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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.

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).

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.

To understand the mechanism of hyperinsulinemia in patients with high blood pressure, we studied 20 untreated essential hypertensives and 20 age, sex and body mass index-matched normotensive control subjects. C-peptide concentrations and C-peptide to insulin molar ratio in response to a 75 g oral glucose challenge were used to evaluate the beta cells function and for calculation of hepatic extraction of insulin. Modified insulin suppression test was employed to compared the insulin-stimulated glucose uptake and insulin clearance rate between two groups. Patients with hypertension had significantly higher plasma glucose, insulin and C-peptide responses as compared to normal subjects (P < 0.05, p < 0.01, and P < 0.03, respectively). Mean steady state plasma glucose (SSPG) concentrations were also higher in hypertensive group than normotensive group (11.5 +/- 1.4 vs 6.7 +/- 0.9 mmol/L, p < 0.01) despite that mean steady state plasma insulin (SSPI) values were relatively similar, indicating the presence of insulin resistance. Hepatic insulin extraction was found to be elevated in patients with high blood pressure when compared to normal subjects (82 +/- 3 vs 72 +/- 2%, p < 0.05). However, there were no difference in insulin clearance rate between two groups (592 +/- 38 vs 559 +/- 40 mL/m2/min, p = NS). In conclusion, hyperinsulinemia in patients with hypertension result from hypersecretion of beta cells and increased hepatic extraction of insulin. No difference was found in insulin clearance rate between hypertensive and normotensive subjects.

Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.

A significant increase in insulin resistance has been implicated in many human diseases and the absence of a simple, accurate, reproducible measurement of in vivo insulin sensitivity has become a major concern. In order to evaluate the reproducibility of insulin sensitivity measured by the modified insulin suppression test, 12 healthy young Chinese men were subjected to the same test two weeks apart. After three days on a standard diet and an overnight fast, somatostatin (350 micrograms/h), insulin (25 mU/m2/min) and glucose (240 mg/m2/min) were infused concomitantly for three hours. A steady state plasma glucose (SSPG) concentration achieved during the last 30 minutes of infusion represented the measurement of insulin sensitivity. Comparisons between the metabolic clearance rate of insulin (MCRi), plasma total triglyceride and lipoprotein cholesterol fractions on two different days were carried out. The results indicated that mean SSPG concentrations on Day 1 (5.73 +/- 0.43 mmol/L) correlated with mean SSPG concentrations on Day 14 (5.51 +/- 0.38 mmol/L; r = 0.82, p < 0.002). The relationship slope did not differ from 1 (0.74, p > 0.05), the intercept was close to the origin (1.24 mmol/L, p > 0.05) and the mean coefficient of intra-individual variation was 10.3%. There was no difference between the MCRi for Day 1 and Day 14 (529 +/- 26 vs 526 +/- 24 mL/m2/min, p = NS), with a mean coefficient of intra-individual variation of 6.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.

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)

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.

The effect of alloxan-induced insulin deficiency on high density lipoprotein (HDL) metabolism was studied in rabbits. Rabbits with alloxan-induced diabetes had significantly higher (P less than 0.001, mean +/- SEM) plasma concentrations of glucose (541 +/- 13 vs. 130 +/- 2 mg/dl), triglyceride (2851 +/- 332 vs. 101 +/- 10 mg/dl), and total plasma cholesterol (228 +/- 55 vs. 42 +/- 4 mg/dl) than did normal control rabbits. However, diabetic rabbits had lower plasma HDL-cholesterol (7.2 +/- 1 vs. 51.3 +/- 1.3 mg/dl, P less than 0.001) and HDL apoA-I (38.3 +/- 6.0 vs. 87.2 +/- 4.3 mg/dl, P less than 0.001) concentrations. HDL kinetics were compared in diabetic and normal rabbits, using either 125I-labeled HDL or HDL labeled with 125I-labeled apoA-I, and it was demonstrated that HDL fractional catabolic rate (FCR) was slower and residence time was longer in the diabetic rabbits when either tracer was used. The slow FCR and the low apoA-I pool size led to reduced apoA-I/HDL synthetic rate in diabetic rabbits (0.97 +/- 0.11 vs. 0.34 +/- 0.07 mg per kg per hr). Thus, the reduced plasma HDL-cholesterol concentrations seen in rabbits with alloxan-induced insulin deficiency was associated with a lower total apoA-I/HDL synthetic rate. Since insulin treatment restored to normal all of the changes in plasma lipoprotein concentration and kinetics seen in diabetic rabbits, it is unlikely that the phenomena observed were secondary to a nonspecific toxic effect of alloxan. These data strongly support the view that insulin plays an important role in regulation of HDL metabolism.