Jorgen Jeppesen

Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia

We examined the relation between insulin resistance, plasma glucose and insulin responses to meals, lipoprotein lipase (LPL) activity, and postprandial lipemia in a population of 37 healthy nondiabetic individuals. Plasma glucose and insulin concentrations were determined at frequent intervals from 8 AM through midnight (breakfast at 8 AM and lunch at noon); resistance to insulin-mediated glucose disposal was determined by measuring the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of glucose, insulin, and somatostatin; LPL activity was quantified in postheparin plasma; and postprandial concentrations of triglyceride (TG)-rich lipoproteins were assessed by measuring the TG and retinyl palmitate content in plasma and the Svedberg flotation index (Sf) > 400 and Sf 20 to 400 lipoprotein fractions. Significant simple correlation coefficients were found between various estimates of postprandial lipemia and SSPG (r = .38 to .68), daylong insulin response (r = .37 to .58), daylong glucose response (r = .10 to .39), and LPL activity (r = -.08 to -.58). However, when multiple regression analysis was performed, only SSPG remained independently associated with both postprandial TG and retinyl palmitate concentrations. These data provide evidence that insulin resistance plays an important role in regulating the postprandial concentration of TG-rich lipoproteins, including those of intestinal origin.

Effect of Metformin on Postprandial Lipemia in Patients With Fairly to Poorly Controlled NIDDM

OBJECTIVE To quantify the effect of metformin on the metabolism of triglyceride (TG)-rich lipoprotein of intestinal origin in patients with non-insulin-dependent diabetes mellitus (NIDDM) who had responded to sulfonylurea but still had fasting hyperglycemia. RESEARCH DESIGN AND METHODS Sixteen patients with NIDDM who had demonstrated a fall in fasting plasma glucose concentration > 2.2 mmol/l in response to glipizide treatment but continued to have fasting plasma glucose concentrations > 8.3 mmol/l were studied. Fasting glucose, GHb, lipid and lipoprotein concentrations were determined, and resistance to insulin-mediated glucose disposal was estimated by measuring the steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of somatostatin, glucose, andinsulin. In addition, plasma glucose, insulin, and TG concentrations were measured at frequent intervals from 0800 to 2400, with patients eating breakfast at 0800 and lunch at 1200. Vitamin A was also given at lunch, and the retinyl ester content in plasma and in chylomicron (Svedberg flotation constant [Sr] > 400) and the chylomicron remnant (Sr 20–400) fractions were used to quantify the concentration of postprandial intestinal TG-rich lipoprotein from 1200 to 2400. RESULTS Fasting plasma glucose concentrations (6.8 ± 0.4 vs. 10.5 ± 0.4 mmol/l), GHb levels (7.9 ± 0.3 vs. 10.8 ± 0.5%), and day-long plasma glucose concentrations were all significantly lower after metformin treatment (P < 0.001), which was associated with a significant (P < 0.001) fall in SSPG concentration (11.0 ± 0.9 to 9.6 ± 0.6 mmol/l). In addition, postprandial concentrations of glucose, insulin, free fatty acids, and TG were lower (P < 0.001) following metformin treatment. Postprandial retinyl ester concentrations were also lower in plasma by 33 ± 5.7% (P < 0.001) and in both the chylomicron (32 ± 7.2%, P < 0.001) and chylomicron remnant (26 ± 7.0%, P < 0.005) fractions. CONCLUSIONS Addition of metformin to sulfonylurea-treated patients with NIDDM with less than optimal glycemic control was associated with improved glycemic control, lower postprandial insulin and TG concentrations, and a decrease inpostprandial concentration of TG-rich lipoproteins of intestinal origin. All of these changes might be expected to decrease risk of coronary heart disease.

Resistance to insulin-stimulated glucose uptake and dyslipidemia in Asian Indians

Persons from the Indian subcontinent have elevated coronary heart disease risk. We measured insulin resistance with the insulin suppression test in 22 Asian Indian men and women and an equal number of control subjects of European ancestry matched for age and body mass index. Asian men and women had increased glucose and insulin responses to oral glucose tolerance tests (P < .05 by ANOVA) and had approximately 60% higher steady-state plasma glucose levels during the insulin suppression test (P < .001 by ANOVA), consistent with insulin resistance. In response to mixed meals, Asian women had higher plasma free fatty acids and glycerol concentrations than women of European ancestry (P < .02 by ANOVA), whereas Asian Indian men had similar free fatty acid and glycerol levels compared with men of European ancestry despite higher plasma insulin levels. Thus, results in both sexes were consistent with resistance to insulin suppression of free fatty acid levels in Asian Indians. Asian Indians of both sexes had higher fasting plasma triglyceride (P < .01) and lower high-density lipoprotein cholesterol (P < .01) concentrations than men and women of European ancestry. Resistance to insulin-stimulated glucose uptake and to insulin suppression of free fatty acid levels in Asian Indians is associated with a number of metabolic abnormalities that are demonstrated risk factors for coronary heart disease, including increased glucose, insulin, and triglyceride concentrations and decreased high-density lipoprotein cholesterol concentrations.

Hematocrit and Hemoglobin Are Independently Related to Insulin Resistance and Compensatory Hyperinsulinemia in Healthy, Non-Obese Men and Women

In this study, we evaluated the relationship between resistance to insulin-mediated glucose disposal and hematocrit (Hct) and hemoglobin (Hgb) concentrations in 150 normal, healthy volunteers: 100 men and 50 women. Insulin resistance was defined as the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Since the steady-state plasma insulin (SSPI) concentrations are similar in all individuals, the SSPG concentrations provide a direct measure of insulin resistance: the higher the SSPG, the more insulin-resistant the subject. The results indicated that SSPG was significantly (P < .001) related to Hct and Hgb in both men and women, with correlation coefficients (r) ranging from 0.38 to 0.43. A series of other variables were also related to Hct and Hgb, including blood pressure, plasma glucose and insulin responses to oral glucose, and plasma triglyceride and high-density lipoprotein (HDL) concentrations. When multiple regression analysis was used to evaluate these relationships, the only variables that were consistently found to be associated with Hct and Hgb were insulin resistance and plasma insulin response to oral glucose. Thus, these results suggest that Hct and Hgb concentrations be added to the cluster of variables related to insulin resistance and compensatory hyperinsulinemia.

Additive effects of obesity, hypertension, and type 2 diabetes on insulin resistance.

Resistance to insulin-mediated glucose disposal has been previously shown to be increased in association with obesity, high blood pressure, and non-insulin-dependent diabetes mellitus. We initiated the present study to quantify the separate effects of hypertension and non-insulin-dependent diabetes mellitus on insulin resistance in both nonobese and obese subjects. To accomplish this, 88 subjects were divided into the following five experimental groups: normal blood pressure, nonobese (n = 17); normal blood pressure, obese (n = 18); high blood pressure, nonobese (n = 18); high blood pressure, obese (n = 19); and high blood pressure, obese, non-insulin-dependent diabetes mellitus (n = 16). Plasma glucose and insulin concentrations were measured before and after a 75-g oral glucose load. Resistance to insulin-mediated glucose disposal was estimated by determining the steady-state plasma insulin and glucose concentrations during the last 30 minutes of a continuous infusion of somatostatin (5 micrograms/min), exogenous insulin (25 mU/m2 per minute), and glucose (240 mg/m2 per minute). Since the steady-state plasma insulin concentrations are similar in all subjects, the higher the steady-state plasma glucose, the more insulin resistant the individual. Nonobese subjects with normal blood pressure had the lowest plasma glucose and insulin responses and steady-state plasma glucose concentrations, and their values were significantly different from the other four groups. Obese or nonobese subjects with high blood pressure had significantly higher plasma glucose responses and steady-state plasma glucose concentrations than did their respective weight-matched control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of glipizide treatment on postprandial lipaemia in patients with NIDDM

SummaryThe primary goal of the present study was to examine the effects of improved glycaemic control associated with glipizide treatment on postprandial lipaemia in non-insulin-dependent diabetic patients. The metabolism of triglyceride-rich lipoproteins of intestinal origin was assessed by measuring the retinyl palmitate content in plasma and the Svedberg flotation index (Sf)>400 and Sf 20–400 lipoprotein fractions. Fasting plasma glucose concentrations (14.5±0.5 vs 9.0±0.5 mmol/l), glycated haemoglobin levels (13.1±0.6 vs 9.7±0.6%), and daylong plasma glucose concentrations were all significantly lower after glipizide treatment (p<0.001). The improvement in glycaemic control was associated with increases in insulin-mediated glucose uptake (p<0.001) and plasma post-heparin lipoprotein and hepatic lipolytic activities (p<0.02). Both fasting plasma triglyceride (3.09±0.51 vs 2.37±0.34 mmol/l), and postprandial triglyceride concentrations (p<0.05–0.001) were lower following glipizide treatment, associated with a significant fall in retinyl palmitate content in all three lipoprotein fractions (p<0.02–0.001), with the most substantial decrease seen in the Sf 20–400 fraction. These data indicate that glipizide-induced improvement in glycaemic control was associated with changes in the metabolism of triglyceride-rich lipoproteins of intestinal origin that would be anticipated to reduce risk of coronary heart disease in non-insulin-dependent diabetic patients.

White blood cell count and insulin resistance in healthy nonsmoking men

Several studies have shown that elevated leukocyte or white blood cell (WBC) count is an independent risk factor for cardiovascular disease.1-4 The pathogenetic link between WBC count and cardiovascular disease is unclear. An association exists between cigarette smoking and WBC count, but even after controlling for smoking WBC count is an independent predictor of cardiovascular disease. WBC count is associated with other cardiovascular risk factors,3,5-7 and the most consistent finding is a negative association between WBC count and high-density lipoprotein (HDL) cholesterol. In this context, it has been shown that HDL cholesterol is related to insulin resistance and hyperinsulinemia.8 Our study was initiated to define a potential relation between WBC count, insulin resistance, and the variables associated with this defect, such as glucose intolerance, hyperinsulinemia, hypertriglyceridemia, high blood pressure, and low-HDL cholesterol (syndrome X),g in a population of healthy men. Methods. The study was approved by Stanford Human Subjects Committee, and each subject gave written, informed consent before entering the study. One hundred two consecutive healthy men participated in our study with a mean age ( + SD) of 50 + 13 years and a mean body mass index (BMI) of 25.6 + 3.3 kg/m2. Each subject was considered normal on the basis of history, physical examination results, blood pressure < 160/90 mm Hg, hemogram, routine blood chemistry test, and a standard oral glucose tolerance test. None of the subjects reported smoking within the previous 3 years or were taking any medications known to affect carbohydrate or lipid metabolism and WBC count. None of the subjects reported any recent allergic or infectious disease. All experimental procedures were tolerated well. The experimental procedures and analytic methods have been described in detail elsewhere.lO In brief, after a 12-hour overnight fast, blood specimens were collected for determination of fasting plasma triglyceride, cholesterol, and lipoprotein concentrations. An oral glucose tolerance