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Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

The insulin-modified intravenous glucose tolerance test (IM-IVGTT) is increasingly used to measure insulin sensitivity. However, the assessment of beta-cell secretion is usually made using rough indices. The aim here is to evaluate the ability of the minimal model of C-peptide secretion and kinetics recently proposed for the standard IVGTT (S-IVGTT) to also assess beta-cell function during the IM-IVGTT. C-peptide and glucose data from the IM-IVGTT in 15 normal humans were analyzed. The results show that the same rich beta-cell picture from the S-IVGTT can be obtained during an IM-IVGTT. In particular, in each individual, the time course of beta-cell secretion can be reconstructed and the functional indices of glucose control on first-phase (phi1), second-phase (phi2), and basal (phi(b)) insulin secretion can be estimated (phi1 = 191 +/- 29, phi2 = 10.9 +/- 1.4 x 10(-9) x min(-1), and phi(b) = 5.7 +/- 1.0 x 10(-9) x min(-1), mean +/- SE). Finally, the comparison between IM-IVGTT and S-IVGTT phi1, phi2, and phi(b) values suggest they are not affected by insulin administration.

Diabetes mellitus confers a threefold to fivefold increased risk of mortality from vascular disease. The primary cause of this increased incidence of vascular disease is atherosclerosis, but the mechanisms accounting for the increase are unclear. Chronic hyperglycemia is a common feature of all forms of diabetes mellitus and may contribute greatly to the increased incidence of atherosclerosis, via promotion of both lipoprotein and tissue glycation, which may have atherogenic effects. The present study investigated the effect of chronic hyperglycemia on measures of low-density lipoprotein (LDL) metabolism and atherosclerosis in streptozotocin-induced diabetic (STZ-DM) and control cynomolgus monkeys after 6 months of study. Consistent with a chronic hyperglycemic state, diabetic monkeys had significant increases in glycated hemoglobin (GHb) and glycated plasma LDL concentrations, but had minimal changes in total plasma cholesterol (TPC) or triglyceride (TG) concentrations during the study. Forty-eight hours before necropsy, control and in vitro-glycated LDL were differentially radiolabeled and coinjected into diabetic and control monkeys. There was a significant increase in arterial LDL accumulation in femoral arteries from diabetic monkeys compared with controls, with similar trends in other arterial sites. The effect of LDL glycation on arterial LDL accumulation was minimal in both groups. Arterial segments from diabetic monkeys also had greater amounts of arterial cholesterol content compared with controls. Histomorphometric analyses showed that diabetic monkeys had significantly greater intimal areas in the femoral artery and abdominal aorta compared with controls. Diabetic monkeys also had reduced arterial remodeling, or compensation, in the femoral artery and abdominal aorta. However, there was no difference in advanced glycation end products (AGE) in arterial collagen between groups. In conclusion, experimentally induced diabetes mellitus increases arterial LDL accumulation and atherosclerosis extent in cynomolgus monkeys before changes in AGE formation. The increased atherogenesis may be due to changes in lipoproteins or direct effects of hyperglycemia on the artery wall.

Both insulin resistance and abdominal fat patterning are related to aging, and have been related to cardiovascular disease (CVD) risk factors such as dyslipidemia and hypertension. However, previous studies have not used direct methods to quantify the independent strength of the association of each of these two putative primary factors with metabolic outcomes. We quantified overall obesity by the body mass index (BMI) and used a previously validated magnetic resonance imaging (MRI) method to quantify abdominal fat in 63 healthy nondiabetic individuals aged 22 to 83 years. We also measured the glucose and insulin response to an oral glucose tolerance test and the insulin sensitivity ([SI] by modified minimal model analysis). Body fat patterning was evaluated by the waist to hip ratio (WHR) and by MRI, which allowed direct measurement of subcutaneous (SCF) and intraabdominal (IAF) fat depots at the umbilicus in these subjects. These independent parameters were related to risk factors for CVD (blood pressure, lipids, and lipoproteins) and to plasma concentrations of free fatty acids (FFAs). Measures of overall obesity (BMI), total fat [TF], and/or SCF measured at the abdomen by MRI), glucose/insulin metabolism and SI, and central fat patterning (WHR or IAF measured by MRI) were correlated with mean arterial pressure (MAP), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels in univariate analysis and after controlling for age and gender. An index of central fat patterning (WHR) added to the informativeness of the insulin area under the curve (IAUC) in explaining 24% of the variability in plasma TG concentration, but measures of overall obesity were not independently related. Both the BMI and TF contributed to the IAUC in explaining 32% to 34% of the variability in MAP, but central fat patterning was not independently related. No index of overall obesity, fat patterning, glucose/insulin metabolism, and/or SI, was independently related to the plasma concentration of HDL-C after controlling for any one of the other two. Direct measurement of glucose/insulin metabolism and SI, as well as fat patterning, provides information on their relative associations with CVD risk factors. The measures of glucose/insulin metabolism and SI were more consistently related to dyslipidemia and hypertension than were the overall obesity and fat patterning in this healthy population.

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Controversy exists regarding the effects of estrogen and estrogen/progestin replacement therapies on glucose tolerance and insulin resistance. Also unknown are whether changes in glucose tolerance and insulin resistance with hormone therapy affect arterial glycation and atherosclerosis. We studied ovariectomized female monkeys fed a lipid-lowering diet and given either no hormone replacement therapy (n = 25) or conjugated equine estrogens (CEE) alone (n = 22) or combined with medroxyprogesterone acetate ([MPA] n = 21) for 30 months. Monkeys receiving combined hormone replacement had significantly higher fasting glucose and insulin levels and higher insulin responses to a glucose challenge compared with controls or those given estrogen alone. Monkeys given estrogen-only therapy had lower body weights, lower measures of abdominal adiposity, and decreased serum androgen concentrations. However, due to the effective dietary lipid decrease, there was no additional effect of hormone treatment on atherosclerosis. Also, there was no correlation between either arterial glycation or insulin levels and atherosclerosis extent. Thus, although there were adverse effects of combined hormone replacement therapy on carbohydrate metabolism, we were unable to determine whether these effects altered the extent of atherosclerosis.

Recent studies have shown that central obesity (increased waist to hip ratio [WHR]) is related to insulin resistance and aging. Furthermore, in central-obesity states, the intraabdominal fat (IAF) depot has been postulated to contribute most to the development of insulin resistance. Therefore, the observed insulin resistance of aging may be related more to changes in body composition than to aging per se. The purpose of this study was to explore the association of IAF with age and insulin sensitivity (SI) after controlling for obesity. We examined 60 healthy nondiabetic subjects (normal 75-g oral glucose tolerance test, aged 23 to 83, 15 men and 45 women). We chose subjects so that those < or = 125% and greater than 125% of ideal body weight were equally represented in each age decade. We quantified total and subcutaneous abdominal fat and IAF at the umbilicus using a validated magnetic resonance imaging (MRI) scanning technique and determined SI using a modified minimal model. IAF correlated significantly with age (r = .49, P = .0001) in the group as a whole, as well as in men (r = .58, P = .022) and women (r = .48, P = .0008) separately. In all subjects, SI was significantly related to IAF (r = -.50, P < .0001) but was not related to age (r = .00, P = .98). In multivariate analysis for various combinations of age, sex, and measures of fat distribution, WHR accounted for 28% and IAF for 51% of the variance in SI, whereas age, sex, and interactions of age and sex accounted for only 1%.(ABSTRACT TRUNCATED AT 250 WORDS)

Lactate clearance by liver plays an important role in lactate homeostasis and in the development of lactic acidosis. The role of lactate delivery to liver as a limiting factor in hepatic uptake of lactate is unclear. Lactate delivery of mechanisms could be important if rates of lactate transport approximate rates of lactate metabolism by liver. The rates of lactate transport into liver have been determined in vitro with isolated liver cells and the results have been conflicting. Therefore, the present studies measure the rate of transport of [14C]-L-lactate, and its poorly metabolizeable stereoisomer, [14C]-D-lactate, into rat liver in vivo using a portal vein injection technique. The transport of [3H]-water and of [14C]-sucrose, an extracellular reference compound, were also studied. Portal blood flow was determined from the kinetics of [3H]-water efflux in liver and was 1.93 +/- 0.22 mL/min/g. The volumes of distribution of [14C]-L-lactate, and [14C]-sucrose were 1.31 +/- 0.22, 0.71 +/- 0.07, and 0.22 +/- 0.07 mL/g, respectively. The extraction of unidirectional influx of [14C]-L-lactate and [14C]-D-lactate by rat liver was 93% +/- 10% and 91% +/- 9%, respectively. The rate of lactate transport into rat liver in vivo, 1.8 mumols.min-1.g-1, is approximately twofold greater than the rate of lactate metabolism by rat liver reported in the literature. Therefore, lactate uptake by liver may not be limited by transport under normal conditions. However, conditions such as decreased portal blood flow, which slow lactate delivery to liver by 50% or more, could cause lactate uptake by liver to be limited by transport of circulating lactate.