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Biomedical subjects

H E Lebovitz

Publications and source records attributed to H E Lebovitz.

At least 73 records · Page 4Linked to original sources
PubMed1984

Etiology and pathogenesis of diabetes mellitus.

The concept that diabetes mellitus is not a single disease. but rather a clinical syndrome characterized by inappropriately elevated fasting or post-prandial blood glucoses and the development of long-term microvascular, macrovascular, and neuropathic changes is of very recent origin and stems from numerous investigations into the epidemiology, genetics, etiology, and pathogenesis of clinical diabetic states. This article reviews some of these data and indicates that the various forms of diabetes mellitus have markedly different etiologies and pathogenetic mechanisms and that these must be recognized in order to understand and care for patients.

Diabetes Mellitus↗
PubMed1983

Mechanism of action of the second-generation sulfonylurea glipizide.

Glipizide, a second-generation sulfonylurea, has potent antidiabetic actions in patients with noninsulin-dependent diabetes mellitus. The effects of glipizide treatment on insulin sensitivity, glucose-mediated insulin secretion, and glucose utilization were measured in newly diagnosed or untreated patients with noninsulin-dependent diabetes mellitus. The data indicate that the antidiabetic action of glipizide is primarily mediated by a potentiation of insulin action and, to a less significant and more variable degree, by an increase in nutrient-mediated insulin secretion. Studies in normal mice and dogs show that glipizide potentiation of insulin action is associated with an increase in plasma membrane insulin receptor number, involves some postreceptor events, and is significantly greater on peripheral uptake of glucose than suppression of hepatic glucose production. The initial event in glipizide action on beta cells appears to be binding to a specific plasma membrane receptor.

Animals↗
PubMed1983

Long-term safety and efficacy of glipizide.

We studied the effect of long-term glipizide therapy in a small group of closely monitored patients. Fasting plasma glucose, glucose tolerance, glucose-stimulated insulin secretion, and insulin sensitivity were measured on multiple occasions throughout the investigation. Our observations show that glipizide therapy is effective in certain patients with noninsulin-dependent diabetes mellitus over a prolonged time period. The major effect of the drug appears to be mediated by its alteration of insulin sensitivity, but glipizide also causes a sustained increase in glucose-stimulated insulin secretion in most patients.

Blood Glucose↗
PubMed1983

Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus.

Clinical usage of the sulfonylurea drugs is based on experience in well-controlled long-term studies in large numbers of patients. The results of such studies indicate that approximately 60 to 70 percent of the patients with noninsulin-dependent diabetes mellitus of recent onset will respond initially to sulfonylurea therapy with satisfactory control of glycemia, about 15 to 20 percent will not respond initially (primary failures), and another 15 to 20 percent who respond initially will lose their responsiveness during the first few years of treatment (secondary failures). In extensive studies in small numbers of patients, we found that successful management of noninsulin-dependent diabetes mellitus with glipizide was correlated with increased insulin responsiveness and that patients who did not have an increase in their insulin-mediated glucose disposal during glipizide therapy were primary failures. Successful treatment of noninsulin-dependent diabetes mellitus with sulfonylureas is associated with onset of of the disease at 40 years of age or later, normal or increased body weight, duration of disease less than five years, and a history of either no previous insulin therapy or therapy with less than 20 units of insulin per day. The use of specific sulfonylurea drugs is predicated on differences in their metabolism, side effects, and perhaps potency.

Administration, Oral↗
PubMed1983

Hormonal and metabolic regulation of human chondrosarcoma in vitro.

Prostaglandin A1 has a profound inhibitory effect on uridine incorporation into RNA of normal cartilage whereas N6-monobutyryladenosine 3',5'-cyclic monophosphate is either stimulatory or without an effect. Sera from intact and growth hormone-treated hypophysectomized rats stimulate RNA synthesis but serum from untreated hypophysectomized rats does not. The present study investigated the in vitro regulation of [3H]uridine incorporation into RNA of six human chondrosarcomas to determine if malignant human chondrocytes are under similar metabolic and hormonal regulation. Prostaglandin A1 (25 micrograms/ml) markedly inhibited uridine incorporation in all six tumors (56 to 80%). N6-Monobutyryladenosine 3',5'-cyclic monophosphate (1 mM) inhibited uridine incorporation in five tumors (20 to 50%). Uridine incorporation was stimulated by growth hormone-dependent serum factors in one tumor and by growth hormone-independent serum factors in two tumors. Two tumors were more responsive to serum from growth hormone-treated hypophysectomized rats than to serum from intact rats, and one tumor was unresponsive to serum stimulation. The data indicate that: (a) prostaglandin A1 is a very potent inhibitor of RNA synthesis in human chondrosarcomas; (b) N6-monobutyryladenosine 3',5'-cyclic monophosphate affects human chondrosarcomas differently than it does normal cartilage; and (c) responses of human chondrosarcomas to serum growth factors vary among individual tumors.

Bucladesine↗
PubMed1982

In vitro stimulation of alkaline phosphatase activity in immature embryonic chick pelvic cartilage by adenosine 3'5'-monophosphate.

Cyclic AMP content in embryonic chick pelvic cartilage increases significantly as the embryo ages from 8 to 10 d. This in ovo elevation in cyclic AMP content precedes maximal cartilage alkaline phosphatase activity by some 24 h. We studied whether this temporal relationship may be causally related, using an in vitro organ culture. Incubation of pelvic cartilage from 9- and 10-d embryos in medium containing monobutyryl cyclic AMP (BtcAMP) resulted in significant increases in alkaline phosphatase activity (220 and 66 percent, respectively) as compared to that of cartilages incubated in medium alone. This stimulation was both concentration- and time-dependent with maximal response at 0.5 mM BtcAMP and 4-h incubation, respectively. Similar incubations of cartilage in medium containing 1-methyl-3-isobutyl xanthine (MIX), 0.25 mM, also resulted in increased alkaline phosphatase activity (114 percent). However, pelvic cartilage from 11-d embryos incubated in medium containing BtcAMP or MIX showed no increase in alkaline phosphatase activity. We postulated that developmental age was the factor responsible for this difference in response and that immature cartilage (that with little or no alkaline phosphatase activity) would respond to BtcAMP whereas mature cartilage (that with significant alkaline phosphatase activity) would not. This was tested by incubating end sections of 11-d cartilage, which have little alkaline phosphatase activity, and center sections, which have significantly alkaline phosphatase activity, with both BtcAMP and MIX. Alkaline phosphatase activity in end sections (immature cartilage) was stimulated by BtcAMP and MIX, whereas it was not stimulated in the center sections. Actinomycin D and cycloheximide inhibited BtcAMP and MIX stimulation of alkaline phosphatase activity. Thus, the in vitro data suggest that cyclic AMP is a mediator for the stimulation of alkaline phosphatase activity in embryonic cartilage.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Triiodothyronine stimulates maturation of porcine growth-plate cartilage in vitro.

We studied the effect of triiodothyronine (T3) on mammalian growth-plate cartilage in vitro. Growth-plate cartilages from fetal pigs scapulae were incubated for 3 to 7 d in serum-free medium alone or medium containing T3. Alkaline phosphatase activity, a marker of hypertrophied chondrocytes, was increased in T3 (10 nM)-treated growth-plate cartilage 152 +/- 36% above that of cartilage incubated in medium alone after 3 d of incubation, and 324 +/- 47% after 7 d of incubation. There was a dose-response increase in alkaline phosphatase activity to T3 over the range of 0.01-10 nM. The rise in alkaline phosphatase activity was specific for T3 since growth-plate cartilage alkaline phosphatase activity was not increased by cortisol, insulin, parathyroid hormone, or 5% fetal calf serum. Histological studies of growth-plate cartilage showed that T3 in a concentration-dependent manner increased the width of the zone of maturation (hypertrophied chondrocytes). Histochemical staining for alkaline phosphatase activity demonstrated that T3 caused the recruitment of new cells into the zone of maturation. T3 also stimulated incorporation of L-[3H]leucine into protein and 35SO4 into proteoglycan in growth-plate cartilage. In contrast, T3 did not increase alkaline phosphatase activity or radiolabeled precursor incorporation into nongrowth-plate scapular cartilage. These studies demonstrate that T3 directly stimulates maturation and, to a lesser degree, growth-related processes in fetal mammalian growth-plate cartilage.

Alkaline Phosphatase↗
PubMed1982

Triiodothyronine stimulation of in vitro growth and maturation of embryonic chick cartilage.

We studied the direct effect of T3 on cartilage growth and maturation in vitro. Pelvic cartilages from 9-day-old chick embryos were incubated in a serum-free organ culture system which supported cartilage growth over a 5-day interval. The addition of T3 (15 nM) to the medium increased cartilage wet weight (approximately 100%), dry weight (77%), length (35%), and total soluble protein (67%) over 3 days compared to cartilage incubated in medium alone. The DNA content was only slightly increased (2%) by T3 over the interval. T3 stimulated the same parameters of growth similarly after 5 days of incubation. In addition, T3 increased the incorporation of [14C]leucine into protein (82%) and 35SO4 into proteoglycan (53%). A dose-dependent increase in cartilage wet weight was seen with T3 (0.0015-15 nM) over 3 days of incubation. Cartilage incubated with T3 demonstrated microscopic changes in maturation, with development of large numbers of hypertrophied chondrocytes, and biochemical evidence of maturation, with increased alkaline phosphatase activity (130%). The dose-response range for T3 stimulation of alkaline phosphatase activity (0.015-0.15 nM) was considerably more restricted than that for stimulation of growth (0.0015-15 nM). These studies demonstrate that T3 in physiological concentrations directly affects cartilage growth and maturation, primarily through stimulating chondrocyte hypertrophy.

Animals↗
PubMed1981

Chondrosarcoma growth: influence of diabetes, caloric restriction, and insulin treatment.

Diabetes and malnutrition result in decreased somatomedin production and cartilage growth in rats. The growth and metabolism of the Swarm rat chondrosarcoma are dramatically affected by somatomedins. Data presented here show that streptozotocin diabetes and diet restriction inhibit in vivo chondrosarcoma growth. Tumors grown in diabetic rats were significantly smaller than tumors grown in diet-restricted rats showing the same changes in body weight. Insulin treatment increased the rate of tumor growth in diabetic rats. Tumors grown in rigidly controlled diabetic rats were as large as tumors grown in nondiabetic controls. Diet restriction and diabetes reduced the capacity of the serum of the rat to stimulate alpha-amino[14C]isobutyrate uptake and [3H]uridine incorporation into RNA in chondrosarcoma pieces grown in nondiabetic rats. This somatomedin activity of the serum was restored by treating diabetic rats with insulin. There was a significant correlation between the in vitro stimulatory effect of a particular serum pool on chondrosarcoma metabolism and in vivo chondrosarcoma growth in the animals from whom the serum was obtained. These studies demonstrate that the in vivo growth of malignant chondrocytes is similar to that of normal chondrocytes with respect to the role of nutrition and insulin.

Animals↗
PubMed1981

Hormonal activation of ornithine decarboxylase in embryonic chick pelvic cartilage.

We assessed whether hormones and metabolic factors known to stimulate anabolic processes in the embryonic chick pelvic cartilage would stimulate ornithine decarboxylase (ODC) activity. In vitro organ culture of these pelvic cartilages in time-course experiments with N(6)-monobutyryl cyclic AMP (BtcAMP), insulin, and 5% rat serum demonstrated maximal stimulation of ODC activity between 4 and 6 h with each factor. However, at 2 h insulin and serum significantly stimulated ODC activity (P less than 0.05) and BtcAMP did not. ODC was stimulated above control (100%) with the following factors: parathyroid hormone (PTH) (555 +/- 15%), BtcAMP (324 +/- 34%), 1-methyl-3-isobutylxanthine (MIX) (223 +/- 6%), prostaglandin E1 (PGE1) (227 +/- 15%), 3,3',5-triiodothyronine (T3) (184 +/- 22%), insulin (182 +/- 14%), multiplication-stimulating activity (MSA) (178 +/- 6%), 5% rat serum (253 +/- 57%). THe increase in ODC activity seen with BtcAMP and insulin was not due to a change in Km or a decreased rate of degradation of the enzyme. Actinomycin D (1 microgram/ml) inhibited stimulation of ODC activity by T3 and the cyclic AMP-mediated factors (PTH, BtcAMP, MIX, PGE1), but had only minimal effects on ODC stimulation by insulin, MSA, or serum. Amanitin inhibited both BtcAMP and T3 stimulation of ODC, but had no effect on insulin stimulation of ODC. Thus, hormones and metabolic factors known to stimulate anabolic processes in chick embryonic pelvic cartilage also increase ODC activity through at least two mechanisms: transcriptional (cyclic AMP-mediated and T3) and posttranscriptional (insulin, serum, MSA).

1-Methyl-3-isobutylxanthine↗
PubMed1981

Selective potentiation of insulin-mediated glucose disposal in normal dogs by the sulfonylurea glipizide.

Investigative data have suggested that the extrapancreatic actions of the sulfonylureas may be paramount in their chronic antidiabetic action. The present study examines the effects of chronic sulfonylurea treatment on in vivo insulin action. Peripheral insulin levels, hepatic glucose production (Ra), and overall glucose disposal (Rd) were studied in six awake, normal dogs given both 0.5 and 1.0 mU/kg per min pork insulin for 2.5 h. This produces stable hyperinsulinemia from 15 to 150 min. Fasting euglycemia was held constant by the glucose clamp technique and averaged 99% basal glucose in all studies. Ra and Rd were determined from infusion of [3-(3)H]glucose, begun 90 min prior to insulin infusion. 10 mg of the sulfonylurea glipizide, was given daily to the test animals for the 10 to 20 d following appropriate control studies, then was withheld for 24 h, and the dogs were restudied. Glipizide treatment did not significantly alter basal glucose turnover, Ra, mean glucose values, or mean insulin levels as determined by radioimmunoassay. Increase in Rd above basal glucose turnover in response to insulin (delta Rd) was significantly (P less than 0.05) increased by glipizide treatment at both insulin dosage levels (paired analysis). At 1.0 mU/kg per min insulin, delta Rd rose from 2.6 mg/kg per min before glipizide to 6.5 mg/kg per min after glipizide treatment. At 0.5 mU/kg per min insulin, delta Rd went from 1.1 mg/kg per min before glipizide to 2.2 mg/kg per min after glipizide treatment. Glipizide treatment doubled the effects of insulin on Rd, while showing no significant effect upon insulin suppression of Ra. We conclude that a significant extrapancreatic chronic action of glipizide lies in its ability to selectively potentiate Rd.

Animals↗
PubMed1981

Adenosine 3',5'-monophosphate: a modulator of embryonic chick cartilage growth.

We tested the hypothesis that cyclic AMP plays a significant role in modulating the growth of embryonic chick cartilage by determining whether cyclic AMP levels change in growing embryonic cartilage and whether cyclic AMP could stimulate embryonic cartilage growth in a long term in vitro organ culture. Cyclic AMP levels were low (0.1 pmol/mg wet wt) in 8-d chick embryo pelvic cartilage, and increased progressively through the 11th d of embryonic development at which time they reached a maximum (1.8 pmol/mg wet weight) and thereafter remained constant. We developed an in vitro organ culture system to determine whether cyclic AMP, a factor known to stimulate radiolabeled precursor incorporation into macromolecules in short-term studies does, in fact, stimulate growth of cartilage. Individual pelvic cartilages were isolated from 9-d chick embryos, placed in serum-free medium (BGJb-FJ modification) and incubated for 3 to 5 d during which time they increased in size (39 and 60% in length, respectively), wet weight (90 and 141%, respectively), and content of total soluble protein (30 and 48%, respectively). N6-monobutyryl cyclic AMP (BtcAMP) added to the medium caused a dose-dependent (0.05 to 1.0 mM) stimulation of growth. After 3 d of incubation, 1.0 mM BtcAMP increased wet weight (125%), [14C]leucine incorporation into protein (75%), and [3H]thymidine incorporation into DNA (48%) compared with control cartilages incubated in medium alone. 1-methyl-3-isobutyl xanthine, a phosphodiesterase inhibitor, also increased cartilage growth above control while sodium butyrate, AMP, and ATP had no effect. Histological examination of cartilage grown in medium was similar to that of cartilage developing in ovo, whereas, cartilage grown in medium containing BtcAMP showed marked hypercellularity with many immature chondrocytes. Our observations are compatible with the hypothesis that cyclic AMP can significantly modulate the growth of embryonic cartilage.

1-Methyl-3-isobutylxanthine↗
PubMed1981

Hormone responsiveness of a transplantable rat chondrosarcoma: III. ultrastructural evidence of in vivo hormone dependence.

The effects of growth hormone (GH) and/or cortisone and thyroxine (T4) treatment on the ultrastructure of the transplantable Swarm rat chondrosarcoma grown in hypophysectomized rats were studied. Marked atrophy of the tumor occurred when it was grown in hypophysectomized rats. Maximal restoration of tumor growth in hypophysectomized rats was achieved when cortisone, T4, and GH were administered in combination. An intermediate degree of tumor growth restoration was observed when tumor-bearing hypophysectomized rats were given cortisone and T4 or GH alone. Cortisone and T4 treatment was associated with increased rough endoplasmic reticulum and nucleolar enlargement, while GH treatment was associated with marked dilatation of the endoplasmic reticulum. When GH, cortisone, and T4 were given in combination, a marked increase in exocytotic/pinocytotic vesicles and apparent deposition of cartilage matrix were noted. The data indicate that GH has dramatic influences on the tumors and, when GH, cortisone, and T4 are administered together, these hormones have a synergistic effect on the growth of the Swarm rat chondrosarcoma.

Animals↗
PubMed1980

Disordered control of thirst in hypothalamic-pituitary sarcoidosis.

We evaluated water metabolism in 11 patients with hypothalamic-pituitary sarcoidosis. Seven patients had abnormal water metabolism: one had partial antidiuretic hormone (ADH) deficiency, one had severe ADH deficiency, one had severe ADH deficiency and deficient thirst, one had only deficient thirst, and three had excessive thirst. In four of the five with thirst disturbances, there was loss of congruence of osmotic thresholds for thirst and ADH release. Five of our patients presented with polyuria and polydipsia, but only two had true diabetes insipidus, whereas three had organic primary polydipsia with adequate endogenous ADH. That disordered thirst resulting in polydipsia was more common than true diabetes insipidus is at odds with previously held views on the prevalence of ADH deficiency in this condition.

Adolescent↗
PubMed1980

Therapy of insulin-independent diabetes mellitus: general considerations.

Rational approaches to the therapy of patients with insulin-independent diabetes should be based on correcting the underlying defects. The major metabolic abnormalities present in patients with insulin-independent diabetes are: (1) impaired insulin action, (2) defective glucose-mediated insulin secretion, and (3) hyperglucagonemia. All of these defects could be due to a generalized plasma membrane abnormality that affects insulin and glucose receptors or to a generalized disturbance in postreceptor insulin action. Insulin action may be increased by sulfonylureas, possibly by alterations in intracellular cyclic AMP content, or by weight-reducing diets. Insulin secretion may be increased by gastrointestinal hormones, sulfonylureas, serotonin antagonists, or weight-reducing diets. Individual patients with insulin-independent diabetes have varying degrees of insulin resistance or impaired glucose-mediated insulin secretion. The use of therapeutic agents to correct the predominant defect should provide the most effective means of controlling the hyperglycemia and glucose intolerance of the individual patient.

Blood Glucose↗
PubMed1980

Sulfonylurea treatment of insulin-independent diabetes mellitus.

The ultimate clinical utility of the sulfonylurea drugs in the treatment of insulin-independent diabetes mellitus will be determined only when the mechanisms of action of these agents are understood. We are presently evaluating the long-term effects of the sulfonylurea glipizide on a group of patients with insulin-independent diabetes. Our studies thus far indicate that a major effect of this drug is a potentiation of insulin action, which leads to an improvement in glucose utilization. However, glipizide, in distinction from those sulfonylureas that have been examined previously, also causes a long-term increase in glucose-stimulated insulin secretion. These effects are unrelated to diet therapy and can still be demonstrated in patients treated for more than 2 yr. Further investigation will determine whether sulfonylurea therapy can offer unique benefits to certain patients with insulin-independent diabetes.

Blood Glucose↗
PubMed1980

Regulation of chondrosarcoma metabolism by cyclic adenosine 3'5'-monophosphate.

The in vitro effects of cyclic AMP on amino acid transport and synthesis of macromolecules in the Swarm rat chondrosarcoma were investigated using the cyclic AMP analogue, N6-monobutyryl cyclic AMP (MBcAMP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX). Amino acid transport was assessed by measuring alpha-amino-[1-14C]isobutyrate (AIB) uptake. The synthesis of macromolecules was estimated by measuring radiolabeled precursor incorporation into total proteins, proteoglycan, and RNA. MBcAMP stimulated [14C]AIB uptake, [3H]uridine transport, and UTP formation. MBcAMP inhibited 35SO4 and [3H]leucine incorporation into proteoglycan and stimulated [3H]uridine incorporation into RNA. MIX elevated endogenous cyclic AMP levels in the Swarm rat chondrosarcoma and mimicked the effects of MBcAMP on AIB transport and radiolabeled precursor incorporation into macromolecules. For comparative purposes, the effects of MBcAMP on AIB uptake and macromolecule synthesis in rat costal cartilage segments were investigated. MBcAMP and MIX stimulated AIB uptake by costal cartilage segments, inhibited [3H]leucine incorporation into total protein and 35SO4 incorporation into proteoglycan, and had no effect on [3H]uridine incorporation into RNA.

Amino Acids↗