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Biomedical subjects

K Polonsky

Publications and source records attributed to K Polonsky.

27 records · Page 2Linked to original sources
PubMed1983

Differential immunoreactivity of plasma glucagon components in man: studies with different glucagon antibodies.

To evaluate the relationship between glucagon antibody antigenic determinants and selective reactivity with plasma void volume (Vo) and lower molecular weight immunoreactive glucagon (IRG) components, we studied plasma IRG levels and molecular profiles in normal subjects and patients with disturbances in plasma glucagon levels using three glucagon antibodies, 30K and P7 raised against the whole peptide and antibody X4 raised against the C-terminal tryptic fragment of glucagon. In normal subjects and pancreatectomized patients, plasma IRG levels were 2- to 3-fold higher with the C-terminus-directed antibody X4 than with either 30K or P7, but in glucagonoma and uremic patients, this discrepancy was smaller. Gel filtration analysis revealed that these antibodies reacted identically with 3500 mol wt IRG and 9000 mol wt IRG in normal, glucagonoma, pancreatectomized, and uremic plasma. Relative immunoreactivity of Vo IRG was approximately 5:2:1 with antibodies X4, 30K, and P7, respectively. In two subjects with unexplained hyperglucagonemia, recovery of IRG was entirely in the Vo, with antiserum X4 reacting one third as well as 30K and P7 not reacting at all. Furthermore, this material did not dilute out in parallel to glucagon standard. These data indicate differential immunoreactivity of the high molecular weight circulating IRG component, with a series of three glucagon antibodies reacting similarly with all other plasma IRG fractions, and suggest that Vo IRG material in plasma is predominantly the result of an immunologically cross-reacting peptide sequence in a plasma protein. The selective immunoreactivity of this component with different antibodies has important implications for the glucagon RIA and may have some bearing on other immunoassays as well.

Antibodies↗
PubMed1983

Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism.

The metabolism of exogenously infused porcine insulin and glucagon was assessed concurrently in normal fasted dogs under anaesthesia. Hepatic and renal extraction of glucagon were 25.6 +/- 2.3 and 43.7 +/- 3.9%, respectively, and its metabolic clearance 16.5 +/- 0.8 ml/kg/min. Hepatic and renal extraction accounted for 28.5 +/- 4.2 and 28.7 +/- 3.7% of total glucagon clearance, respectively. Insulin MCR was 18.3 +/- 1.5 ml/kg/min and its hepatic and renal extraction were 49.6 +/- 3.4 and 41.7 +/- 4.4% accounting for 51.9 +/- 4.4 and 27.3 +/- 3.9% of total insulin clearance, respectively. Neither total glucagon metabolic clearance nor its hepatic or renal components saturated even in the face of circulating glucagon levels extending into the pharmacologic range up to 14 ng/ml. In contrast however, with increasing arterial concentrations of insulin, saturability of metabolism was apparent as evidenced by significant reductions in MCR as well as hepatic and renal extraction. This demonstration of saturability of hepatic insulin metabolism occurred at levels encountered in the portal vein after meals and is compatible with the concept that the hepatic capacity for extraction of this hormone may be an important site of control of the proportion of secreted insulin reaching the periphery. The metabolic handling of each hormone was shown to be independent of the other. Despite similarities in the interaction of insulin and glucagon with the target cell, there are important differences in the mechanisms of metabolism of these peptides as the major degradative sites.

Animals↗
PubMed1982

Relation of counterregulatory responses to hypoglycemia in type I diabetics.

We compared counterregulatory metabolic and hormonal responses in 8 normal controls with responses in 16 Type I (insulin-dependent) diabetics, 7 of whom had had repeated attacks of severe hypoglycemia, in an effort to determine whether these responses are related to the occurrence of hypoglycemia in the latter group. In response to insulin-induced hypoglycemia, peak values for glucose production (5.7 +/- 0.5 vs. 2.5 +/- 0.3 mg per kilogram of body weight per minute) (P less than 0.0001), glucagon (195 +/- 26 vs. 93 +/- 18 pg per milliliter) (P less than 0.0001), and growth hormone (63 +/- 8 vs. 37 +/- 5 ng per milliliter) (P less than 0.006) were significantly higher in the controls than in the diabetics. However, peak values for glucose production, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were similar in the diabetics with and without clinical hypoglycemia. Thus, with the present dose and method of insulin administration we were unable to predict the presence of severe hypoglycemic reactions in a group of Type I diabetics. Although deficient counterregulatory hormone responses are important in the pathogenesis of hypoglycemic reactions, we conclude that other factors in the daily lives of such patients also play a major part in determining whether reactions will occur.

Adolescent↗
PubMed1982

Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin.

Oral glucose (25 g) fed to seven healthy, conscious dogs resulted in an increase in peripheral plasma glucose from 109 +/- 3 to 178 +/- 10 mg/dl. Concurrently serum insulin increased in the portal vein to levels approximately threefold greater than those in the periphery. Hepatic insulin delivery rose from 10.8 +/- 0.7 to 59.0 +/- 19.9 m U/min at 60 min. coincident with an increased hepatic insulin extraction from 3.3 to 41.4 mU/min (corresponding to an increase in hepatic extraction from 31 +/- 4 to 59 +/- 7%), both returning to basal at 3 h. In each animal there was a positive correlation between hepatic insulin delivery and extraction (r = 0.80, P less than 0.001 for the seven experiments combined). These changes in heptic insulin delivery and extraction after glucose metabolism associated with insulin action. As hepatic insulin extraction increased, hepatic glucose output declined, both parameters returning to basal levels by 3 h, indicating a negative correlation between hepatic insulin extraction and hepatic glucose output (r = 0.63, P less than 0.001; n = 7). The factors that mediate this marked and rapidly occurring increase in hepatic insulin extraction after oral glucose are unknown, and may include hepatic insulin delivery, glucose levels in the blood flow, and gut factors released by oral glucose intake. The association of changes in hepatic insulin extraction in vivo with an insulin effect on the liver as measured hepatic glucose output is consistent with in vitro observations relating insulin degradation to receptor binding.

Animals↗
PubMed1982

The in vivo metabolism of somatostatin 28: possible relationship between diminished metabolism and enhanced biological action.

We have compared the metabolism of infused somatostatin 14 (SS14) and somatostatin 28 (SS 28) in anesthetized dogs. After iv infusion of either peptide, plasma SS-like immunoreactivity (SLI) coeluted from Bio-Gel P10 columns with the corresponding synthetic peptide marker. The hepatic extraction, renal extraction, MCR, and plasma half-life of plasma SLI and after SS28 infusion were 11.0 +/- 1.5%, 50 +/- 4.8%, 9.9 +/- 1.4 ml/kg.min, and 2.8 +/- 0.3 min, respectively. Corresponding values after SS14 infusion were 43.1 +/- 7.4%, 82.2 +/- 6.6%, 21.9 +/- 6.5 ml/kg.min, and 1.7 +/- 0.2 min. These differences between SS28 and SS14 were all statistically significant (P less than 0.05). When equimolar amounts of each peptide were given as bolus injections, both led to a significant reduction in portal venous blood flow. After the injection of SS14, the reduction in flow was short-lived and returned to baseline by 4 min. However, between 2-7.5 min after the injection of SS28, the reduction in blood flow was significantly greater than that induced by SS14, and returned to baseline only by 15 min. These studies indicate that the metabolism of plasma SLI is significantly slower during the steady state infusion of SS28 in pharmacological doses than after similar infusions of SS14. SS28 led to a more prolonged reduction in portal blood flow than SS14; this effect is probably due to its slowed metabolism. This suggests that further modification of the SS28 molecule may increase its therapeutic potential by slowing its in vivo metabolism.

Animals↗
PubMed1982

Evidence for the presence of somatostatin 28 in plasma.

Somatostatin-like immunoreactivity (SLI) from dog and rat plasma eluted from Biogel P-6 columns as three distinct peaks. A large-molecular-weight peak was present in the void volume of the column, an intermediate-sized peak (SLI28) coeluted with synthetic somatostatin 28 (S-28), and a small-molecular-weight peak (SLI14) coeluted with SRIF. Material from the SLI28 peak diluted in parallel to the S-28 standard in the radioimmunoassay and behaved identically to S-28 on high pressure liquid chromatography (HPLC). Levels of SLI28 in the portal vein were consistently greater than the simultaneously measured peripheral levels (portal peripheral ratio 2.2 +/- 0.2). Venous samples drawn from multiple sites suggested that SLI28 is segregated by the duodenum and/or pancreas and the intestine. This data is consistent with the possibility that S-28 is a hormone distinct from SRIF.

Animals↗
PubMed1981

A familial glucagonoma syndrome: genetic, clinical and biochemical features.

A family with multiple endocrine neoplasia type I (MEN-I) is described in which three members had A-cell pancreatic tumors. Two of these members had classic glucagonoma syndromes. The proband, a 62 year old woman, had a high (less than or equal to 9.2 ng/ml) basal plasma glucagon level, most of which eluted in the 3,500 dalton fraction. Plasma glucagon increased following the ingestion of mixed meals and arginine. Secretin, which, in the dog, has been reported to inhibit normal glucagon secretion, provoked a twofold increase in 3,500 dalton plasma glucagon concentration. Increased plasma glucagon in the proband was associated with mild hyperglycemia and insulin resistance. Somatostatin infusion suppressed peripheral glucagon and insulin levels, and increased blood glucose levels. The unique responses to secretin and somatostatin observed in this patient may be diagnostically important in syndromes of inappropriate or autonomous glucagon secretion.

Adenoma, Islet Cell↗
PubMed1979

Reduction in portal vein blood flow by somatostatin.

Intravenous somatostatin boluses produced striking diminution in portal vein blood flow in dogs (maximally 40--55%). This effect was of rapid onset, without observable changes in hepatic artery flow, systemic blood pressure, pulse or central venous pressure. The duration of action was short, but could be sustained by continuous intravenous infusion. These observations are consistent with an endocrine role of somatostatin in the regulation of nutrient balance.

Animals↗