A. L. M. Swislocki

Relationships between plasma-free fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non-insulin-dependent diabetic individuals☆

Measurements of fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations were made in 32 individuals--16 with normal glucose tolerance and 16 with non-insulin dependent diabetes mellitus (NIDDM)--further subdivided into two equal groups on the basis of body weight. In addition, endogenous glucose production was estimated in 32 subjects. Both fasting plasma glucose (251 +/- 14 v 86 +/- 1 mg/dL) and FFA (672 +/- 35 v 434 +/- 45 microEq/L) concentrations were significantly higher in patients with NIDDM (P less than .001), and the differences between normal and diabetic existed in both weight groups. Rates of endogenous glucose production were also significantly elevated (P less than .001) in diabetic (120 +/- 6 mg/m2 X min) as compared to normal subjects (73 +/- 6 mg/m2 X min), and these differences were also independent of degree of obesity. However, there were no significant differences between normal subjects and patients with NIDDM in either fasting or postprandial insulin concentrations. The similarity in insulin values for normal and diabetic subjects was true of both obesity groups, although insulin concentrations were somewhat higher in normal obese individuals as compared to their normal nonobese counterparts. Significant relationships were seen between values for fasting plasma glucose and endogenous glucose production (r = .89), fasting plasma glucose and fasting FFA (r = .64), and FFA levels and endogenous glucose production (r = .58) when all nonobese subjects were considered together. Essentially identical relationships, both qualitatively and quantitatively, were seen within the obese group.(ABSTRACT TRUNCATED AT 250 WORDS)

Deleterious metabolic effects of high-carbohydrate, sucrose-containing diets in patients with non-insulin-dependent diabetes mellitus

The effects of variations in dietary carbohydrate and fat intake on various aspects of carbohydrate and lipid metabolism were studied in patients with non-insulin-dependent diabetes mellitus (NIDDM). Two test diets were utilized, and they were consumed in random order over two 15-day periods. One diet was low in fat and high in carbohydrate, and corresponded closely to recent recommendations made by the American Diabetes Association (ADA), containing (as percent of total calories) 20 percent protein, 20 percent fat, and 60 percent carbohydrate, with 10 percent of total calories as sucrose. The other diet contained 20 percent protein, 40 percent fat, and 40 percent carbohydrate, with sucrose accounting for 3 percent of total calories. Although plasma fasting glucose and insulin concentrations were similar with both diets, incremental glucose and insulin responses from 8 a.m. to 4 p.m. were higher (p less than 0.01), and mean (+/- SEM) 24-hour urine glucose excretion was significantly greater (55 +/- 16 versus 26 +/- 4 g/24 hours p less than 0.02) in response to the low-fat, high-carbohydrate diet. In addition, fasting and postprandial triglyceride levels were increased (p less than 0.001 and p less than 0.05, respectively) and high-density lipoprotein (HDL) cholesterol concentrations were reduced (p less than 0.02) when patients with NIDDM ate the low-fat, high-carbohydrate diet. Finally, since low-density lipoprotein (LDL) concentrations did not change with diet, the HDL/LDL cholesterol ratio fell in response to the low-fat, high-carbohydrate diet. These results document that low-fat, high-carbohydrate diets, containing moderate amounts of sucrose, similar in composition to the recommendations of the ADA, have deleterious metabolic effects when consumed by patients with NIDDM for 15 days. Until it can be shown that these untoward effects are evanescent, and that long-term ingestion of similar diets will result in beneficial metabolic changes, it seems prudent to avoid the use of low-fat, high-carbohydrate diets containing moderate amounts of sucrose in patients with NIDDM.

Persistence of hypertriglyceridemic effect of low-fat high-carbohydrate diets in NIDDM patients.

Although low-fat high-carbohydrate diets are recommended for patients with non-insulin-dependent diabetes mellitus (NIDDM) in an effort to reduce the risk of coronary artery disease (CAD), the results of short-term studies have shown that these diets can lead to changes in carbohydrate and lipid metabolism associated with an increased risk of CAD. This study has extended these earlier observations by determining the metabolic effects of such diets over a longer period in these patients. The comparison diets contained either 40 or 60% of the total calories as carbohydrates, with reciprocal changes in fat content from 40 to 20% consumed in random order for 6 wk in a crossover experimental design. The ratio of polyunsaturated to saturated fat and the total cholesterol intake were held constant in the two diets. Plasma glucose and insulin concentrations were significantly (P < .001) elevated throughout the day when patients consumed the 60% carbohydrate diet, and 24-h urinary glucose excretion more than doubled (0.8 vs. 1.8 mol/24 h). Fasting plasma total and very-low-density lipoprotein (VLDL) triglyceride (TG) concentrations increased by 30% (P < .001) after 1 wk on the 60% carbohydrate diet, and the magnitude of carbohydrate-induced hypertriglyceridemia persisted unchanged throughout the 6-wk study period. Total plasma cholesterol concentrations were similar after both diets. However, VLDL cholesterol (VLDL-chol) was significantly increased, whereas both low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) chol concentrations were significantly decreasedafter consumption of the 60% carbohydrate diet. Consequently, neither total-chol-to-HDL-chol nor LDL-chol-to-HDL-chol ratios changed. The results of this study indicate that high-carbohydrate diets lead to several changes in carbohydrate and lipid metabolism in patients with NIDDM that could lead to an increased risk of CAD, and these effects persist for >6 wk. Given these results, it seems reasonable to suggest that the routine recommendation of low-fat high-carbohydrate diets for patients with NIDDM be reconsidered.

Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with Type 2 (non-insulin-dependent) diabetes

SummaryIn order to define the effect of Type 2 (non-insulin-dependent) diabetes mellitus on the ability of insulin to regulate plasma-free fatty acid (FFA) concentrations, we determined the plasma FFA response to the intravenous infusion of various amounts of insulin. Plasma FFA concentrations were higher in patients with Type 2 diabetes (two way analysis of variance, p<0.001) over a plasma insulin concentration which ranged from approximately 5 to 55 mU/l of insulin. Although plasma FFA concentrations were higher in patients with Type 2 diabetes at any given insulin concentration, the relative ability of insulin to suppress plasma FFA concentration to half the initial value was comparable in normal individuals and patients with Type 2 diabetes, occurring at a plasma insulin concentration of approximately 20 mU/l. These data demonstrate that plasma FFA levels are regulated over a narrow range of plasma insulin concentrations in humans, and that plasma concentrations are higher than normal in patients with Type 2 diabetes throughout this range.

Effect of Source of Dietary Carbohydrate on Plasma Glucose and Insulin Responses to Mixed Meals in Subjects With NIDDM

It has been demonstrated that carbohydrate-rich foods result in different plasma glucose responses when eaten alone by normal subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). This study was designed to test if the glycemic response to mixed meals can be altered by selecting carbohydrate-rich foods based on their glycemic potency. Consequently, three test meals were developed that should have yielded high-, intermediate-, and low-glycemic responses based on the published glycemic index of all the carbohydrate foods in the meals. The test meals were consumed by normal individuals and patients with NIDDM, and the resultant plasma glucose and insulin responses were determined. The results indicated that the plasma glucose responses after the meals did not vary as a function of their glycemic potency in either the normal or NIDDM subjects. There were no significant differences in the plasma insulin responses for either group. These results indicate that the plasma glucose response to mixed meals did not vary as a function of the calculated glycemic potencies. Therefore, the glycemic response to a mixed meal was not predicted on the basis of the published values of the glycemic index of the individual carbohydrate foods included in the meal.

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.

Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha adrenergic blockade during prazosin therapy.

Patients with essential hypertension show an increase in vascular resistance. It is unclear whether this is caused by structural changes in the arterial wall or by hyperresponsiveness of vascular smooth muscle to endogenous alpha adrenergic agonists. Using the dorsal hand vein compliance technique we compared the changes in diameter of superficial veins in response to phenylephrine, an alpha 1 adrenergic receptor agonist, and to nitroglycerin, a venorelaxant, in patients with essential hypertension and in normotensive subjects. The dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) in the hypertensive subjects was 257 ng/min (geometric mean; log mean +/- SD was 2.41 +/- 0.54). In the control subjects the ED50 was 269 ng/min (geometric mean; log mean was 2.43 +/- 0.43). Maximal response (Emax) for phenylephrine was 84 +/- 13% in the hypertensive subjects and 90 +/- 6% in the control subjects. Differences in the group means of the ED50 (P = 0.92) or the Emax (P = 0.27) were not significant. There were no significant differences in the ED50 (P = 0.54) or the Emax (P = 0.08) for nitroglycerin between the two groups. These results show no evidence for a generalized change in alpha adrenergic responsiveness in hypertension and support the concept that increased blood pressure responses to alpha adrenergic stimulation in hypertensives are due to structural and geometric changes in the arterial wall rather than to an increased responsiveness of postsynaptic alpha adrenergic receptors. The phenylephrine studies were repeated in seven hypertensive patients during treatment with prazosin, an alpha 1 adrenergic antagonist. The mean dose ratio of the shift in phenylephrine ED50 (ED50 during prazosin therapy/ED50 before prazosin therapy) was 6.1. This indicates that small doses of prazosin (1-2 mg) cause significant in vivo shifts in the dose-response relationship of alpha adrenergic agonists. The dorsal hand vein compliance technique is useful in detecting systemic effects of alpha adrenergic antagonists.

High density lipoprotein turnover in patients with hypertension.

Although hyperinsulinemia and decreased high density lipoprotein cholesterol concentration can occur in patients with hypertension, there is no information available concerning the dynamic state of high density lipoprotein metabolism. To address this issue, we quantified high density lipoprotein turnover in 12 patients with mild hypertension and 11 matched subjects with normal blood pressure. Patients with high blood pressure had lower high density lipoprotein cholesterol concentrations. Fractional catabolic rates of 125I-apolipoprotein AI (apoAI)/high density lipoprotein were faster in patients with hypertension (0.36±0.02 versus 0.26±0.02 I/day, p<0.001). Total synthetic rates of apoAI were also significantly greater in patients with high blood pressure (17.4±1.1 versus 13.2±0.6 mg/kg/day, p<0.001). Although significant correlation was observed between blood pressure and fractional catabolic rate of 125I-apoAI/high density lipoprotein in the experimental population (r=0.52, p<0.01), no relation was found when patients with normal blood pressure or hypertension were considered separately. However, a highly significant positive correlation was found between l25I-apoAI/high density lipoprotein fractional catabolic rate and insulin concentration in the entire population (r=0.72, /p<<0.001). In conclusion, the patients with mild hypertension studied were hyperinsulinemic, had a faster fractional catabolic rate of 125I-apoAI/high density lipoprotein, and a lower high density lipoprotein-cholesterol concentration. It is suggested that the changes seen in high density lipoprotein-cholesterol concentration and l25I-apoAI/high density lipoprotein fractional catabolic rates were secondary to the hyperinsulinemia and not due to the high blood pressure per se.