Ronald K. Kalkhoff

Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women

The relationship of body fat distribution to metabolic profiles was determined in 80 healthy premenopausal white women of a wide range of obesity levels [percentage of ideal body weight (% IBW) 92-251]. Distribution of fat between the upper and lower body was assessed from the waist/hips girth ratio (WHR), which varied from 0.64 to 1.02. In 23 women, in vivo insulin sensitivity was also determined from the steady-state plasma glucose (SSPG) level at comparable insulin levels of approximately 100 microU/mL attained by the intravenous infusion of somatostatin, glucose, and insulin. Increasing WHR was accompanied by progressively increasing fasting plasma insulin levels (r = 0.47, P less than 0.001), insulin and glucose areas after glucose challenge (r = 0.53, P less than 0.001; r = 0.50, P less than 0.001, respectively) and fasting plasma triglyceride concentrations (r = 0.48, P less than 0.001). Obesity level was similarly correlated with these metabolic indices. Partial and multiple regression analysis and analysis of variance with a linear contrast model revealed that the effects of body fat topography were independent of, and additive to, those of obesity level. Within obese subjects alone (%IBW: 130), %IBW had no predictive value, but WHR remained a significant predictor of plasma glucose, insulin, and triglyceride concentrations. The WHR also correlated with the plasma cholesterol level, but this association was largely dependent on its relationship to %IBW. Both WHR and %IBW correlated with the insulin resistance index, SSPG (r = 0.60, P less than 0.01; r = 0.61, P less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple lentigines syndrome: Case report and review of the literature

The multiple lentigines syndrome is reviewed and a new case is presented. The major features of this syndrome are lentigines and other cutaneous abnormalities, cardiac defects, meurologic defects, cephalofacila dysmorphism, shortness of stature, skeletal anomalies, genitourinary abnormalities, and a family history consistent with an autosomal dominant mode of inheritance. The multiple lentigines syndrome manifests markedly variable expressivity; no single finding is pathognomonic and few patients have all major features. We propose specific criteria for diagnosis.

Changes in lipoprotein composition during the menstrual cycle.

Composition of major plasma lipoproteins was studied in 14 normal women during different phases of the menstrual cycle for three consecutive months. The results were compared to measurements in ten normal age-matched men for a comparable period, to delineate possible sex differences in lipoprotein metabolism in young adults. Blood samples were obtained every 3--5 days after a 14-hr overnight fast and processed for determinations of total plasma cholesterol, LDL- and HDL-cholesterol, and apoproteins B and A-1. In premenopausal women, a significant, 10%--25% cyclical suppression of total plasma cholesterol, LDL-Chol, and LDL-apoB occurred during the luteal phase, which was significantly lower than unchanging concentrations found in men at any time interval. HDL-Chol remained in a significantly higher fixed concentration range in the female subjects as compared to the men. These sex differences in lipoprotein metabolism may have relevance to the reduced susceptibility of premenopausal women to atherosclerosis.

Plasma insulin disturbances in primary hyperparathyroidism

Plasma insulin dynamics were evaluated in 10 patients with primary hyperparathyroidism before and after parathyroidectomy and correction of hypercalcemia. Before surgery fasting plasma insulin concentrations and insulin responses to administered glucose, tolbutamide, and glucagon were significantly greater than postoperative values. Hyperinsulinemia was not associated with altered glucose curves during glucose or glucagon tolerance tests, but a relatively greater insulin response to tolbutamide resulted in an increased hypoglycemic effect following its administration. The glucose-lowering action of intravenous insulin was slightly impaired before treatment. Intramuscular injections of parathormone to six normal men for 8 days induced mild hypercalcemia and hypophosphatemia and reproduced augmented plasma insulin responses to oral glucose and intravenous tolbutamide. 4-hr intravenous infusions of calcium to another group of six normal men raised serum calcium concentrations above 11 mg/100 ml. This did not alter glucose or insulin curves during oral glucose tolerance but markedly accentuated insulin responses to tolbutamide and potentiated its hypoglycemic effect. When highly purified parathormone was incubated with isolated pancreatic islets of male rats, glucose-stimulated insulin secretion was unaffected. These findings suggest that chronic hypercalcemia of hyperparathyroidism sustains a form of endogenous insulin resistance that necessitates augmented insulin secretion to maintain plasma glucose homeostasis. This state is insufficient to oppose tolbutamide-induced hypoglycemia because of an additional direct, selective enhancement of hypercalcemia on pancreatic beta cell responsiveness to the sulfonylurea. The possible direct role of parathormone in these events has not been established.

Metabolic effects of progesterone

Progesterone has important effects on carbohydrate, lipid and protein metabolism. This steroid induces hyperinsulinemia, possibly by direct action on pancreatic islets, while promoting glycogen storage in the liver. Paradoxically, it antagonizes the effects of insulin on glucose metabolism in adipose tissue and skeletal muscle. Progesterone stimulates deposition of body fat but had catabolic effects on protein metabolism. Provisional evidence is offered that the steroid may influence ketone body production by the liver as well. When these steroid actions are considered together, their most relevant expression appears to be the physiologic changes observed during normal pregnancy.

Impact of Maternal Fuels and Nutritional State on Fetal Growth

Several maternal plasma fuel abnormalities have been described in gestational diabetes mellitus (GDM), and all may contribute to the development of fetal macrosomia, generally because of the surfeit of calories they provide. Elevated maternal plasma glucose and amino acid concentrations represent key disturbances, because they are also well-known fetal pancreatic β-cell secretagogues. Fetal hyperinsulinemia contributes to macrosomia in a special way by selectively accelerating fuel utilization and storage in insulin-sensitive fetal tissues. Maternal obesity intensifies the insulin resistance already present in late pregnancy and probably exaggerates the metabolic abnormalities attending GDM that impact on fetal growth and development. However, the means by which maternal obesity per se promotes the development of heavy babies in nondiabetic pregnancies remains poorly defined. Significant correlations exist between newborn birth weight and the levels of maternal plasma glucose, amino acids, free fatty acids, and triglycerides in diabetic pregnancies. However, the relative influence of each disturbance on fetal birth weight remains controversial and requires more detailed investigation.

Relationship between neonatal birth weight and maternal plasma amino acid profiles in lean and obese nondiabetic women and in type I diabetic pregnant women

Profiles of hemoglobin A1c (HbA1c) and concentrations of plasma glucose and 18 plasma amino acids were obtained in ten nonobese, insulin-dependent type I diabetic women, in 9 age- and weight-matched normal women and in ten obese nondiabetic women throughout pregnancy and postpartum. In late gestation, the period of maximum fetal growth, average HbA1c, plasma glucose, and total amino acid concentrations in diabetic mothers were significantly elevated above lean control values. No differences existed between the obese and lean control groups. Lean diabetic mothers also had significantly heavier babies (mean +/- SEM) relative to the 50th percentile for gestational age and sex (119 +/- 9%) than did the lean control group (94 +/- 3%, P less than .05). Relative birth weights among control lean and obese mothers did not differ significantly (94 +/- 3% v 104 +/- 5%). Late pregnancy profiles of HbA1c and average plasma glucose did not correlate with relative weight of neonates whereas average total plasma amino acids and six individual amino acids did correlate with this parameter. These data suggest that maternal plasma amino acid concentrations may influence fetal weight generally and may have an important role in the development of fetal macrosomia in diabetic pregnancies.

Effects of Pregnancy and Sex Steroid Administration on Skeletal Muscle Metabolism in the Rat

To determine whether the insulin resistance, exaggerated fasting hypoglycemia, and hypoalaninemia of late human and rat gestation may reflect altered skeletal muscle metabolism, hindlimbs of nonpregnant (NPG) and 3-wk-pregnant (PG) rats were noncyclically perfused in situ. In 12- and 24-h-fasted NPG rats, 50–500 μU/ml of insulin significantly augmented glucose uptake 3-9-fold. In PG rats uptake was suppressed 40–50% at comparable hormone concentrations. Release of alanine and phenylalanine was suppressed 20–35% by 250 μU/ml or more of insulin in NPG rats. However, comparable insulin concentrations failed to suppress their release in PG rats. No differences between groups existed with respect to oxygen uptake, glycerol, lactate, or pyruvate release. Suppression of insulin sensitivity in 12-day-pregnant rats was not observed. Since plasma estradiol (E) and progesterone (P) are increased in pregnancy, E-benzoate (5 μg/day) and/or P (5 mg/day) were injected s.c. into female rats for 21 days. In 12-h-fasted animals, E treatment potentiated whereas P treatment mildly antagonized insulin-induced glucose uptake relative to control values. Separate effects of E and P were offset when administered in combination. Individual or combined regimens did not alter oxygen uptake, or release of alanine, phenylalanine, lactate, or pyruvate. In late gestation, insulin action on skeletal muscle is resisted with respect to glucose uptake, alanine release, and proteolysis. Fasting hypoalaninemia is not due to impaired alanine release from muscle, but may reflect increased fetal extraction. Fasting hypoglycemia may represent, in part, maternal gluconeogenic precursor deficiency due to fetal alanine removal. E and/or P treatment do not duplicate the observed metabolic Changes.

Metabolic Effects of Weight Loss in Obese Subjects: Changes in Plasma Substrate Levels, Insulin and Growth Hormone Responses

Oral glucose tolerance and intravenous tolbutamide, glucagon and insulin tolerance were assessed in six obese patients before and after an average weight loss of eighty-five pounds and a reduction from 83 to 27 per cent above ideal body weight. Results were compared to ten nonobese subjects of similar age. Before treatment fasting plasma glucose, free fatty acids and immunoreactive insulin exceeded normal levels. Total plasma alpha-amino acid nitrogen levels were unaffected by obesity. Post-challenge insulin responses during the first three tolerance tests were two to four-fold above control responses, and increments of immunoreactive growth hormone during insulin tolerance were subnormal in the obese. After weight reduction only minor differences in mean yjilues existed between obese and control groups. These findings indicate that disturbances in fasting plasma substrate levels as well as plasma insulin and growth hormone responses fii obese individuals are reversible after substantial weight reduction.

Fluctuations of calcium, phosphorus, sodium, potassium, and chlorine in single alpha and beta cells during glucose perifusion of rat islets.

To study the relationship between islet hormonal secretion and intracellular content of five elements, a rat islet perifusion technique was used in 24 paired experiments. Control and experimental chambers each containing 100 islets, received 2.8 and 16.7 mM D-glucose, respectively. Effluent was collected frequently for hormone measurements. At eight different time intervals form 0--30 min islets were fixed and prepared for scanning electron microscopy. Over 900 unobscured alpha and beta cells were selected by size and shape criteria. Energy dispersive x-ray analysis was applied to each single cell to determine relative content of calcium (Ca), potassium (K), sodium (Na), chlorine (Cl), and phosphorus (P). Experimental chambers exhibited typical acute (0--9 min) and second phase (10--30 min) insulin secretion in association with suppression of glucagon release after 10 min. At 2 min an abrupt upward K spike in both alpha and beta cells was followed at 3--4 min with a 1.5- to 2-fold rise of Ca and a reciprocal decrease in K, Na, Cl, and P. From 3 to 30 min biphasic insulin secretion. Reduced alpha cell calcium after 6 min preceded suppression of glucagon secretion. After 2 min K related inversely to Ca content in both alpha and beta cells. These results could not be reproduced when D-galactose was substituted for D-glucose. We conclude that sequential changes of Ca content that are reciprocally related to K are predictive of beta cell insulin release and suppression of alpha cell glucagon secretion.