Loren G. Lipson

The effects of terbutaline on acid base, serum electrolytes, and glucose homeostasis during the management of pre term labor

Terbutaline (T) is a beta-adrenergic compound which is commonly employed as a tocolytic agent in preterm labor. We evaluated the metabolic and biophysical consequences of infusion of T into six pregnant women in preterm labor. Our results showed that the infusion of T led to the development of hyperglycemia, hyperinsulinemia, hyperlactacidemia, hypokalemia, a fall in serum colloid osmotic pressure and pH, a rise in maternal heart rate, and a fall in maternal blood pressure. These changes in electrolytes in the serum occurred in the absence of any significant alterations in their urinary excretion. These data suggest that the infusion of T causes hyperglycemia that results in a rise in serum insulin and lactate, which, in turn, leads to a fall in serum potassium, ionized calcium, and pH. Volume expansion as manifested by a fall in colloid osmotic pressure may contribute to the reduction in the levels of ionized and total calcium. Thus, careful monitoring of electrolytes and hydration status is warranted when beta-mimetic agents are used, specifically T, for tocolytic therapy.

Diabetes in the elderly: Diagnosis, pathogenesis, and therapy

The prevalence of diabetes mellitus increases with age; it occurs in approximately 10 percent of Americans 60 years of age and in 16 to 20 percent of those 80 years old. Type II diabetes mellitus is primarily found in the elderly, and it is estimated that an additional 20 percent of the elderly population has age-associated hyperglycemia, which may be part of a spectrum between normality and type II diabetes. The diabetic group is at risk for both microvascular and macrovascular complications of diabetes, whereas the group with the hyperglycemia of aging may be at risk for macrovascular-type complications. Thus, 40 percent of our senior population has abnormal carbohydrate tolerance and is at risk for diabetic-type chronic complications. The basis for both the diabetic state as well as for the hyperglycemia of aging is probably multifactorial--involving both altered insulin secretion and altered insulin action. Unique problems arise in treating older diabetic patients. Physiologic changes occurring during normal aging, age-associated pathologic processes, the increased prevalence of other chronic diseases, and polypharmacy must all be considered in selecting appropriate therapy for these patients. A rational approach for the maintenance of glucose homeostasis is presented for older patients with diabetes.

Treatment of hypertension in diabetic men: Problems with sexual dysfunction

Hypertension occurs 2 to 3 times more frequently in diabetic persons than in nondiabetic persons. Care must be taken in treating hypertension in diabetic patients because the choice of antihypertensive agent may worsen the diabetic state or its complications or cause additional health problems for the patient. Sexual dysfunction is a common problem in diabetic patients; however, diabetes need not be the cause. Diabetic men with hypertension have an increased sensitivity to the side effect of sexual dysfunction, which occurs from the use of centrally acting antihypertensive agents. By using prazosin, an alpha 1-adrenergic blocking agent, this cause of sexual dysfunction was eliminated. The reasons for the increased prevalence of hypertension in diabetic patients are discussed and a rational approach is given for the treatment of elevated blood pressure in these individuals.

The role of calmodulin in insulin secretion: The presence of a calmodulin-stimulatable phosphodiesterase in pancreatic islets of normal and pregnant rats

Abstract Calmodulin-stimulatable phospodiesterase activity has been demonstrated to be present in islets of Langerhans. Under the conditions used in the present study, this activity contributes approximately 25% of the total cyclic AMP phosphodiesterase activity measureable in islet sonicates of normal rats. The addition of calcium alone to the sonicates resulted in a partial stimulation equivalent to approximately half that achieved by the addition of both calcium and calmodulin. This partial stimulation is attributed to the presence of endogenous calmodulin since the calcium-stimulated activity could be decreased to a similar basal level by the addition of either EGTA or phenothiazine. The possibility that changes in the activity of this enzyme might account for the increased insulin secretion seen in late preganancy was examined. Cyclic AMP phosphodiesteras activity was measured in sonicates of islets prepared from age-matched normal female and 20-day pregnant rats. There was no significant difference in the amounts of either the total or calmodulin-stimulated activity between pregnant and control animals. The presence of calmodulin-stimulatable cyclic AMP phosphodiesterase in pancreatic islets indicates that its role should be considered in models of calcium mediated regulation of insulin secretion. Although it does not appear that an alteration in the activity of this enzyme is involved in the increased insulin secretion which occurs late in pregnancy, changes in this enzyme may well occur in other states of altered insulin secretion.

Estrone Treatment Dissociates Primary Versus Secondary Consequences of “Diabetes” (db) Gene Expression in Mice

Feeding 0.001% estrone in a diet to C57BL/KsJ mice homozygous for the recessive obesity gene “diabetes” (db) permitted dissociation of the primary consequences of obesity gene expression from the secondary consequences of diabetes effected through interaction between the db gene and other diabetogenic genes in the inbred background. Estrone-treated db/db mice were similar to untreated mutants in exhibiting hyperphagia and marked obesity. However, estrone-treated mutants did not develop the hyperinsulinemia, hyperglycemia, and islet atrophy characteristic of untreated db/db mice. Thus, expression of the primary defect could be studied in the absence of the myriad secondary sequelae elicited by chronic hyperinsulinemia and hyperglycemia. Reduced numbers of hepatocyte plasma membrane insulin receptors (50% of normal) persisted in the estrone-treated mice in the absence of hyperinsulinemia, indicating that this deficiency was a consequence of the primary genetic defect and not merely a downregulation phenomenon secondary to hyperinsulinemia. Comparison of insulin secretion from comparably sized + / + islets versus islets from estrone-treated db/db mice showed no intrinsic defects in β-cell sensitivity to glucose. In conclusion, db-induced obesity can be dissociated from hyperinsulinemia, hyperglycemia, β-cell dysfunction, and hyperphagia but is associated with a generalized membrane defect reflected in part by the persistent deficiency of plasma membrane insulin receptors.

The Dynamic Insulin Secretory Response of Isolated Pancreatic Islets of the Diabetic Mouse: Evidence for a Gene Dosage Effect on Insulin Secretion

Expression of the autosomal recessive (db) gene in homozygous (db/db) C57BL/KsJ mice results in a severe and eventually fatal diabetic syndrome. Many studies of the diabetic mouse have used lean litter-mates (+ /?) as controls despite evidence suggesting a gene dosage effect in heterozygous animals. In order to study the gene dosage effect of the diabetes (db) gene on insulin release in the heterozygote, perifusion experiments were performed on isolated islets of Langerhans of diabetic (db/db), heterozygous (+/db), and normal (+ / +) control mice. Islets of normal controls exhibited a fivefold greater increase in insulin release than did those of diabetics in response to 16.7 mM D-glucose. The insulin secretory response of islets of heterozygotes to glucose was intermediate, being twofold greater than that of diabetics but only about half of that of normal controls. Biphasic insulin release in response to glucose was observed only in islets of normal controls. Islets of all three genotypes exhibited biphasic insulin release in response to 10 mM D-glyceraldehyde; however, overall insulin release in both heterozygotes and diabetics remained diminished as compared with the response of normal controls. This is in contrast to the situation we have previously reported in islets of fasted or aging rats in which, though manifesting defects in glucose-stimulated insulin release, the islets are able to respond normally to 10 mM D-glyceraldehyde in respect to both the dynamic secretory pattern and quantity of insulin released. Our data suggest a gene dosage effect of the (db) gene on glucose-stimulated insulin release in heterozygous (+/db) C57BL/KSJ mice.

The high affinity calcium inhibition of parathyroid adenylate cyclase is not calmodulin dependent

SummaryTo investigate the possible role of calmodulin in the calcium sensitivity of parathyroid adenylate cyclase (AC), the effect of the calmodulin inhibitor trifluoperazine hydrochloride (TFP) on the calcium sensitivity of forskolin-stimulated AC activity was investigated in membranes prepared from normal porcine parathyroid glands. TFP inhibited AC in a concentration-dependent manner, the IC50 being approximately 100 μM. The inhibition of the enzyme occurred at roughly the same concentration of TFP in the presence and absence of calcium. Another calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), also inhibited AC in a calcium-independent manner with a IC50 of approximately 200 μM. The pattern of calcium inhibition of AC was compared in membranes prewashed with either EGTA or 2 μM ionic calcium plus 100 μM TFP in an attempt to remove endogenous calmodulin. Neither treatment significantly altered the apparent affinities of the two previously reported calcium inhibition sites, nor did they alter the relative contribution of the individual calcium inhibition sites to the overall calcium inhibition. Inclusion of 100 μM TFP in the incubation mixture resulted in no change in the apparent affinities of the calcium inhibition site although it did result in a significant decrease in the relative contribution of the high affinity site (P<0.05). Addition of exogenous calmodulin (5–50 μg/ml) had no significant effect on AC. We conclude from these studies that the inhibition of parathyroid AC by calcium is independent of calmodulin and that this enzyme has intrinsic high sensitivity to calcium.

CHAPTER 6 – Human Diseases as Models of Accelerated Aging

Aging appears to be an ongoing imperative of life. Using the principles of aging and certain pathophysiologic illnesses displaying accelerated aging, one can continue to look for clues. In diabetes mellitus, progeria, and Werners syndrome, fibroblast function is altered in a pattern similar to aging. All three patient groups suffer morbidity and mortality from cardiovascular illness similar to the general aging population. This chapter discusses features of these diseases that are common with aging. Although aging influences the onset of diabetes and diabetes causes premature aging, other conditions are marked by premature aging. Hutchinson-Gilford syndrome, Werners syndrome, acrogeria, ataxia telangiectasia, Cockaynes syndrome, Downs syndrome, familial cervical liposysplasia, Seip syndrome, and familial hypercholeterolemia are all inherited syndromes associated with premature aging. More research and observation are needed to understand the mechanism of aging completely. This chapter also discusses various models proposed for aging, including the error theory of aging, the free radical theory of aging, and the Hayflick model of aging.