Ethan A. H. Sims

Effects of Physical Training and Diet Therapy on Carbohydrate Metabolism in Patients with Glucose Intolerance and Non-insulin-dependent Diabetes Mellitus

The effects of 12 wk of physical training in addition to hypocaloric diet (DPT group, N = 10) on body composition, carbohydrate (CHO) tolerance, and insulin secretion and action were compared with the effects of diet therapy alone (D group, N = 8) in CHO-intolerant and non-insulin-dependent diabetic subjects. Fat mass, fat-free mass (FFM), mean fasting plasma glucose, serum C-peptide, and insulin concentrations decreased similarly in both groups. The mean plasma glucose response to a mixed meal decreased approximately 20% in both treatment groups, and, after i.v. glucose, decreased 12% in the D group (P < 0.05), but did not change in the DPT group (NS between groups). The acute serum insulin response (0–6 min) after IG increased significantly in the DPT group only (NS between groups). The mean basal endogenous glucose production (BEGP) decreased 17% (P < 0.025) in the DPT group and by 31% (P < 0.01) in the D group (NS between groups). Hepatic sensitivity to insulin, estimated by BEGP suppression during the euglycemic clamp, increased significantly by 25% in both groups. Total glucose disposal during the euglycemic clamp increased from 3.51 ± 0.04 milligrams of glucose per kilogram of fat-free mass per minute (mg/kg-FFM/min) to 4.45 ± 0.54 mg/kg-FFM/min (P < 0.05) in the DPT group, but no change occurred in the D group (NS between groups). Separation of total glucose disposal rates into CHO oxidative and nonoxidative rates using indirect calorimetry during the euglycemic clamp showed that the mean CHO oxidation rate increased in the D group (P < 0.05), but not in the DPT group (NS between groups). There was, however, a significant difference in the mean CHO nonoxidative rate between the two groups (P < 0.05), increasing in the DPT group but decreasing in the D group. In both groups, the improvements in fasting plasma glucose and meal tolerance appeared to be attributable mostly to decreased BEGP, with increased hepatic sensitivity to insulin. However, glucose disposal was accomplished by different mechanisms in the two groups.

Dietary-induced alterations in thyroid hormone metabolism during overnutrition.

Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.

Serial Studies of Renal Function During Pregnancy and the Puerperium in Normal Women

Until recently there has been uncertainty as to whether kidney function in normal pregnancy differs significantly from that in the nonpregnant state. The earlier studies reviewed by Smith (1), Chesley (2) and Bucht (3) were for the most part limited to the immediate preand postpartum period when deviations from the nonpregnant state are less marked. On the other hand, the studies of Nice (4) demonstrated a marked increase of urea clearance in mid-pregnancy while those of Bonsnes and Lange (5) and Bucht (3) showed significant increases in both renal plasma flow and in glomerular filtration rate during mid-pregnancy which persisted to approximately the thirtyeighth week. At the time the present study was begun, no serial studies of renal function during normal pregnancy and in the postpartum period had been reported and it was the purpose of this study to make such observations. Serial studies eliminate the element of apprehension encountered in single studies which, as emphasized by Miles and DeWardener (6), may distort the results. Our findings confirm the increased renal function in pregnancy, and define the resultant lowering of the normal range of values for plasma urea and plasma creatinine during pregnancy. Previous observations are extended to include the puerperium and indicate that there is a decline of renal plasma flow to subnormal values during this period.

Thermic effect of infused glucose and insulin in man. Decreased response with increased insulin resistance in obesity and noninsulin-dependent diabetes mellitus.

The thermic effect of infused glucose and insulin was measured by combining the hyperinsulinemic euglycemic clamp technique with indirect calorimetry, in 10 normal weight volunteers (group I), 7 obese subjects with normal glucose tolerance (group II), and 13 obese subjects with abnormal glucose tolerance or noninsulin-dependent diabetes mellitus before (group IIIa) and after weight loss of 10.8 +/- 0.4 kg (group IIIb). During hyperinsulinemia (760-1,100 pmol/liter), total glucose disposal from combined endogenous production and glucose infusion was 545 +/- 49, 441 +/- 70, 233 +/- 35, 231 +/- 31 mg/min and energy expenditure changed by + 0.476 +/- 0.080, +0.293 +/- 0.095, -0.114 +/- 0.063, and +0.135 +/- 0.082 kJ/min in group I, II, IIIa, and IIIb, respectively. The increased energy expenditure correlated with glucose storage (measured cost of processing the glucose: 1.33 kJ/g). In group IIIa there was no increase in energy expenditure in response to glucose and insulin infusions. After therapy (group IIIb) there was a significant recovery (P less than 0.05) of the thermic effect of infused glucose although total glucose disposal was unchanged. It is proposed that the recovered thermic effect of infused insulin/glucose is due to the different contributions of gluconeogenesis in the fasting state and during the glucose clamp before and after weight loss. In addition we hypothesize that some of the lower thermic effect of food reported in obese noninsulin-dependent diabetics may be explained by decreased energy expenditure due to a greater suppression of hepatic gluconeogenesis as well as by lower storage rate.

Longitudinal changes in body composition and energy balance in lean women with normal and abnormal glucose tolerance during pregnancy

OBJECTIVE The objective of this study was to evaluate the longitudinal changes in energy expenditure and body composition in relationship to alterations in carbohydrate metabolism in women with normal and abnormal glucose metabolism. We hypothesized that women with decreased insulin sensitivity before conception would have less fat accretion and smaller increases in energy expenditure. STUDY DESIGN Six women with normal glucose tolerance and 10 women with abnormal glucose tolerance were evaluated before conception, and in early (12 to 14 weeks) and late (34 to 36 weeks) gestation. Body composition was estimated by hydrodensitometry, resting energy expenditure, and glucose and fat metabolism by indirect calorimetry, endogenous glucose production by infusion of [6-6 2H2] glucose, and insulin sensitivity using a hyperinsulinemic-euglycemic clamp (40 mU/m2/min). RESULTS There was a smaller increase in fat mass (1.3 kg [P = .04]) in early pregnancy in women with abnormal glucose tolerance before pregnancy. Indirect calorimetry measured gestational age-related increases in basal oxygen utilization, with or without correction for fat-free mass (VO2, P = .002), resting energy expenditure (expressed in kilocalories, P = .0001), and carbohydrate oxidation (P = .0003). The insulin-mediated elevation in VO2 increased in later gestation VO2 (P = .005), as did resting energy expenditure (P = .0001) and fat oxidation (P = 0.0001). However, there was a decrease in respiratory quotient (P = .0001), carbohydrate oxidation (P = .002), and nonoxidative carbohydrate metabolism (P = .0001) with advancing gestation during insulin infusion. In early pregnancy, changes in fat mass correlated inversely with changes in insulin sensitivity (r= -0.52, P = .04) and changes in basal VO2 correlated inversely with decreases in basal endogenous glucose production (r = -0.74, P = .01). CONCLUSION In early gestation, the changes in maternal fat mass and basal oxygen consumption are inversely related to the changes in insulin sensitivity. This response in lean women with decreased insulin sensitivity before conception may have survival value by providing a larger amount of available substrate to meet fetoplacental needs during gestation.

SECRETION RATE OF ALDOSTERONE IN NORMAL PREGNANCY

There is a progressive rise in excretion of the metabolites of the estrogens (1) and of progesterone 1 (2) during pregnancy in humans. In late pregnancy, these hormones are largely placental in origin (3-6). The physiological role of the adrenal gland in pregnancy is still not well understood. The high levels of blood hydrocortisone found in pregnancy were initially explained as a reflection of an increased secretion of adrenal cortical hormones (7). More recently, it has been shown that the high blood levels of hydrocortisone in pregnancy could be accounted for by the increased binding of this hormone to blood proteins (8). It has been reported that aldosterone is secreted in increased amounts during pregnancy (9, 10). From available evidence, it has been concluded that in humans aldosterone is not a secretory product of the placenta (11-14), but that it is formed in the adrenal gland. In earlier studies (15-17), bioassay of the crude urinary extract revealed little or no increase in the salt-retaining factor in pregnancy as compared with the normal nonpregnant state. Barnes and Quilligan (18) reported the same findings with a bioassay of urinary extracts purified by three paper chromatographic systems. In 1956, Venning and Dyrenfurth (19) bioassayed extracts

Experimental obesity in man: cellular character of the adipose tissue

Studies of adipose tissue cellularity were carried out in a group of nonobese adult male volunteers who gained 15-25% of their body weight as the result of prolonged high caloric intake. Adipose cell size (lipid content per cell) was determined in tissue obtained from three subcutaneous sites (gluteal, anterior abdominal wall, and triceps) and total adipose cell number estimated from measurement of total body fat. Five experimental subjects gained an average of 16.2 kg of body weight, of which 10.4 kg was determined to be fat. Expansion of the adipose mass was accompanied by a significant and relatively uniform increase in fat cell size in each subcutaneous site tested. Total adipose cell number did not change as a result of weight gain and expansion of the adipose depot in adult life. Subsequent loss of weight and restoration of original body fat was associated with a reduction in adipose cell size at each subcutaneous site, but no change in total number. In two control subjects who neither gained nor lost weight there were no changes in total adipose cell number or cell size. These observations suggest that expansion and retraction of the adipose depot in adult life is accompanied by changes in adipose cell size only. Significant differences in both the size and total number of adipose cells were observed between subjects in both the experimental and control groups. In addition, within individuals of both groups there were significant differences in cell size when adipose cells from the three subcutaneous sites were compared. These findings indicate that wide variations in adipose cell size and number exist in nonobese individuals having similar adipose depot sizes.

Subclinical abnormalities of glucose metabolism in subjects with previous gestational diabetes

To investigate whether there are subclinical abnormalities of glucose metabolism in women with previous gestational diabetes that are consistent with a high incidence of diabetes mellitus in later life, eight patients with previous gestational diabetes and normal oral glucose tolerance were evaluated by means of body composition studies, intravenous glucose tolerance tests, and the hyperinsulinemic-euglycemic clamp coupled with 6-6 dideuterated glucose infusion, indirect calorimetry, and measurement of islet cell antibodies. Eight control subjects were matched for percent body fat and diet and studied in a similar fashion. Abnormalities of insulin response and insulin resistance were present in four (50%) of patients with previous gestational diabetes. Insulin resistance was significantly greater in the patients than in the control subjects. When compared with lean patients, obese patients with previous gestational diabetes had significantly greater insulin response to the intravenous glucose tolerance test and insulin resistance. These changes are consistent with reported findings of an early and progressive development of overt diabetes in patients who had gestational diabetes.

Glucose Metabolism and the Response to Insulin by Human Adipose Tissue in Spontaneous and Experimental Obesity: EFFECTS OF DIETARY COMPOSITION AND ADIPOSE CELL SIZE

[1-(14)C]glucose oxidation to CO(2) and conversion into glyceride by adipose tissue from nonobese and obese subjects has been studied in vitro in the presence of varying medium glucose and insulin concentrations as functions of adipose cell size, the composition of the diet, and antecedent weight gain or loss. Increasing medium glucose concentrations enhance the incorporation of glucose carbons by human adipose tissue into CO(2) and glyceride-glycerol. Insulin further stimulates the conversion of glucose carbons into CO(2), but not into glyceride-glycerol. Incorporation of [1-(14)C]glucose into glyceride-fatty acids by these tissues could not be demonstrated under any of the conditions tested. Both adipose cell size and dietary composition influence the in vitro metabolism of glucose in, and the response to insulin by, human adipose tissue. During periods of ingestion of weight-maintenance isocaloric diets of similar carbohydrate, fat, and protein composition, increasing adipose cell size is associated with (a) unchanging rates of glucose oxidation and increasing rates of glucose carbon incorporation into glyceride-glycerol in the absence of insulin, but (b) decreasing stimulation of glucose oxidation by insulin. On the other hand, when cell size is kept constant, increasing dietary carbohydrate intake is associated with an increased basal rate of glucose metabolism and response to insulin by both small and large adipose cells. Thus, the rate of glucose oxidation and the magnitude of the insulin response of large adipose cells from individuals ingesting a high carbohydrate diet may be similar to or greater than that in smaller cells from individuals ingesting an isocaloric lower carbohydrate diet.The alterations in basal glucose metabolism and insulin response observed in adipose tissue from patients with spontaneous obesity are reproduced by weight gain induced experimentally in nonobese volunteers; these metabolic changes are reversible with weight loss. The relationships among adipose cell size, dietary composition, and the metabolism of adipose tissue are similar in spontaneous and in experimental obesity.

Incidence and Significance of Islet Cell Antibodies in Women With Previous Gestational Diabetes

Islet cell antibodies (ICAs) are markers for patients at risk for insulin-dependent diabetes and are associated with progressive β-cell destruction. This prospective study was performed to estimate the incidence of these antibodies in 187 women with previous gestational diabetes. With a specific protein A monoclonal antibody (MoAb) assay, the incidence of ICAs was only 1.6% (3 of 187). Oral and intravenous glucose tolerance tests were performed in these 3 women and compared with 6 women with previous gestational diabetes without ICAs and 5 control women. Glucose tolerance was impaired only in the 3 women with ICAs, who also had an increase (P < 0.03) in fasting plasma glucose and a decrease (P < 0.03) in early first-phase insulin response. We conclude that the more specific MoAb method indicates a lower incidence of ICA in women with a history of gestational diabetes than previously reported and that a decreased first-phase insulin response is associated with the presence of ICAs, suggesting progressive islet cell damage.