.05). CONCLUSION: We suggest that the angiotensinogen T174M allele might be associated with insulin resistance in nondiabetic men with and without CHD.

Effect of weight loss on resting energy expenditure in hypertensive and normotensive obese women.

Hyperinsulinemia and the associated increased sympathetic nervous activity have been proposed to implicate in the development of hypertension and obesity. The role of hyperinsulinemia in mediated resting energy expenditure (REE) in hypertensive obese subjects is not clear. The effect of weight loss on REE between hypertensive and normotensive obese women are also unknown. We measured fasting plasma glucose, insulin, lipids concentrations, REE and body composition by bioelectrical impedance methods before and after a weight loss program in 9 newly diagnosed hypertensive and 10 normotensive obese women. As compared with age-matched lean control women (n=14), obese subjects had higher fasting plasma glucose, insulin concentrations and REE values. However, these variables were not different between obese groups. Although REE and fasting plasma insulin concentrations correlated well in simple correlation (r=0.708, p<0.001), this relationship disappeared after adjusting for values of fat free mass (FFM). Weight loss for approximately 10% of initial weight led to significant decreases of blood pressure and fasting plasma insulin concentrations in both obese groups. Fasting plasma cholesterol, LDL cholesterol and triglyceride concentrations decreased in hypertensive obese individuals. Significant fall of REE in hypertensive group (p<0.05) and normotensive group (p<0.02) were observed following weight loss. However, the ratio of REE to FFM decreased significantly only in hypertensive subjects (114.6+/-5.2 KJ/day x Kg(-1) to 107.2+/-4.6 KJ/day x Kg(-1), p<0.05). In conclusion, obese women, either hypertensive or normotensive, had higher fasting plasma insulin concentrations and REE than those of lean controls, although these variables were not different between obese groups. No significant relation between fasting plasma insulin and REE could be found. Weight loss produced a significant decrease of REE/FFM only in hypertensive obese women. Further study to evaluate the effect of weight loss on energy expenditure in hypertensive obese subjects is necessary.

Plasminogen activator inhibitor-1 and angiotensin I converting enzyme gene polymorphism in patients with hypertension.

Deletion polymorphism of angiotensin I-converting enzyme (ACE) gene has been reported to be an independent risk factor for myocardial infarction. Plasminogen activator inhibitor-1 (PAI-1) was proposed to be a link between the renin-angiotensin system and thrombotic risk. This study was undertaken to investigate the possible association between the insertion/deletion (I/D) polymorphism of the ACE gene and plasma PAI-1 levels in 160 patients with mild-to-moderate hypertension. The I/D genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Baseline levels of PAI-1 antigen and activity and tissue plasminogen activator (t-PA) antigen were determined in fasting morning plasma samples. It was found that patients with homozygote deletion (DD, n = 37) ACE genotype did not have significantly higher plasma levels of PAI-1 antigen (31.2 +/- 15.6 ng/mL v 28.4 +/- 15.1 ng/mL or 27.2 +/- 13.2 ng/mL, P = .42), PAI-1 activity (16.2 +/- 10.6 IU/mL v 14.1 +/- 9.4 IU/ mL or 15.0 +/- 9.9 IU/mL, P = .60), or t-PA antigen (14.6 +/- 6.0 ng/mL v 13.4 +/- 4.9 ng/mL or 14.6 +/- 5.7 ng/mL, P = .40) as compared to those with heterozygote (DI, n = 67) or homozygote insertion (II, n = 56) genotypes. On multiple regression analysis, the ACE genotypes did not appear to be significant predictors for plasma PAI-1 levels and t-PA antigen after adjustment with age, sex, body mass index, plasma triglyceride, cholesterol, and glucose. In conclusion, the results indicated that the I/D polymorphism of the ACE gene was not related to plasma PAI-1 levels in a Chinese population with hypertension. The ACE genotypes may not have a role in influencing the fibrinolysis in hypertension.

Gemfibrozil treatment of hypertriglyceridemia: improvement on fibrinolysis without change of insulin resistance.

The fibrinolytic and metabolic changes associated with gemfibrozil treatment of hypertriglyceridemia were evaluated in 16 patients with type IV hyperlipidemia by criteria of triglyceride levels > 250 mg/dl and total cholesterol levels < 220 mg/dl. The plasma triglyceride level was significantly lower (323 +/- 71 vs 189 +/- 57 mg/dl; p = 0.000) and high-density lipoprotein cholesterol level significantly higher (33.5 +/- 4.6 vs 38.0 +/- 6.7 mg/dl; p = 0.005) after 3 to 4 months of gemfibrozil treatment. However, the glucose and insulin metabolism measured by oral glucose challenge and insulin suppression tests showed no significant changes after gemfibrozil therapy. In contrast, plasma plasminogen activator inhibitor-1 antigen (36.9 +/- 12.4 vs 27.3 +/- 11.4 ng/ml; p = 0.008) and activity (15.5 +/- 5.5 vs 11.8 +/- 3.0 IU/ml; p = 0.009) and tissue plasminogen activator antigen (13.2 +/- 4.0 vs 10.4 +/- 3.7 ng/ml; p = 0.007) were significantly depressed, and tissue plasimogen activator activity (0.57 +/- 0.31 vs 0.69 +/- 0.38 IU/ml; p = 0.015) was significantly elevated by gemfibrozil. The data indicate that lowering plasma triglyceride and raising high-density lipoprotein cholesterol levels by gemfibrozil treatment also improved the fibrinolytic system without changes of insulin resistance and glucose intolerance in patients with isolated hypertriglyceridemia.

Angiotensin I converting enzyme gene polymorphism and insulin resistance in patients with hypertension.

BACKGROUND: The homozygote deletion (DD) genotype of the angiotensin I converting enzyme (ACE) gene has been shown to be associated with an increased risk of coronary heart disease independent of other risk factors. OBJECTIVE: To investigate the possible association of the insertion/deletion (I/D) polymorphism of the ACE gene with insulin resistance in a Chinese population with and without hypertension. SUBJECTS AND METHODS: The I/D polymorphism of the ACE gene was determined for 361 Chinese including 148 women and 96 men with normal blood pressures and 64 male and 53 female patients with mild-to-moderate hypertension. Insulin resistance was estimated by the insulin suppression test and glucose intolerance evaluated with an oral glucose-tolerance test for all of the subjects. RESULTS: Three hypertensive subgroups with DD, DI and II genotypes having similar ages and body mass indexes presented insignificantly different degrees of glucose intolerance and insulin resistance both among men and among women. Similar results were found for normotensive subjects. In addition, ACE genotypes were not significant predictors of insulin resistance and glucose intolerance either among men or among women after adjustment for age, body mass index, and hypertension. CONCLUSION: The present data indicated that the I/D polymorphism of the ACE gene was not related to insulin resistance for Chinese hypertensive and normotensive subjects. The increased risk of coronary heart disease associated with the DD genotype need not be mediated through the mechanism of insulin resistance and glucose intolerance for Chinese patients with hypertension.

Angiotensin I converting enzyme gene polymorphism in Chinese patients with hypertension.

Reports from different ethnic populations failed to show consistent findings on the association of hypertension with insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene. In this population association study in Chinese, we compared the distribution of the ACE genotypes and allele frequency in 150 healthy controls with normal blood pressure and 148 hypertensive patients categorized by age. Although the frequencies of homozygote deletion (DD) genotype and deletion allele were greater in Chinese with hypertension than in normotensive controls (0.23 vs 0.13 and 0.44 v 0.37, respectively), the differences were not significant by chi2 analysis (P = .07 and .09, respectively). Furthermore, we did not find the trend of decreasing number of DD genotype in older hypertensive Chinese patients. The results indicated a much lower prevalence of ACE/DD genotype in Chinese than in Caucasians and a modest association between I/D polymorphism of the ACE gene and hypertension in Chinese.

Effect of doxazosin on fibrinolysis in hypertensive patients with and without insulin resistance.

The fibrinolytic and metabolic changes associated with doxazosin treatment were evaluated in 20 patients with mild to moderate hypertension. Steady-state plasma glucose (SSPG) concentration was used to subdivide hypertensive patients into two groups of 10 each: Insulin-resistant (SSPG > 190 mg/dl) and nonresistant (SSPG < 190 mg/dl). The blood pressure was normalized after 4 to 6 months of doxazosin treatment in both groups, but it was associated with significantly lower fasting plasma triglyceride level, lower integrated insulin response to a 75 gm oral glucose load, lower SSPG concentration, significant decreases in plasma plasminogen activator inhibitor type one antigen and activity and tissue plasminogen activator antigen, and a significant increase in tissue plasminogen activator activity only in the insulin-resistant group but not in the nonresistant group. It was also noted that the improvement of the fibrinolytic and metabolic abnormalities in the insulin-resistant group tended to return to the less abnormal levels seen in the non-resistant group. The data suggested that doxazosin treatment of hypertension attenuated much of the abnormalities of insulin resistance but had little effect on insulin-sensitive patients. It may support a link between impaired fibrinolysis and insulin resistance in patients with hypertension.

Gemfibrozil treatment of endogenous hypertriglyceridemia: effect on insulin-mediated glucose disposal and plasma insulin concentrations.

Gemfibrozil or placebo was administered for 3 months to 24 individuals with endogenous hypertriglyceridemia and normal glucose tolerance. Mean ( +/- SEM) fasting plasma triglyceride (TG) concentrations decreased (4.01 +/- 0.55 to 1.34 +/- 0.12 mmol/L; P < 0.001) and high density lipoprotein cholesterol concentrations increased (0.54 +/- 0.03 to 0.67 +/- 0.04 mmol/L; P < 0.001) in gemfibrozil-treated patients, associated with lower (P < 0.01-0.001) plasma free fatty acid and TG concentrations when measured at hourly intervals in response to breakfast (0800 h) and lunch (1200 h). However, day-long plasma glucose and insulin responses to meals in the 2 groups were similar before and after treatment, as were the steady state plasma glucose and insulin concentrations at the end of a 180-min infusion of somatostatin, insulin, and glucose. Thus, marked decreases in both plasma TG and free fatty acid concentrations seen in association with gemfibrozil neither enhanced insulin-mediated glucose disposal nor lowered ambient plasma insulin concentrations in patients with endogenous hypertriglyceridemia.

Impaired fibrinolysis and insulin resistance in patients with hypertension.

Plasma plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) antigens and activities were measured in 28 patients with hypertension and 12 normal controls. Steady state plasma glucose (SSPG) concentrations were also determined after an infusion of somatostatin, insulin and glucose. Patients with hypertension were further subdivided into two groups: insulin resistance (SSPG > 190 mg/dL, n = 14) and no insulin resistance (SSPG < 190 mg/dL, n = 14). As compared to normal controls, hypertensive patients, either with or without insulin resistance, had a significant (P < .005) increases in PAI-1 activity (18.6 +/- 1.3 upsilon 8.1 +/- 0.8 IU/mL), PAI-1 antigen (31.1 +/- 2.0 upsilon 12.7 +/- 0.9 ng/mL) and tPA antigen (15.5 +/- 0.9 upsilon 8.8 +/- 0.9 ng/mL), and significant decrease in tPA activity (0.43 +/- 0.05 upsilon 1.02 +/- 0.16 IU/mL) than normotensive controls. Furthermore, hypertensive patients with insulin resistance had significantly higher PAI-1 activity (22.0 +/- 2.2 upsilon 15.3 +/- 0.8 IU/mL, P = .006) and tPA antigen (17.4 +/- 1.2 upsilon 13.6 +/- 1.3 ng/mL, P = .02) than did hypertensive patients without insulin resistance. However, PAI-1 antigen was insignificantly higher (34.1 +/- 2.9 upsilon 28.1 +/- 2.4 ng/mL, P = .06) and tPA activity insignificantly lower (0.42 +/- 0.08 upsilon 0.43 +/- 0.08 IU/mL, P = .47) in hypertensive patients with insulin resistance than in those without insulin resistance. In addition, PAI-1 activity and tPA antigen were significantly correlated with blood pressure, SSPG, triglyceride, HDL-cholesterol and integrated glucose response to an oral load of 75 g glucose. Thus, patients with hypertension have impaired fibrinolytic activity due to increased PAI-1 when compared to normotensive controls, and the magnitude of this fibrinolytic defect is greater in hypertensive patients who have insulin resistance. Insulin resistance with associated metabolic abnormalities may be one of the causes for impaired fibrinolysis in hypertension.

Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22.

Resistance to insulin-mediated glucose disposal is a common finding in patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as in nondiabetic individuals with hypertension. In an effort to identify the generic loci responsible for variations in blood pressure in individuals at increased risk of insulin resistance, we studied the distribution of blood pressure in 48 Taiwanese families with NIDDM and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. We found no evidence for linkage of the angiotensin converting enzyme locus on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures. In contrast, we obtained significant evidence for linkage or systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (LPL) locus on the short arm of chromosome 8 (P = 0.002, n = 125 sib-pairs, for the haplotype generated from two simple sequence repeat markers within the LPL gene). Further strengthening this linkage observation, two flanking marker loci for LPL locus, D8S261 (9 cM telomeric to LPL locus) and D8S282 (3 cM centromeric to LPL locus), also showed evidence for linkage with systolic blood pressure (P = 0.02 and 0.0002 for D8S261 and D8S282, respectively). Two additional centromeric markers (D8S133, 5 cM from LPL locus, and NEFL, 11 cM from LPL locus) yielded significant P values of 0.01 and 0.001, respectively. Allelic variation around the LPL gene locus accounted for as much as 52-73% of the total interindividual variation in systolic blood pressure levels in this data set. Thus, we have identified a genetic locus at or near the LPL gene locus which contributes to the variation of systolic blood pressure levels in nondiabetic family members at high risk for insulin resistance and NIDDM.

Resistance to insulin-mediated glucose disposal in patients with noninsulin-dependent diabetes mellitus in the absence of obesity or microalbuminuria--a Clinical Research Center study.

To challenge the view that resistance to insulin-mediated glucose uptake in noninsulin-dependent diabetes mellitus (NIDDM) is limited to patients with microalbuminuria, high blood pressure, or obesity, we compared measurements of insulin resistance in 29 normal volunteers and 31 normotensive patients with NIDDM (mean +/- SE fasting plasma glucose, 160 +/- 10 mg/dL). The patients with NIDDM were nonobese (body mass index, < 27 kg/m2), with urinary albumin excretion (UAE) less than 20 micrograms/min on the basis of two overnight urine collections. The two groups were similar in age and body mass index. Although patients with NIDDM had neither high blood pressure nor microalbuminuria; both their blood pressure (125 +/- 2/79 +/- 1 vs, 113 - 2/73 +/- 2 mm Hg) and UAE excretion (4.7 +/- 0.58 vs. 2.12 +/- 0.17 micrograms/min) were somewhat higher than those in the control population. Resistance to insulin-mediated glucose disposal was quantified by measurement of the steady state plasma glucose (SSPG) and insulin (SSPI) concentrations during the last 30 min of an 180-min infusion of somatostatin (5 micrograms/min), insulin (25 mU/min-m2), and glucose (240 mg/min-m2). The results showed that SSPI concentrations were similar in the two groups (64 +/- 3 vs. 62 +/- 3 microU/mL), but SSPG concentrations were approximately twice as high in patients with NIDDM (258 +/- 15 vs. 139 +/- 11 mg/dL;P < 0.001); demonstrating the presence of severe insulin resistance. Furthermore, the magnitude of the differences in the SSPG values of the two groups did not change and remained highly significant when adjusted for small differences in age, body mass index, blood pressure, and UAE. Finally, SSPG did not correlate with age, body mass index, blood pressure, or UAE in either group. These data again demonstrate that insulin resistance exists in patients with NIDDM, and that this defect is present in the absence of obesity, high blood pressure, or microalbuminuria.

Effect of glipizide treatment on response to an infused glucose load in patients with NIDDM.

OBJECTIVE: This study was initiated to compare the effect of sulfonylurea treatment on the response to an infused glucose load of patients with non-insulin-dependent diabetes mellitus (NIDDM) at a basal insulin concentration and in response to physiological hyperinsulinemia. RESEARCH DESIGN AND METHODS: We used the insulin suppression test, in which subjects were infused for 180 min with somatostatin, exogenous insulin, and glucose. Since similar steady-state plasma insulin (SSPI) concentrations are reached in all subjects, the resultant steady-state plasma glucose (SSPG) concentration permits comparison of the ability of a given individual to maintain glucose homeostasis in response to the infused glucose load. RESULTS: We studied 15 nonobese patients at two different SSPI concentrations, before and after glipizide treatment, at basal (68 +/- 4 pmol/l) and high (470 +/- 31 pmol/l) levels. Values for SSPG concentrations were lower after treatment at both the basal (15.3 +/- 0.5 vs. 18.5 +/- 0.6 mmol/l; P < 0.001) and the high (10.6 +/- 0.7 vs. 14.2 +/- 0.7 mmol/l; P < 0.001) SSPI concentrations. To compare the responses of each patient before and after treatment, we calculated the fractional glucose metabolic rate, i.e., (glucose infusion rate--urinary glucose loss) divided by SSPG. To provide an alternative method of comparing the effect of sulfonylurea treatment, we divided the incremental increase in fractional metabolic glucose rate between the studies done at the low and high SSPI by the incremental increase in SSPI between the two studies (insulin sensitivity index [SI]). CONCLUSIONS: The results of these calculations indicated that glipizide treatment was associated with a significant increase in fractional glucose metabolic rate at a basal insulin concentration (29 +/- 3 to 42 +/- 2 ml.m-2.min-1, P < 0.001), and in response to the incremental change in SSPI (14 +/- 4 to 23 +/- 3 ml.m-2.min-1, P < 0.02). Finally, SI also increased in association with sulfonylurea (0.24 +/- 0.06 to 0.43 +/- 0.07 ml.m-2.min-1/microU.ml-1, P < 0.001).

Suppression of non-esterified fatty acid concentrations by insulin in patients with hypertension.

BACKGROUND: Recent studies have suggested that insulin resistance may be involved in the development of hypertension. Although skeletal muscle accounts for the majority of peripheral insulin resistance, the effect of insulin on adipose tissue, (i.e., antilipolysis) has rarely been defined in hypertensive patients. To understand the effect of high blood pressure on adipose tissue lipolytic activity in vivo, plasma non-esterified fatty acid (NEFA) concentrations at basal insulin, and during physiological hyperinsulinemic state was compared in patients with essential hypertension and a group of normotensive subjects. METHODS: Twenty patients with untreated essential hypertension and 20 age, sex, body mass index (BMI)-matched normotensive subjects were studied. Oral glucose tolerance test (OGTT) in response to a 75-g oral glucose load was carried out for three hours after an overnight fasting. On separate morning, modified insulin suppression test was performed for three hours, which involved a constant infusion of insulin (25 mU/m2/min) glucose (240 mg/m2/min) and somatostatin (350 micrograms/h). The four values obtained every 10 min at last half hour were read as steady state plasma glucose (SSPG), insulin (SSPI) and final NEFA concentrations. RESULTS: Patients with hypertension had significantly higher fasting plasma insulin (101 +/- 9 vs 69 +/- 8 pmol/L, p < 0.02) and NEFA (543 +/- 38 vs 453 +/- 25 mumol/L, p < 0.05) concentrations compared to normotensive subjects. In response to OGTT, the plasma glucose and insulin concentrations increased significantly in the hypertensive group when compared with normotensive group (p < 0.05 and p < 0.01, respectively), whereas plasma NEFA concentrations were suppressed to a similar extent in these two groups. During modified insulin suppression test, the mean SSPG concentrations were significantly higher (10.1 +/- 0.7 vs 7.8 +/- 0.8 mmol/L, p < 0.01) in patients with hypertension compared with normal subjects despite that the mean SSPI concentrations were similar. Plasma NEFA concentrations fell markedly during the period of physiological hyperinsulinemia and achieved similar levels during the last 30 min of infusion in both hypertensive and normal individuals (92.3 +/- 4.9 vs 86.5 +/- 7.3 mumol/L, p = NS). CONCLUSIONS: Patients with hypertension are glucose intolerant, hyperinsulinemic and insulin resistant compared to a group of normotensive subjects. Hypertensive patients have higher than normal fasting plasma NEFA and insulin concentrations indicating that they might lose the ability to regulate adipocyte metabolism in fasting state.

Effect of weight loss on blood pressure and insulin resistance in normotensive and hypertensive obese individuals.

In this study, the effect of weight loss on blood pressure and various facets of glucose and insulin metabolism was examined in 22 subjects with mild to moderate obesity; 11 with high blood pressure (diastolic blood pressure > 95 mm Hg) and 11 with normal blood pressure (diastolic blood pressure < 90 mm Hg). The two groups were similar in mean (+/- SEM) body mass index at baseline (30.2 +/- 1.0 v 31.6 +/- 1.1 kg/m2), and each group lost approximately 8 kg during the 3-month study period. Blood pressure fell significantly (P < .003) following the 8 kg weight loss in both the normotensive (122 +/- 3/81 +/- 3 to 110 +/- 3/74 +/- 2 mm Hg) and hypertensive (149 +/- 3/98 +/- 1 to 135 +/- 3/86 mm Hg) subjects. Furthermore, the plasma glucose and insulin responses to a 75 g oral glucose load were significantly lower (P < .001) following weight loss. Finally, insulin resistance, as assessed by determining the steady-state plasma glucose (SSPG) concentration at the end of a 180 min infusion of somatostatin, insulin, and glucose, was also lower (P < .002) after the 8 kg weight loss in the normotensive (243 +/- 23 to 172 +/- 15 mg/dL) and hypertensive subjects (266 +/- 18 to 181 +/- 25 mg/dL). Since the steady-state plasma insulin concentrations were, if anything, slightly lower after weight loss in both groups, the lower post-weight loss SSPG values actually underestimate the improvement of insulin resistance. Thus, weight loss of 8 kg in moderately obese individuals leads to significant decreases in blood pressure and plasma glucose and insulin concentrations in response to an oral glucose challenge and degree of insulin resistance.

Metabolic abnormalities following heart transplantation in patients with idiopathic cardiomyopathy.

The purpose of this study was to evaluate the risk factors for coronary artery disease associated with initiation of immunosuppressive therapy in patients with a pre-heart transplant diagnosis of idiopathic cardiomyopathy. This study was performed in 15 consecutive patients, mean +/- SEM age of 39 +/- 2 years, with a pre-operative diagnosis of idiopathic cardiomyopathy, who underwent cardiac transplantation at the Tri-Services General Hospital, Taipei, Taiwan, from July 1992 to June 1993. All patients were treated with cyclosporine, azathioprine and prednisolone, and the following measurements were performed prior to hospital discharge (mean +/- SEM) 36 +/- 3 days after successful transplantation: 1) fasting plasma lipid and lipoprotein concentrations; 2) plasma glucose and insulin concentrations in response to a 75 g oral glucose challenge; and 3) steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a continuous infusion of somatostatin, insulin, and glucose. Since the SSPI concentrations are similar in all individuals, the SSPG concentrations provide an estimate of the ability of insulin to stimulate glucose disposal. Only six of the patients had a normal oral glucose tolerance test and the following diagnoses were found in the remaining nine patients: not diagnised (n = 3), impaired glucose tolerance (n = 4), and non-insulin-dependent diabetes (n = 2). Plasma lipid and lipoprotein concentrations were also frequently abnormal in the heart transplant patients; eight of the 15 patients had a plasma cholesterol > 5 mmol/l, nine had a high density lipoprotein (HDL)-cholesterol concentration < 1 mmol/l, and nine had a ratio of total to HDL-cholesterol > 5.0. Finally, the SSPG concentration was greater than 11.0 mmol/l in eight of the 15 patients, a value rarely exceeded in healthy volunteers. In conclusion, significant metabolic abnormalities were present at discharge in patients who had undergone successful cardiac transplantation for idiopathic cardiomyopathy. These metabolic abnormalities were probably caused by the use of immunosuppressive drugs. Given the magnitude of these changes, it would seem prudent to initiate therapeutic programs in patients with cardiac transplants that are not simply aimed at preventing rejection, but also address the metabolic abnormalities associated with the immunosuppressive agents used to prolong allograft survival.