C. B. Hollenbeck

Measurement of Plasma Glucose, Free Fatty Acid, Lactate, and Insulin for 24 h in Patients With NIDDM

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 < 175 mg/dl), and 9 with severe NIDDM (fasting plasma glucose > 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 < .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 < .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 < .001) greater than normal throughout the period of observation. These results demonstrate that there are differences in substrate level between individuals with normal glucose tolerance and patients with NIDDM and differing degrees of glucose intolerance, unrelated to ambient insulin level, and these changes persist over 24 h.

Effect of Metformin on Carbohydrate and Lipoprotein Metabolism in NIDDM Patients

The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after ∼ 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was <25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P < 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.

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.

Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance

SummaryPlasma glucose and insulin concentration following a 75 g oral glucose challenge and glucose uptake during a hyperinsulinaemic glucose clamp study were determined in 50 non-obese individuals. The study population was divided into five groups on the basis of their glucose tolerance: normal, impaired glucose tolerance, Type 2 (non-insulin-dependent) diabetes mellitus with fasting plasma glucose of less than 8 mmol/l, between 8–15 mmol/l, and more than 15 mmol/l. The plasma insulin response was significantly greater (p<0.001) than normal in those with either impaired glucose tolerance or Type 2 diabetes and a fasting plasma glucose concentration less than 8 mmol/l. In contrast, the plasma insulin response was similar to normal in the other two groups of patients with Type 2 diabetes, i.e. fasting plasma glucose concentration 8–15 mmol/l or greater than 15 mmol/l. Glucose uptake rates were significantly lower (p<0.001) than normal in subjects with impaired glucose tolerance and all three groups of patients with Type 2 diabetes. Although glucose uptake rates during the glucose clamp studies were relatively similar in all four groups of glucose intolerant subjects, the values were significantly lower in those patients with Type 2 diabetes who had a fasting plasma glucose concentration greater than 8 mmol/l (p<0.01), These data indicate that a significant degree of insulin resistance exists in patients with impaired glucose tolerance or Type 2 diabetes, relatively independent of fasting plasma glucose concentration. Indeed, glucose uptake during glucose clamp studies fell 8-fold over a range in fasting plasma glucose concentration of from 4.5 to 6.5 mmol/l. In contrast, the plasma insulin response increased over the same range of fasting plasma glucose concentrations. The fact that this defect in insulin action can be seen in patients who are hyperinsulinaemic, not hypoinsulinaemic, and only modestly hyperglycaemic, is consistent with the hypothesis that resistance to insulin-stimulate glucose uptake is a basic characteristic of patients with impaired glucose tolerance or Type 2 diabetes.

Relationship Between the Plasma Insulin Response to Oral Glucose and Insulin-stimulated Glucose Utilization in Normal Subjects

The relationship between in vivo insulin-stimulated glucose utilization (euglycemic clamp technique) and various estimates of the plasma insulin response to oral glucose was defined in 62 subjects with normal glucose tolerance. Both the incremental insulin increase above fasting (r = 0.61) and the total integrated insulin response (r = 0.65) were highly correlated (P < 0.001) with in vivo insulin action, and the relationship between total insulin response and insulin action remained significant (r = 0.61, P < 0.001) when corrected for variations in total glucose response, age, and obesity. In a subset of these subjects (N = 27) we were also able to assess state of habitual physical activity by estimating maximal oxygen consumption during bicycle ergometry. A significant correlation also existed between insulin action and response in these subjects (r = 0.67, P < 0.001), which remained significant (r = 0.65) when differences in total glucose response, obesity, age, and maximal oxygen consumption were taken into account. These data demonstrate that there is a significant correlation between insulin response and insulin action in normal individuals that can account for approximately one-third of the total variance in insulin action seen in subjects with normal glucose tolerance. Thus, determination of plasma insulin levels after an oral glucose challenge can only provide a qualitative estimate of insulin-stimulated glucose Utilization.

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.

Why Do Low-Fat High-Carbohydrate Diets Accentuate Postprandial Lipemia in Patients With NIDDM?

OBJECTIVE To understand why low-fat high-carbohydrate (CHO) diets lead to higher fasting and postprandial concentrations of triglyceride (TG)-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Patients with NIDDM were placed randomly on diets containing either 55% CHO, 30% fat, and 15% protein or 40% CHO, 45% fat, and 15% protein for 6 weeks, followed by crossover to the other diet. Test meals at the end of each diet period were consumed at 8:00 A.M. and 12:00 P.M. (noon) and contained 20 and 40% of daily calories, respectively. Vitamin A was also given at noon, and TG-rich lipoproteins of intestinal origin were identified by the presence of vitamin A esters. Frequent measurements were made throughout the 24-h study period of plasma glucose, insulin, and TG concentrations. Plasma samples obtained from 12:00 P.M. (noon) until 12 A.M. (midnight) were subjected to ultracentrifugation, and measurements were made of TG and vitamin A ester concentrations in plasma and in both the Svedberg flotation constant (Sf) >400 (chylomicron) and Sf 20-400 (chylomicron remnant) lipoprotein fractions. In addition, very-low-density lipoprotein (VLDL)-TG turnover rate was estimated by following the decay of [3H]VLDL-TG. Finally, postheparin lipoprotein lipase and hepatic lipase activities were measured at the end of each dietary period. RESULTS Mean ± SE hourly concentrations of glucose (8.0 ± 0.8 vs. 7.5 ± 0.7 mmol/1), insulin (184 ± 26 vs. 158 ± 19 pmol/1), and TG (2.8 ± 0.2 vs. 2.1 ± 0.2 mmol/1) were higher (P < 0.05-0.001) after the 55% CHO diet. The 55% CHO diet also led to an increase (P < 0.05-0.01) in the mean ± SE hourly concentrations of vitamin A esters in plasma (2.3 ± 0.3 vs. 1.6 ±0.1 μmol/l) and in both the chylomicron (2.0 ± 0.3 vs. 1.4 ±0.1 μmol/l) and chylomicron remnant fractions (0.36 ± 0.04 vs. 0.14 ± 0.03 μmol;/l). In addition, the VLDL-TG production rate was higher (17.2 ± 1.4 vs. 12.8 ± 1.0 mg · kg−1 · h−1, P < 0.003) and the VLDL-TG fractional catabolic rate lower (0.22 ± 0.02 to 0.28 ± 0.02 l/h, P < 0.005) after the 55% CHO diet. Finally, there was an increase in lipoprotein lipase activity (7.0 ± 0.8 to 8.1 ± 0.7 μmol free fatty acids released · ml−1 · h−1, P < 0.02) in response to the CHO-enriched diet. CONCLUSIONS A low-fat high-CHO diet in patients with NIDDM led to 1) higher day-long plasma glucose, insulin, and TG concentrations; 2) postprandial accumulation of TG-rich lipoproteins of intestinal origin; 3) increased production of VLDL-TG; and 4) increased postheparin lipoprotein lipase activity. These data provide a mechanism for the hypertriglycer-idemic effect of CHO-enriched diets in patients with NIDDM and demonstrate that multiple risk factors for coronary heart disease are accentuated when these individuals consume diets recommended to reduce this risk.

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.

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.

A Comparison of the Relative Effects of Obesity and Non-insulin-dependent Diabetes Mellitus on In Vivo Insulin-stimulated Glucose Utilization

Insulin clamp studies were carried out in 50 individuals, 25 with normal glucose tolerance and 25 with non-insulin-dependent diabetes mellitus (NIDDM). Both diagnostic groups were further subdivided on the basis of body mass index (BMI) into an obese (BMI > 28 kg/ m2) or nonobese group (BMI < 28 kg/m2). The obese and nonobese subjects in each diagnostic category had similar plasma glucose levels in response to an oral glucose challenge. In addition, insulin-stimulated glucose utilization, as assessed by determination of glucose metabolic clearance rate (MCR), was not different as a function of obesity. Glucose MCR (mean ± SEM) in obese subjects (mean BMI = 32.1) with normal glucose tolerance was 162 ml/min/m2, as compared with a value of 205 ml/min/m2 in nonobese individuals (mean BMI = 23.8). This difference was not statistically significant. Similarly, glucose MCR in obese patients (mean BMI = 34.7) with NIDDM was 55 ml/min/m2, as compared with a value Of 80 ml/min/ m2 in nonobese subjects (mean BMI = 24.9) with NIDDM. However, as can be seen from the above data, glucose MCR in patients with NIDDM, either nonobese or obese, was markedly reduced (P < 0.001) when compared with that of normal subjects. These data emphasize the profound effect of NIDDM on reducing in vivo insulin action, and point out that the impact of obesity on insulin resistance is minor in comparison.