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Biomedical subjects

J B Redmon

Publications and source records attributed to J B Redmon.

8 recordsLinked to original sources
PubMed1991

[Hyperinsulinemia as a consequence of systemic venous drainage in patients with pancreas transplantation].

To evaluate the metabolic consequences of pancreatic transplantation with systemic venous drainage on beta cell function, we examined insulin and C-peptide responses to arginine and secretin in type I diabetic recipients of pancreas transplantation (n = 16), and normal controls (n = 28). Basal insulin levels were 24 +/- 3 microU/l in pancreas recipients, and 7 +/- 1 microU/l in controls (p less than 0.001). Stimulated insulin levels following arginine (MANOVA, p less than 0.001), and secretin (MANOVA, p less than 0.001) were 1.5 to 3 fold elevated compared to controls. In contrast, integrated C-peptide responses following stimulation with arginine or secretin did not differ significantly between the two groups. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first pass hepatic insulin clearance although insulin resistance secondary to immunosuppressive therapy (including prednisone) may also play a contributing role. To avoid hyperinsulinemia and its possible long term adverse consequences, transplantation of pancreas allografts in sites with portal rather than systemic venous drainage may be preferable.

Adult↗
PubMed1991

Somatostatin and epinephrine decrease insulin messenger ribonucleic acid in HIT cells through a pertussis toxin-sensitive mechanism.

The sites of action for somatostatin and epinephrine to inhibit insulin secretion have been reported to be exclusively in the exocytotic pathway. We used HIT cells, a clonal line of beta-cells, to examine whether these hormones might have as yet undescribed, nonexocytotic effects on insulin messenger RNA levels. We observed that both somatostatin and epinephrine not only inhibit insulin secretion (53 +/- 2% and 50 +/- 2% of control, respectively) but also decrease insulin mRNA levels (54 +/- 5% and 66 +/- 5% of control, respectively) and insulin content in HIT cells (61 +/- 2% and 51 +/- 1% of control, respectively). The latter two effects are discernible by 24 h, maximal by 48 h, and are prevented by preincubation of HIT cells with pertussis toxin. These new observations suggest that somatostatin and epinephrine negatively modulate insulin availability through a guanine nucleotide binding protein-mediated step in insulin synthesis before the exocytotic pathway. This general mechanism may allow these two hormones to serve as more long-term regulators of insulin availability in distinction to their shorter term and more readily reversible inhibitory effects on the exocytotic pathway.

Animals↗
PubMed1990

Failure of insulin to antagonize cAMP-mediated glycogenolysis in rat ventricular cardiomyocytes.

Isolated rat ventricular cardiomyocytes were used to study the effects of insulin on glycogen metabolism in cells treated with various agents that activate adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. Incubation of myocytes with isoproterenol produced a rapid concentration-dependent increase in cAMP concentration, cAMP-dependent protein kinase activity, and phosphorylase activity and a simultaneous decrease in the glycogen synthase activity ratio. Various cAMP analogues also produced a concentration-dependent increase in phosphorylase activity and a decline in the glycogen synthase activity ratio. Incubation of cells with insulin produced no change in basal phosphorylase activity but produced a rapid 40% increase in the glycogen synthase activity ratio. Inclusion of insulin in cell incubations containing increasing concentrations of isoproterenol did not modify the increases in cAMP concentration, protein kinase activity, or phosphorylase activity. Insulin also did not antagonize the ability of any of the cAMP analogues tested to activate phosphorylase, irrespective of the suitability of the particular cAMP analogue as a substrate for cAMP phosphodiesterases. The failure of insulin to antagonize the glycogenolytic effects of isoproterenol or cAMP analogues was paralleled by its failure to activate low-Km phosphodiesterase activity, but the cAMP analogue, 8-parachlorophenylthio-cAMP produced a small reproducible activation of the low-Km enzyme. In contrast to hepatocytes and adipocytes, where some effects of insulin appear to be due to activation of the phosphodiesterase and hydrolysis of cAMP, the effects in cardiomyocytes appear to be independent of an insulin-sensitive phosphodiesterase or of the effects on other components of the cAMP cascade.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts.

Successful pancreas transplantation in type I diabetic patients restores normal fasting glucose levels and biphasic insulin responses to glucose. However, virtually no data from pancreas recipients are available relative to other islet hormonal responses or hormonal counterregulation of hypoglycemia. Consequently, glucose, glucagon, catecholamine, and pancreatic polypeptide responses to insulin-induced hypoglycemia and to stimulation with arginine and secretin were examined in 38 diabetic pancreas recipients, 54 type I diabetic nonrecipients, and 26 nondiabetic normal control subjects. Glucose recovery after insulin-induced hypoglycemia in pancreas recipients was significantly improved. Basal glucagon levels were significantly higher in recipients compared with nonrecipients and normal subjects. Glucagon responses to insulin-induced hypoglycemia were significantly greater in the pancreas recipients compared with nonrecipients and similar to that observed in control subjects. Glucagon responses to intravenous arginine were significantly greater in pancreas recipients than that observed in both the nonrecipients and normal subjects. No differences were observed in epinephrine responses during insulin-induced hypoglycemia. No differences in pancreatic polypeptide responses to hypoglycemia were observed when comparing the recipient and nonrecipient groups, both of which were less than that observed in the control subjects. Our data demonstrate significant improvement in glucose recovery after hypoglycemia which was associated with improved glucagon secretion in type I diabetic recipients of pancreas transplantation.

Arginine↗
PubMed1990

Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients.

To evaluate the metabolic consequences of pancreas transplantation with systemic venous drainage on beta-cell function, we examined insulin and C-peptide responses to glucose and arginine in type I (insulin-dependent) diabetic pancreas recipients (n = 30), nondiabetic kidney recipients (n = 8), and nondiabetic control subjects (n = 28). Basal insulin levels were 66 +/- 5 pM in control subjects, 204 +/- 18 pM in pancreas recipients (P less than 0.0001 vs. control), and 77 +/- 17 pM in kidney recipients. Acute insulin responses to glucose were 416 +/- 44 pM in control subjects, 763 +/- 91 pM in pancreas recipients (P less than 0.01 vs. control), and 589 +/- 113 pM in kidney recipients (NS vs. control). Basal and stimulated insulin levels in two pancreas recipients with portal venous drainage were normal. Integrated acute C-peptide responses were not statistically different (25.3 +/- 4.3 nM/min in pancreas recipients, 34.2 +/- 5.5 nM/min in kidney recipients, and 23.7 +/- 2.1 nM/min in control subjects). Similar insulin and C-peptide results were obtained with arginine stimulation, and both basal and glucose-stimulated insulin-C-peptide ratios in pancreas recipients were significantly greater than in control subjects. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first-pass hepatic insulin clearance, although insulin resistance secondary to immunosuppressive therapy (including prednisone) probably plays a contributing role. To avoid hyperinsulinemia and its possible long-term adverse consequences, transplantation of pancreas allografts into sites with portal rather than systemic venous drainage should be considered.

Adult↗
PubMed1987

Short-term feedback regulation of cAMP by accelerated degradation in rat tissues.

A recent study showed that cAMP analogs lowered cAMP levels in rat hepatocytes (Corbin, J.D., Beebe, S.J., and Blackmore, P.F. (1985) J. Biol. Chem. 260, 8731-8735). The present work demonstrates that cAMP analogs also lowered cAMP in a rapid, concentration-dependent manner in heart and fat cells. In order to determine if the cAMP-dependent protein kinase mediated this effect, techniques were developed to assay the protein kinase activity ratio in hepatocytes treated with cAMP analogs. The activation of protein kinase and phosphorylase in hepatocytes by 8-pCl phi S-cAMP (where 8-pCl phi S- indicates 8-parachlorothiophenyl-) was concentration-dependent and occurred in parallel to proportionate decreases in cAMP. More than 20% of the cAMP binding sites on the protein kinase were unoccupied at concentrations of 8-pCl phi S-cAMP that produced maximal cAMP lowering. Thus, the possibility that 8-pCl phi S-cAMP lowered cAMP by displacing it from protein kinase binding sites, making it available for hydrolysis, seemed unlikely. In adipocytes, the lowering of cAMP by 8-pCl phi S-cAMP occurred in parallel with increases in lipolysis and activation of low Km phosphodiesterase, suggesting that the phosphodiesterase was responsible for the cAMP lowering. Further evidence for this assertion was the finding that in hepatocytes preloaded with low concentrations of 8-pCl phi S-cAMP, glucagon lowered 8-pCl phi S-cAMP by about 50%, an amount similar to the cAMP lowering observed with 8-pCl phi S-cAMP treatment. The results were consistent with a cAMP-dependent protein kinase-catalyzed activation of a phosphodiesterase and suggested that 8-pCl phi S-cAMP-mediated hydrolysis of cAMP mimicked a physiologically significant response. The observation of this phenomenon in several tissues further suggested that it may be a general mechanism for dampening and terminating the hormonal signal through accelerated degradation of cAMP.

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

Discriminative insulin antagonism of stimulatory effects of various cAMP analogs on adipocyte lipolysis and hepatocyte glycogenolysis.

Although insulin effectively blocked hormone-stimulated glycerol output in adipocytes or phosphorylase activation in hepatocytes, the inhibitory effect of insulin on cAMP analog-stimulated cells depended on the cAMP analog used. Of the 20 analogs tested in adipocytes and 13 tested in hepatocytes, the effects of about half of them were effectively blocked by insulin, whereas the effects of many of them were not inhibited at all. In order to approach the explanation for this discriminative insulin action, the inhibitory effects of insulin on the responses to the analogs in the intact cells were correlated with the in vitro cAMP analog specificity for the hepatocyte cAMP-dependent protein kinase isozymes and the low Km, hormone-sensitive phosphodiesterases from both cell types. No correlation was found between insulin resistance of analog-stimulated hepatocyte phosphorylase and the concentration of analog required in vitro for half-maximal activation of either type I or type II cAMP-dependent protein kinase from hepatocytes. However, a good correlation was found between insulin resistance of cAMP analog-stimulated responses and the analog I50 values for the phosphodiesterase from both cell types. Using a new method capable of measuring hydrolysis at low analog concentrations, several of those analogs which had relatively low, but not high, phosphodiesterase I50 values were shown to be directly hydrolyzed by the low Km adipocyte phosphodiesterase. The insulin inhibition of cell responses when stimulated by hydrolyzable analogs, but not by poorly hydrolyzable analogs, is best explained by insulin stimulation of the low Km phosphodiesterases from both cell types.

Adipose Tissue↗