Y.-D. Ida Chen

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.

Insulin Resistance and Insulin Secretion Are Determinants of Oral Glucose Tolerance in Normal Individuals

Plasma glucose values after oral glucose challenge vary widely in nondiabetic subjects. We have now evaluated the role of insulin resistance in determining the plasma glucose response to oral glucose in 74 volunteer subjects with normal glucose tolerance. In these subjects, we determined the plasma glucose and insulin responses over a 3-h period to a 75-g oral glucose challenge, and the steady-state plasma glucose concentration during a continuous infusion of somatostatin, glucose, and insulin (a quantitative measure of insulin resistance). The plasma glucose response was defined as the incremental increase in plasma glucose concentration above the fasting value for 3 h after the oral glucose challenge. Multiple regression analysis was used to define the relationship between the dependent variable (plasma glucose response) and various predictors of this response. These analyses indicated that both the steady-state plasma glucose and the incremental insulin response during the first 30 min after the glucose load were significant predictors of the plasma glucose response. In those individuals in whom insulin action was impaired and the 30-min plasma insulin response was decreased, plasma glucose values reached higher levels. When standardized regression coefficients were determined, the incremental glucose response was directly correlated with steady-state plasma glucose (r = 0.700, P < 0.001) and inversely with the insulin response during the first 30 min (r = 0.268, P = 0.023). Furthermore, the correlation between steady-state plasma glucose and glucose response was significantly greater (P < 0.005) than that between the glucose response and 30-min insulin concentration. These data demonstrate that both insulin action and insulin secretion are determinants of the plasma glucose response to oral glucose in individuals with normal glucose tolerance.

Metabolic Abnormalities Characteristic of Dysmetabolic Syndrome Predict the Development of Transplant Coronary Artery Disease A Prospective Study

BackgroundThis study examines the hypothesis that metabolic abnormalities of dysmetabolic syndrome are risk factors for transplant coronary artery disease (TxCAD). Methods and ResultsSixty-six patients without overt diabetes, 2 to 4 years after surgery, underwent intracoronary ultrasound (ICUS), measurement of plasma glucose and insulin after oral glucose (75 g), and fasting lipid and lipoproteins. TxCAD incidence by angiography or autopsy was prospectively determined during subsequent follow-up (8 years). Coronary artery intimal thickness (IT) and subsequent outcomes were compared in patients stratified as having “high” versus “low” plasma glucose (>8.9 mmol/L) and insulin (>760 pmol/L) 2 hours after glucose challenge; and “abnormal” versus “normal” fasting lipid and lipoprotein concentrations as defined by the National Cholesterol Education Program. Patients with high glucose or insulin concentrations had greater IT: 0.38±0.05 versus 0.22±0.02 mm, P ≤0.05, and 0.39±0.05 versus 0.20±0.02 mm, P ≤0.01, respectively. Freedom from TxCAD was 56±11% versus 81±6% (P <0.01) in patients with high versus low glucose and 57±10% versus 82±7% (P <0.05) in patients with high versus low insulin. Actuarial survival was 60±12% versus 92±5% (P <0.005) in patients with high versus low glucose and 72±9% versus 88±6% (P <0.05) in patients with high versus low insulin. Triglycerides and VLDL were higher and HDL was lower in patients with IT >0.3 mm than with IT ≤0.3 mm. TxCAD incidence was higher in patients with high plasma TG and VLDL and low HDL. ConclusionsThese data suggest that insulin resistance plays a role in TxCAD.

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.

Effect of prazosin treatment on carbohydrate and lipoprotein metabolism in patients with hypertension

This study evaluated the effect of prazosin in controlled mild hypertension and evaluated select metabolic changes that occurred with prazosin monotherapy. Various aspects of glucose, insulin, and lipid metabolism were studied before and after approximately 10 weeks of prazosin treatment in 12 patients with mild hypertension. Prazosin was well tolerated and induced a significant decrease (p less than 0.001) in both systolic and diastolic blood pressures, without any change in body weight. Plasma concentrations of glucose, free fatty acid, and lactate, which were measured hourly from 8 A.M. to 4 P.M. following meals consumed at 8 A.M. and noon, did not change with prazosin treatment. However, the plasma insulin response from 8 A.M. to 4 P.M. decreased significantly (p less than 0.001) following prazosin treatment. In addition, fasting plasma triglyceride and cholesterol concentrations were significantly lower (p less than 0.05) in prazosin-treated persons, as were postprandial triglyceride concentrations (p less than 0.001). Lower total plasma triglyceride and cholesterol concentrations were accounted for by decreases in very low-density lipoprotein cholesterol and triglyceride and low-density lipoprotein cholesterol and triglyceride, whereas both high-density lipoprotein triglyceride and high-density lipoprotein cholesterol concentrations increased following prazosin treatment. Finally, although both apolipoprotein A1 and apolipoprotein B concentrations decreased in association with prazosin treatment, the decrease in apolipoprotein B was much greater in magnitude, leading to an increase in the ratio of apolipoprotein A1 to apolipoprotein B. In this study, treatment of mild hypertension with prazosin led to lower blood pressures and changes in insulin and lipoprotein metabolism that are important in this patient population.

Diabetes and Dyslipidemia A New Model for Transplant Coronary Artery Disease

BACKGROUND Clinical observations suggest that transplant coronary artery disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic heart transplantation in the presence of diabetes and dyslipidemia to further study their role in TxCAD development. METHODS AND RESULTS Major histocompatibility complex-mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts). Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transplantation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (+F). Allograft transplants were divided into four groups: (1) +DM/+F; (2) +DM/-F; (3) -DM/+F; and (4) -DM/-F. Isograft transplants (Lewis to Lewis, +DM/+/-F) were controls. All animals received daily cyclosporine (5 mg/kg). Grafts surviving > 30 days were evaluated for TxCAD on histological sections and graded 0 to 5 for intimal thickness. All streptozotocin-treated animals were diabetic within 2 weeks, with fourfold increases in plasma glucose concentrations versus nondiabetics. Severe TxCAD was observed in diabetic allografts only. The mean grade of TxCAD in diabetic allografts was 3.2 +/- 0.5 versus 1.1 +/- 0.4 in diabetic isografts (P < 0.03) and zero TxCAD in nondiabetic allografts (P < or = 0.0001). Fructose feeding resulted in a 1.5-fold higher triglyceride and a 1.3-fold higher cholesterol level versus the regular diet (-F) but showed no independent contribution to the development of TxCAD. CONCLUSIONS These findings suggest that metabolic derangements associated with diabetes play an important role in TxCAD development in heterotopic ACI-to-Lewis rat heart transplantation. In this model of TxCAD in major histocompatibility complex-mismatched, diabetic, and dyslipidemic rats, immunologic and metabolic mechanisms that contribute to TxCAD can be further delineated and approaches to its prevention assessed.

Insulin resistance, glucose intolerance, and hyperinsulinemia in patients with microvascular angina

Plasma glucose and insulin responses to oral glucose and insulin-mediated glucose disposal were determined in 20 patients with microvascular angina and 20 normal volunteers who were similar in terms of age, gender distribution, and degree of obesity. Plasma glucose and insulin responses to a 75-g oral glucose challenge were significantly higher in those with microvascular angina (P < .001), as were steady-state plasma glucose concentrations after a 180-minute infusion of somatostatin, glucose, and insulin (12.2 +/- 1.0 v 7.6 +/- 0.6 mmol/L, P < .001). Since steady-state plasma insulin concentrations were similar in the two groups (627 +/- 32 v 631 +/- 29 pmol/L), these data indicate that patients with microvascular angina are insulin-resistant, glucose-intolerant, and hyperinsulinemic compared with a matched group of normal volunteers.

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) ÷ 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 [S1]). 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, S1 also increased in association with sulfonylurea (0.24 ± 0.06 to 0.43 ± 0.07 ml · m−2 · min−1/μU · ml−1, P < 0.001).