Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.

The changes in hepatic glucose production (Ra), tissue glucose disposal (Rd), and plasma glucose and insulin concentration that took place over a 16-h period from 10 to 2 p.m. were documented in 14 individuals; 8 with non-insulin-dependent diabetes mellitus (NIDDM) and 6 with normal glucose tolerance. Values for Ra were higher than normal in patients with NIDDM at 10 p.m. (4.73 +/- 0.41 vs. 3.51 +/- 0.36 mg/kg per min, P less than 0.001), but fell at a much faster rate throughout the night than that seen in normal subjects. As a consequence, the difference between Ra in normal individuals and patients with NIDDM progressively narrowed, and by 2 p.m., had ceased to exist (1.75 +/- 0.61 vs. 1.67 +/- 0.47 mg/kg per min, P = NS). Plasma glucose concentration also declined in patients with NIDDM over the same period of time, but they remained quite hyperglycemic, and the value of 245 +/- 27 mg/dl at 2 p.m. was about three times greater than in normal individuals. Plasma insulin concentrations also fell progressively from 10 to 2 p.m., and were similar in both groups throughout most of the 16-h study period. Thus, the progressive decline in Ra in patients with NIDDM occurred despite concomitant falls in both plasma glucose and insulin concentration. Glucose disposal rates also fell progressively in both groups, but the magnitude of the fall was greater in patients with NIDDM. Consequently, Rd in patients with NIDDM was higher at 10 p.m. (3.97 +/- 0.48 vs. 3.25 +/- 0.13 mg/kg per min, P less than 0.001) and lower the following day at 2 p.m. (1.64 +/- 0.21 vs. 1.97 +/- 0.35 mg/kg per min, P less than 0.01). These results indicate that a greatly expanded pool size can exist in patients with NIDDM at a time when values for Ra are identical to those in normal subjects studied under comparable conditions, which suggests that fasting hyperglycemia in NIDDM is not simply a function of an increase in Ra.

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.

Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM.

Fasting and postprandial plasma glucose, free fatty acid (FFA), lactate, and insulin concentrations were measured at hourly intervals for 24 h in 27 nonobese individuals-9 with normal glucose tolerance, 9 with mild non-insulin-dependent diabetes mellitus (NIDDM, fasting plasma glucose less than 175 mg/dl), and 9 with severe NIDDM (fasting plasma glucose greater than 250 mg/dl). In addition, hepatic glucose production (HGP) was measured from midnight to 0800 in normal individuals and patients with severe NIDDM. Plasma glucose concentration was highest in patients with severe NIDDM, lowest in those with normal glucose tolerance, and intermediate in those with mild NIDDM (two-way ANOVA, P less than .001). Variations in plasma FFA and lactate levels of the three groups were qualitatively similar, with lowest concentrations seen in normal individuals, intermediate levels in the group with mild NIDDM, and the highest concentration in those with severe NIDDM (two-way ANOVA, P less than .001). Of particular interest was the observation that plasma FFA concentrations were dramatically elevated from midnight to 0800 in patients with severe NIDDM. The 24-h insulin response was significantly increased in patients with mild NIDDM, with comparable values seen in the other two groups. Values for HGP fell progressively throughout the night in normal individuals and patients with severe NIDDM, despite a concomitant decline in plasma glucose and insulin levels. Although the magnitude of the fall in HGP was greater in NIDDM, the absolute value was significantly (P less than .001) greater than normal throughout the period of observation.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM.

This study was initiated to reevaluate the changes in basal hepatic glucose production (HGP) rate that occur in patients with non-insulin-dependent diabetes mellitus (NIDDM). Measurements were made in 51 volunteers: 18 with normal glucose tolerance and 33 with newly diagnosed NIDDM of varying degrees of severity. To avoid the methodological problems associated with quantifying HGP over short time periods, using non-steady-state isotopic kinetics, radiolabeled glucose was infused for a 12-h period, from 10 P.M. to 10 A.M. with HGP quantified from 9 to 10 A.M.. The results showed that fasting plasma glucose (FPG) concentration and HGP were significantly correlated (r = 0.68, P < 0.001) in patients with NIDDM. However, when the 33 patients with NIDDM were divided into three groups of 11 each on the basis of FPG concentration, it became clear that the relationship between FPG and HGP was complex. Thus, values for HGP in patients with NIDDM and FPG < 180 mg/dl were not higher than in the normal population (1.67 +/- 0.07 vs. 1.69 +/- 0.04 mg.kg-1.min-1, NS). Significant increases (P < 0.01) in HGP above normal were seen in the 11 patients with NIDDM and FPG concentrations between 180 and 250 mg/dl (2.05 +/- 0.07 mg.kg-1.min-1), as well as in those with FPG > 250 mg/dl (2.18 +/- 0.13 mg.kg-1.min-1). Although those with the highest FPG concentrations tended to have the greatest values for HGP, the difference between the latter two groups of patients with NIDDM was not statistically significant. Finally, HGP rates in the 11 patients with FPG concentrations > 250 mg/dl were only 29% higher than values in the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

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).

Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients.

The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after approximately 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was less than 25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P less than 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.

Effect of time on measurement of hepatic glucose production.

Basal hepatic glucose production (HGP) was determined in obese and nonobese normal subjects and patients with noninsulin-dependent diabetes mellitus (NIDDM) using [3-3H]glucose and the nonsteady state equations of Steele. When HGP was estimated at hourly intervals from 0800-1300 h, it became evident that calculated values for HGP fell for the first 2-4 h until a plateau was reached, and this decline was quite precipitous during the first 2 h in patients with NIDDM. Furthermore, when the same patient with NIDDM was studied on two occasions, similar values for HGP were not uniformly obtained unless measurements were made at least 4 h after [3-3H] glucose administration. Since it has been the convention to use the nonsteady state equations of Steele to calculate HGP in patients with NIDDM 2 h after [3-3H] glucose administration, it is almost certain that published values for HGP in patients with NIDDM are falsely high. Based upon the data presented, we suggest that HGP using [3-3H]glucose and the nonsteady state Steele equations be measured for at least a 4-h period in patients with NIDDM in order to increase the validity of the calculated value.

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.

Long term treatment of Graves' hyperthyroidism with sodium ipodate.

To investigate the long term usefulness of sodium ipodate (Oragrafin) in the management of Graves' hyperthyroidism, we studied the effects of ipodate (500 mg, orally, daily for 23-31 weeks) on serum T3, T4, rT3, and some clinical parameters in five newly diagnosed Graves' hyperthyroid patients. Mean pretreatment serum T3, T4, and rT3 concentrations were 780 ng/dl, 25.4 micrograms/dl, and 118 ng/dl, respectively. One day after the first dose of ipodate, serum T3 decreased by 62% (P less than 0.01), and it was within the normal range thereafter throughout treatment. The serum T4 concentration decreased by 20% (P = 0.09) at 24 h and by 43% (P less than 0.05) at 14 days. Subsequently, serum T4 was 41-65% lower than before treatment throughout the study; rT3 increased 24 h after the first dose of ipodate (118% above baseline; P = 0.1), remained elevated (97-109%) for 10 weeks, and then gradually decreased to the pretreatment level. A marked gain in body weight [5.1 +/- 1.1 (+/- SEM) kg] occurred in all patients. After discontinuation of ipodate, mean thyroid radioiodine (RAI) uptake values increased serially in four patients and were similar to pretreatment values: pretreatment, 74 +/- 6% (+/- SEM); after 7 days, 66 +/- 8%; after 14 days, 71 +/- 7%; after 28 days, 69 +/- 7%. The fifth patients's RAI uptake was 12-16% (vs. a pretreatment value of 48%) from 7-28 days after the end of a 31-week course of ipodate. He remained euthyroid without further treatment for the subsequent 4 months. We conclude that 1) ipodate (500 mg daily) reduces serum T4 and T3 levels as fast and as much as does the 1-g daily dose studied previously; 2) long term use (for 23-31 weeks) of ipodate for the treatment of Graves' hyperthyroidism is clinically feasible; no adverse effects occurred during or after ipodate treatment; and 3) RAI uptake returns to pretreatment levels as early as 7 days after the discontinuation of ipodate. Hence, use of ipodate does not prevent use of 131I therapy for those patients for whom it is otherwise desirable.

Does glucagon increase plasma free fatty acid concentration in humans with normal glucose tolerance?

To evaluate the effect of glucagon on regulation of plasma FFA concentration, continuous iv infusions of either somatostatin (S) or somatostatin (S) plus glucagon (G) were administered to 18 individuals with normal glucose tolerance. In 9 of these individuals there was no insulin replacement, whereas in the other 9 individuals enough insulin was infused to restore the insulin concentration to the basal level. Measurements were made of plasma glucose, insulin, G, and FFA concentrations as well as hepatic glucose production (Ra). The results indicated that plasma FFA concentrations were significantly lower when G was infused (S greater than S + G) regardless of whether insulin was infused. However, similar elevations of the plasma G concentration did lead to higher values of Ra and plasma glucose, although the basal concentration of plasma insulin decreased the increases in Ra and plasma glucose caused by G. The ability of a similar amount of insulin to lower plasma FFA concentrations was greater in magnitude than the decrease in Ra. These data indicate that G does not increase plasma FFA concentrations in normal individual, and that insulin plays a role of greater magnitude in suppression of plasma FFA concentrations than in inhibition of Ra.

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.

Glucagon does not increase plasma free fatty acid and glycerol concentrations in patients with noninsulin-dependent diabetes mellitus.

The study was initiated to determine whether physiological elevations of plasma glucagon would increase plasma FFA or glycerol concentrations in patients with noninsulin-dependent diabetes mellitus (NIDDM). To do this, patients were infused for 6 h with somatostatin (SRIF) alone or with SRIF plus glucagon. Furthermore, these studies were performed with an insulin infusion rate that maintains basal insulin levels or without any insulin infusion. Infusion of SRIF alone was associated with an increase in plasma FFA and glycerol concentrations, whereas hepatic glucose production and plasma glucose concentrations fell somewhat. When glucagon was added to SRIF, plasma FFA and glycerol concentrations were again increased, but to a significantly lesser extent. In addition, the addition of glucagon was associated with a modest increase in hepatic plasma glucose production and plasma glucose concentrations. In contrast, plasma FFA and glycerol concentrations fell when SRIF was infused in the presence of basal insulin levels. The decrease in FFA and glycerol levels tended to be accentuated when glucagon was also infused. It should be noted that the increases in hepatic glucose production and plasma glucose concentration after glucagon was added to SRIF were prevented when basal insulin levels were replaced. These results demonstrate that an increase in the plasma glucagon level comparable to that seen in patients with NIDDM was associated with lower, not higher, plasma FFA and glycerol concentrations in patients with NIDDM. Furthermore, these changes were seen in the absence of insulin or when basal insulin levels were replaced. Thus, the higher ambient plasma FFA and glycerol concentrations in patients with NIDDM do not appear to be secondary to increased plasma glucagon levels.

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.

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.

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.

Effect of low fat-high carbohydrate diets in hypertensive patients with non-insulin-dependent diabetes mellitus.

Effects of variations in dietary fat and carbohydrate content on various aspects of glucose, insulin, and lipoprotein metabolism were evaluated in 11 patients with hypertension, who also had non-insulin-dependent diabetes mellitus (NIDDM). All of these patients were being treated with sulfonylureas, thiazides, and beta-adrenergic receptor antagonists. The comparison diets contained either 40 or 60% of total calories as carbohydrate, with reciprocal changes in fat content from 40 to 20%. The diets were consumed in a random order for 15 days in a crossover experimental design. The ratio of polyunsaturated to saturated fat and total cholesterol intake were held constant in the two diets. Plasma glucose and insulin concentrations were significantly (P less than .001) elevated throughout the day when patients consumed the 60% carbohydrate diet. Fasting plasma total and very-low-density lipoprotein (VLDL) and triglyceride (TG) concentrations increased by 30% (P less than .001) after 15 days on the 60% carbohydrate diet. Total plasma cholesterol concentrations were similar on both diets, as were low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol concentrations.

Resistance to insulin-mediated glucose uptake and hyperinsulinemia in women who had preeclampsia during pregnancy.

Plasma glucose and insulin responses to a 75-g oral glucose load, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations after an infusion of somatostatin, insulin, and glucose, were determined 2 months after delivery in 26 women; 13 who had a normal pregnancy and 13 who developed preeclampsia. The plasma glucose response to oral glucose was not different in the two groups, but the plasma insulin response was significantly greater (P < .02) in those who had been preeclamptic. Although the mean (+/- SE) SSPI concentrations during the infusion study were similar in the two groups (51 +/- 2 v 56 +/- 2 microU/mL), the SSPG concentrations were significantly higher (P < .02) in those who developed preeclampsia (160 +/- 17 v 119 +/- 17 mg/dL). Thus, when studied 2 months after delivery, women who developed preeclampsia were relatively insulin resistant and hyperinsulinemic when compared to those who had an uncomplicated pregnancy.

Insulin resistance and abnormal electrocardiograms in patients with high blood pressure.

Plasma glucose and insulin responses to an oral glucose challenge and fasting plasma lipid and lipoprotein concentration were compared in 25 normal individuals and 53 patients with high blood pressure. Patients with hypertension were further subdivided into two groups--normal electrocardiogram (EKG) (n = 24) or abnormal EKG (n = 29)--using the Minnesota code criteria. Patients with hypertension and an abnormal EKG had significantly higher plasma glucose and insulin concentrations following oral glucose than did the control population. Furthermore, plasma triglyceride (TG) concentration was higher and high density lipoprotein cholesterol concentration lower then normal in hypertensive patients with an abnormal EKG, and the ratio of total to HDL cholesterol was higher in this subgroup. Values for patients with high blood pressure and a normal EKG were intermediate. Insulin-mediated glucose uptake was also measured in a subset of patients with hypertension and either a normal (n = 18) or abnormal (n = 17) EKG. When these two subgroups were compared, those with high blood pressure and an abnormal EKG were significantly more insulin resistant than patients with hypertension and a normal EKG. In addition, they also had higher plasma glucose and insulin responses to oral glucose, higher fasting plasma triglyceride and cholesterol concentrations, and an increase in the ratio of total to HDL cholesterol. Thus, patients with high blood pressure have abnormalities of glucose, insulin, and lipid metabolism when compared to a nonhypertensive control group, and the magnitude of these metabolic defects is significantly greater in patients with high blood pressure who have EKG evidence of coronary heart disease.

Improvement in metabolic risk factors for coronary heart disease associated with cilazapril treatment.

Patients with hypertension tend to be glucose intolerant, hyperinsulinemic, and dyslipedemic. Since all of these changes increase risk of coronary heart disease (CHD), it is important to know what effect antihypertensive treatment has on these variables. The current open-labelled, uncontrolled study was initiated in order to extend our understanding of these issues. This study was performed in 19 patients with hypertension who were started on an angiotensin converting enzyme (ACE)-inhibitor, cilazapril, with hydrochlorothiazide (HC) added if needed to control blood pressure. Plasma glucose and insulin responses to oral glucose and lipid concentrations were measured before, 26, and 52 weeks after starting treatment. Patients treated with either cilazapril (n = 9) or cilazapril+HC (n = 10) did not differ in terms of original (mean +/- SEM) blood pressure (159 +/- 5/101 +/- 1 v 156 +/- 4/103 +/- 2 mm Hg), age (53 +/- 2 v 54 +/- 2 years), sex distribution (5M:4F v 7M:3F), or body mass index (24.4 +/- 0.5 v 24.2 +/- 0.9 kg/m2). Blood pressure was also similar after 26 (137 +/- 4/88 +/- 1 v 133 +/- 3/90 +/- 1 mm Hg) and 52 (137 +/- 4/87 +/- 1 v 134 +/- 4/89 +/- 2 mm Hg) weeks of treatment. Plasma glucose and insulin responses decreased by 8 +/- 3% (P less than .05) and 25 +/- 9% (P less than .002), respectively, in cilazapril-treated patients, but did not change in those treated with cilazapril plus HC.(ABSTRACT TRUNCATED AT 250 WORDS)