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Biomedical subjects

S S Solomon

Publications and source records attributed to S S Solomon.

At least 55 records · Page 3Linked to original sources
PubMed1987

Medullary carcinoma of the thyroid, pancreatic nesidioblastosis and microadenosis, and pancreatic polypeptide hypersecretion: a new association and clinical and hormonal responses to long-acting somatostatin analog SMS 201-995.

We describe a 63-yr-old man with disseminated medullary carcinoma of the thyroid and pancreatic nesidioblastosis and microadenosis with pancreatic polypeptide (PP) hypersecretion. His major symptoms were watery diarrhea, flushing, and abdominal bloating; these and the elevated plasma PP levels did not change after resection of the distal two thirds of the pancreas, which contained a 2-cm mass of nesidioblastotic tissue. Postoperatively, a long-acting somatostatin analog, SMS 201-995 (100 micrograms/day), normalized PP secretion acutely and chronically (7 months) and ameliorated his symptoms. The analog had no side-effects and did not alter glucose tolerance, calcitonin hypersecretion, or growth of the medullary carcinoma, but it did inhibit GH secretion. After withdrawal from therapy for 1 month, PP hypersecretion and all symptoms except diarrhea recurred. The coexistence of medullary carcinoma of the thyroid and PP cell nesidioblastosis represents a new variant of the overlap syndromes between multiple endocrine neoplasia types I and II. Patients with medullary carcinoma and unexplained watery diarrhea should have fasting gastroenteropancreatic hormone assays done to screen for a potential gastrointestinal or pancreatic origin for the diarrhea.

Calcitonin↗
PubMed1987

Inhibitor of calmodulin and cAMP phosphodiesterase activity in BB rats.

Diabetes mellitus in humans is associated with increased plasma and tissue levels of cAMP and decreased cAMP phosphodiesterase (PDE) activity. Calmodulin (CM) is a low-molecular-weight protein essential for activation of cAMP PDE. The inhibitor (INH) is a low-molecular-weight substance that inhibits the activity of CM in multiple systems, including PDE. Spontaneously diabetic BB rats (SDR) and their nondiabetic littermates (NDR) were used in this study. Holtzman rats were rendered diabetic by streptozocin (STZ). STZ-induced diabetic rats (STZ-DR) and BB rats were studied with and without the benefit of insulin therapy. Calmodulin was assayed both by bioassay and by specific radioimmunoassay. The inhibitor was bioassayed by its ability to inhibit CM-activated PDE. Results showed that both spontaneous and STZ-induced diabetes are associated with a decrease in activity of the low-Michaelis constant (Km) cAMP PDE in the liver (39%, SDR; 70% STZ-DR). Calmodulin activity was also decreased in the livers of both animals (13%, SDR; 68%, STZ-DR). Similar data were obtained for NDRs. The inhibitor, on the other hand, was increased in the livers of untreated SDRs and STZ-DRs (155%, SDR; 125%, STZ-DR). No change was noted for NDRs. All these changes were restored toward normal after treatment with insulin. These data suggest that in diabetes the defect in the cAMP PDE-CM-INH system is demonstrated in both an environmental model, as illustrated by STZ-DRs, and a genetic model, as shown by SDRs and NDRs. The inhibitor activity, however, is not changed significantly in NDRs. We speculate that the inhibitor activity plays a role in dictating whether the genetic NDR will or will not become clinically diabetic.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Insulin-stimulated conversion of D-[5-3H] glucose to 3HOH in the perifused isolated rat adipocyte.

Characteristics of basal and insulin-stimulated glucose utilization by perifused adipocytes have been investigated by measuring the formation of 3HOH from D-(5-3H) glucose. At a glucose concentration of 0.55 mmol/L, basal glucose utilization ranged from 0.5 to 1.0 nmol/min/10(6) cells. Perifused adipocytes showed a maximal response to insulin of a threefold to fourfold increase in the conversion of (5-3H) glucose to 3HOH with a half-maximal response at an insulin concentration of 20 microU/mL. The response to insulin was blocked by phlorizin and cytochalasin B, competitive inhibitors of glucose transport, consistent with an effect of insulin on glucose transport. Insulin increased the Vmax for glucose metabolism but had no effect on the apparent affinity for glucose utilization. The characteristics of glucose utilization and the stimulation of glucose metabolism by insulin in the perifused adipocyte are therefore similar to characteristics previously observed with incubated adipocytes. Because insulin can readily be removed from the system, perifused adipocytes are especially suited for studying the termination of insulin action. The termination of insulin-stimulated glucose metabolism occurred at the same rate in the presence of tracer (1 nmol/L) (5-3H)-glucose alone as when 0.55 mmol/L glucose or 2 mmol/L pyruvate were added to the perifusion buffer. The halftime for this process in both cases was approximately 40 minutes. These data suggest that the presence of metabolizable substrate is not required for the termination of the insulin response, but the time course suggests that termination requires more than simply insulin-receptor dissociation.

Adipose Tissue↗
PubMed1986

Internalization and degradation of glucagon by human mononuclear cells.

The processing of glucagon by circulating human mononuclear cells was examined. Glucagon bound to the membrane with a turnover time of 4.4 minutes per site after 15 minutes of incubation and 8 minutes per site after 90 minutes. The amount of intact intracellular hormone increased by 3-fold by 90 minutes suggesting a slowing of intracellular processing with prolonged incubation. Excess unlabelled insulin also slowed the processing of glucagon at the degradative step with no effect on binding or internalization of glucagon. Subcellular fractionation of the cells showed that most hormone accumulated in the 500xg pellet and in the 100,000xg supernatant. N-ethylmaleimide blocked intracellular glucagon degradation suggesting a role for intracellular sulfhydryl-dependent enzymes. Kinetic analysis of the dissociation of glucagon revealed a second order process with K values of 2.2 X 10(-2) fm-1 min-1 and 1.4 X 10(-2) fm-1 min-1 for dissociation from membranes and from membranes + intracellular sites, respectively. T 1/2 values were 6 min. for membrane dissociation and 9 min for membranes + cells. These findings suggest that glucagon interaction with mononuclear cells has characteristics similar to other receptor bound ligands including internalization processing and metabolism.

Binding Sites↗
PubMed1986

Elevated growth hormone levels and insulin resistance in patients with cirrhosis of the liver.

Carbohydrate intolerance is frequently seen in patients with hepatic cirrhosis. To study the role of the counter regulatory hormones, glucagon, cortisol and growth hormone in this disease, these hormones were measured in 11 patients with hepatic cirrhosis and six controls during a 4-hour oral glucose tolerance test (OGTT) and in five normal and cirrhotic subjects during steady-state plasma insulin and glucose concentrations (SSPGI) achieved with the euglycemic clamp technique. Fasting plasma glucose was 103 +/- 4.3 mg/dl in cirrhotics and 88 +/- 3.3 mg/dl in controls (p less than 0.001). Immunoreactive insulin (IRI) was 24.3 microU/ml in cirrhotics and 12.7 +/- 2.2 microU/ml in controls (p less than 0.001); immunoreactive glucagon (IRG) was 263 +/- 30 pg/ml in cirrhotics and 122 +/- 17.5 pg/ml in controls (p less than 0.001); serum growth hormone (GH) was 4.4 +/- 0.9 ng/ml in cirrhotics and 0.5 +/- 0.1 ng/ml in controls (p less than 0.001). During OGTT, the 2-hour glucose concentration was 201 +/- 9.7 mg/dl in cirrhotic subjects and 147 +/- 10.0 mg/dl in controls (p less than 0.001). IRG levels were suppressed by 20% of basal values in patients with cirrhosis, while controls showed 10% suppression after an oral glucose load. At 60 minutes, the serum GH was 14.7 +/- 3.9 ng/ml in cirrhotics and 0.3 +/- 0.1 ng/ml in controls (p less than 0.001). The normal suppressive effect of hyperglycemia on GH secretion in controls was sharply contrasted by a paradoxical elevation of serum GH in the cirrhotic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway.

Insulin (INS) stimulates, and diabetes inhibits, low Km cAMP phosphodiesterase (PDE). This mechanism, at least in part, accounts for the lowering of cyclic AMP levels in plasma and tissue of diabetic patients and animals. Phorbol, a tumor-promoting agent known to act through protein kinase C and calcium translocation, exhibits a powerful effect stimulating PDE in rat adipose tissue. Nifedipine, a calcium channel blocker, inhibits insulin, but not phorbol stimulated PDE. These data demonstrate new effects of inositide diacylglycerol-Ca++ pathway components on PDE and suggest some common pathways of activation of low Km cAMP PDE through insulin and phorbol esters.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Spontaneous diabetic BB rat: studies of cyclic adenosine 3',5'-monophosphate phosphodiesterase and calmodulin.

Uncontrolled diabetes in man is associated with increased plasma and tissue levels of cAMP and decreased cAMP phosphodiesterase (PDE) activity. Spontaneously diabetic BB rats (SDR) were used in these experiments. Specific tissues (i.e. liver and epididymal fat) were studied without therapeutic insulin. Another group of normal animals were rendered diabetic by streptozotocin (STZ) and killed without benefit of insulin therapy. Calmodulin (CM), a small molecular weight protein essential for activation of specific cAMP PDE was assayed. STZ diabetes is associated with a decrease (58%) in CM biological activity and in immunoreactive CM in fat (69%) and liver (13%) tissues. Similarly, SDR rats and the nondiabetic genetic controls (NDR) demonstrate decreased CM bioactivity in fat (76% and 56%, respectively) and decreased CM immunoreactivity in liver (68% and 74%, respectively) compared to normal control rats. In addition, maximum velocity (Vmax) of the low Michaelis-Menten constant (Km) cAMP PDE is decreased in SDR animals, as compared to controls in both fat (42%) and liver (39%) tissues. Similar data are presented for NDR animals. STZ diabetes is also associated with a reduction in Vmax of the low Km cAMP PDE in both liver (70%) and fat (70%) tissues. These changes found in the NDR animals suggests that the diabetic defect may be under dual regulation: genetic and environmental.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Cyclic AMP phosphodiesterase in diabetes. Effect of glyburide.

Low-Michaelis constant cAMP phosphodiesterase (PDE; EC3.1.4.C) activity is inhibited in tissues of rats with type I ketosis-prone diabetes and is restored to normal by insulin treatment. To determine whether the oral hypoglycemic agent glyburide affected tissue cAMP PDE activity in non-insulin-dependent oral agent-treatable diabetes, cAMP PDE activity was measured in the liver and fat of animals rendered diabetic by low-dose streptozocin (STZ-DM) and treated for 3 wk with oral glyburide (360 micrograms/kg). The results were compared with PDE activity in the liver and fat of untreated STZ-DM and normal control rats. At the time of death, low-Km cAMP PDE activity [as maximum velocity (Vmax)] in STZ-DM rats was decreased to 66% of control values in the liver and to 65% in fat (P less than .001). PDE activity was restored toward normal by glyburide treatment: 91% in the liver (P less than .01) and 80% in fat (P less than .05). Calmodulin and calmodulin-like activity (PDE-activator activity) in the liver and fat was decreased in diabetes and restored toward normal after glyburide treatment (P less than .05). These data demonstrate that oral agents as well as insulin can restore the activity of cAMP PDE in the low-dose STZ-DM model, which is in some ways similar to type II diabetes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Hormonal control of lipolysis in perifused adipocytes from diabetic rats.

The responsiveness of adipocytes from diabetic rats to lipolytic and antilipolytic stimuli was examined in both an incubation system and a perifusion system. Lipolysis, measured by glycerol release, was initiated with varying concentrations of epinephrine or other agents. Incubated adipocytes prepared from streptozotocin-diabetic rats were more sensitive to low doses of epinephrine than controls, but at higher concentrations of hormone, glycerol release was greater from the control cells. However, maximal lipolytic responses to nonhormonal stimuli, forskolin and methylisobutylxanthine, were clearly greater in incubated adipocytes from diabetic animals. In vivo treatment of both control and diabetic animals with insulin decreased the responsiveness of perifused adipocytes to epinephrine in vitro, further demonstrating the importance of the in vivo hormone levels to lipolytic response of adipocytes. In vitro perifusion with insulin and epinephrine of cells from untreated diabetic animals demonstrated a reduced response to the acute administration of insulin. The interaction of insulin with diabetic adipocytes was further examined by incubating cells with [125I]iodoinsulin and examining the release of intact and degraded hormone during perifusion. The diabetic cells bound more labeled hormone than the control cells, but the release of intact hormone was similar in both types of cells. The diabetic cells, however, released more degraded hormone than did control cells. This suggests that the binding and degradation of insulin in diabetic cells is not impaired and that the decreased responsiveness of these cells to insulin is due to a postreceptor defect. Together these data show that decreased insulin in streptozotocin-diabetes results in increased sensitivity to lipolytic agents. In addition, the diabetes enhances the adipocyte's ability to remove insulin, i.e. increased binding and degradation. Thus, it is likely that the in vitro findings of up-regulation of receptors and increased degradation by the adipocytes are a true reflection of the in vivo insulin deficiency.

1-Methyl-3-isobutylxanthine↗
PubMed1985

The calcium dependence of insulin degradation by rat skeletal muscle.

The effect of calcium on insulin degradation by intact or homogenized skeletal muscle, by skeletal muscle cytosol, and by partially purified skeletal muscle insulin-degrading protease activity was examined. After a 15-min lag phase, intact soleus muscles degraded [125I]insulin to trichloroacetic acid-soluble products in a time-dependent fashion. Degradation was accelerated by the addition of calcium (greater than or equal to 1 mM), such that maximal stimulation (2-fold) was obtained with 10 or 25 mM calcium. Calcium stimulated insulin degradation by skeletal muscle homogenate and by cytosol in a nearly identical manner. Furthermore, after inactivation of the purified skeletal muscle, insulin-degrading protease by dialysis against EDTA, this enzyme was reactivated fully (greater than 80%) by a 100 microM concentration of free Ca2+. These observations identify a previously unrecognized but important influence of calcium on cellular insulin handling and provide further evidence for a major role of the calcium-activated enzyme, insulin protease, in cellular insulin degradation.

Animals↗
PubMed1984

Properties and characterization of low molecular weight inhibitor of calmodulin-dependent cAMP phosphodiesterase from rat liver.

We have identified two different species of inhibitors of calmodulin-dependent cAMP phosphodiesterase: 1) a low molecular weight (LMW) and 2) a high molecular weight (HMW) form. These inhibitors are extracted from rat liver. Both LMW and HMW inhibitors are heat-stable, acidic in nature and lose activity with prolonged storage and/or repeated freezing and thawing. The low molecular weight inhibitor has been purified to about 7,000-fold with 300% recovery. LMW inhibits calmodulin-dependent cAMP phosphodiesterase regardless of the source of calmodulin (e.g. fat, brain, heart, erythrocytes). LMW appears to be lipid in nature with a molecular weight of 1,500-5,000. The role of these inhibitors in diabetes and mechanism of action of insulin is presented.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Development of encephalopathic features similar to Reye syndrome in rabbits.

The progression of neurological abnormalities through four or five clinically distinguishable levels of deepening coma and the development of a fatty liver are the hallmarks of Reye syndrome. A number of animal models have been described that result in fatty liver formation with minimal, static, or catastrophic neurological changes. In this study, we attempted to produce neurological features in rabbits that reflected a rostral-caudal progression of abnormalities that could be categorized into clinically distinguishable levels reminiscent of Reye syndrome. This was accomplished by the intracisternal administration of 0.5-25 mg of 11,14-icosadienoic acid (20:2 omega 6) suspended in a mixture of rabbit serum and isotonic saline solution. A reproducible, dose-titratable spectrum of at least four levels of deepening coma could be produced at will. Increases in serum glutamate-oxaloacetate transaminase and creatine kinase and changes in serum glucose resulted 1-2 hr after the neurological abnormalities were evoked. Other unsaturated fatty acids produced similar responses. Those tested included 18:1 omega 9, 18:2 omega 6, 18:3 omega 3, 20:3 omega 6, 20:4 omega 6, and 22:4 omega 6 fatty acids. Saturated fatty acids, including 6:0, 8:0, 16:0, 18:0, and 20:0, failed to elicit these effects. The abnormalities were sustained for 30-120 min after a single dose. Full recovery was observed in some animals that had not reached the fourth level of our grading system for coma. Pretreatment of the rabbits with aspirin modulated the neurological abnormalities. Twenty micrograms of bee venom melittin, which activates endogenous phospholipase A2, administered intracisternally into rabbits also produced signs of level 3 (our grading system) coma for several hours. These findings suggest a possible role for polyunsaturated fatty acids in the development of Reye syndrome and offer a means of producing the neurological components of that syndrome in a laboratory animal.

Acetaminophen↗
PubMed1983

Glucagon degradation by human mononuclear cells.

Degradation of 125I-iodoglucagon by human mononuclear cell preparations including one containing 18%-27% monocytes, one consisting of 97% pure monocytes and one consisting of 98% lymphocytes was examined. Intact cells were incubated with 125I-iodoglucagon and degradation assessed by measuring an increase in trichloroacetic acid soluble products or in non-immunoprecipitable products. The preparation consisting of intact lymphocytes did not degrade glucagon. Glucagon was degraded by preparations containing monocytes and this degradation increased with time. No difference between monocyte degradation as measured by trichloroacetic acid or immunoprecipitation was found. Degradation by intact monocytes and by mononuclear homogenates increased sixfold from 4 degrees C to 37 degrees C. Subcellular fractionation demonstrated that the majority of the neutral glucagon degrading activity was in the 100,000 g supernatant (cytosol). Kinetic analyses gave Km values of 1.1 x 10(-5) mol/l, 7.5 x 10(-6) mol/l, and 1.2 x 10(-5) mol/l for glucagon degradation by intact mononuclear cells, homogenates, and cytosol, respectively. Inhibitor studies indicated a sulphydryl dependent enzyme was involved in glucagon degradation by both intact cells and cytosol. The monocyte appeared to be the cell responsible for degradation of glucagon by mononuclear cell preparations. The degradation of glucagon under physiological conditions by intact monocytes was mediated by a neutral proteolytic enzyme, primarily localized in the cytosol.

Cell Nucleus↗
PubMed1983

Hormonal responses to intravenous glucose and arginine in patients with pancreatitis.

19 subjects with an acute episode of pancreatitis, and 5 patients with chronic pancreatitis received intravenous glucose tolerance tests with measurement of glucose, insulin and glucagon. Patients recovering from acute pancreatitis demonstrated defects in their ability to dispose of a glucose load. 10 patients had overt glucose intolerance; of these, 4 were insulin-deficient, 3 had a loss of an acute insulin response to glucose, and 3 had marked hyperglucagonemia with normal to increased insulin levels. These abnormalities were seen in response both to intravenous glucose and intravenous arginine. Therefore, according to this study, at least three factors are clearly implicated in the production of glucose intolerance after an acute episode of pancreatitis: hypoinsulinemia, delayed insulin secretory response and hyperglucagonemia.

Acute Disease↗
PubMed1983

Studies of the biological effect and degradation of glucagon in the rat perifused isolated adipose cell.

The time relationships between glucagon-stimulated lipolysis and hormonal degradation are incompletely understood. These studies were designed to examine the rat adipocyte response to hormonal stimulation in the perifusion system. The perifused isolated adipocyte responded to glucagon concentrations as low as 10(-11) M, with maximum lipolysis at 10(-7) M glucagon. The lipolytic response corresponded in timing with exposure to glucagon. At lower concentrations, there was an appreciable lag between exposure to hormone and initiation of lipolytic response. Termination of response occurred with removal of hormone from the perifusion medium. The percentage of undegraded glucagon in the perifusate fractions (as determined by precipitability with trichloroacetic acid) remained above 80% until the point where free hormone was cleared from the system and lipolysis had ceased. The adipocytes continued to release both intact and degraded glucagon into the medium, the latter increasing with time. Release showed first order kinetics for both undegraded and degraded glucagon, with rate constants of 0.0656 +/- 0.0053 and 0.0716 +/- 0.0073 min-1, respectively. These perifusion studies provide a mechanism for assessing the time relationship between glucagon stimulation of lipolysis and its removal and degradation. Furthermore, the increased sensitivity of the fat cell to glucagon demonstrated herein with perifusion suggests that the importance of glucagon as a physiological regulator of lipolysis may have been underestimated by earlier researchers.

Adipose Tissue↗
PubMed1983

Glucose intolerance in spinal cord injury.

Glucose intolerance occurs frequently in patients with spinal cord injuries (SCI). In a retrospective chart analysis 23% of 57 consecutive discharges from a large SCI service had fasting hyperglycemia, and in a screening study, 30% of a group of stable SCI patients had 2-hour glucose values exceeding 200mg/dl after a glucose load and another 40% had values exceeding 140mg/dl. The glucose intolerance in many SCI patients is characterized by hyperinsulinemia after glucose is administered orally or intravenously. More than 40% of a group of glucose intolerant SCI patients had elevated insulin levels, suggesting tissue resistance to endogenous insulin.

Adult↗
PubMed1983

Studies of glucose intolerance in cirrhosis of the liver.

Patients with hepatic cirrhosis often have demonstrable glucose intolerance. We studied 21 patients with cirrhosis of the liver. Oral glucose tolerance tests (OGTT), intravenous arginine stimulation tests (IVAST), and intravenous insulin tolerance tests (IVITT) were performed, and timed blood samples were obtained for the assay of glucose immunoreactive insulin (IRI), C-peptide (C-P), and immunoreactive glucagon (IRG). The 125I-insulin binding to circulating monocytes was studied in some of the patients. All results were compared to those of similar studies performed on healthy controls. During OGTT significant glucose intolerance was demonstrable in the patients with cirrhosis (2 hr plasma glucose 198.8 +/- 14.3 mg/dl in cirrhosis and 116.4 +/- 4.2 in controls; p less than 0.001). Two-hour plasma IRI, C-P, and IRG were significantly higher in the cirrhotic patients than in controls (p less than 0.001; less than 0.001; less than 0.025). In response to IVAST, the patients with cirrhosis showed a greater first-phase insulin secretion and controls had a slightly better second-phase insulin release. Plasma IRG rose from a basal value of 446 pg/ml to 1100 in the patients with cirrhosis and from 171 pg/ml to 494 in controls. After intravenous insulin administration, there was only a 40% decline in plasma glucose concentration from basal values in the patients with cirrhosis whereas the controls showed a 60% decline, demonstrating that the patients with cirrhosis had significant insulin resistance. Moreover, the half-life of insulin was prolonged in the patients with cirrhosis (t 1/2 = 15.5 min in cirrhosis and 10.3 in controls; p less than 0.001); and the ratio of C-P to insulin during OGTT was also reduced, indicating that the patients with cirrhosis have reduced hepatic clearance of insulin. The specific binding of 125I-insulin to circulating monocytes was 2.7% in cirrhosis, 2% in obese controls, and 4% in lean controls. There was a significant negative correlation between the fasting plasma insulin values and the specific binding of insulin. In conclusion, patients with hepatic cirrhosis have significant glucose intolerance characterized by hyperinsulinemia, hyperglucagonemia, insulin resistance, and down-regulation of insulin receptors. Although hyperinsulinemia is probably caused by reduced hepatic clearance of insulin, hyperglucagonemia is primarily due to increased pancreatic secretion.

Adult↗