Plasma Immunoreactive Insulin Concentrations Research Articles

The Relationship Between Obesity, Plasma Immunoreactive Insulin Concentration and Blood Pressure in Newly Diagnosed Indian Type 2 Diabetic Patients

The association of blood pressure with clinical and biochemical measures was studied in 185 newly diagnosed Type 2 diabetic patients, 74 impaired-glucose-tolerant (IGT) and 128 non-diabetic control subjects. Hyperglycaemic subjects were older than control subjects (controls 40 (24-59) years, IGT 48 (29-64) years, diabetic 43 (29-60) years, median (5th-95th centile) both p < 0.05). They were also more obese (body mass index (BMI) controls 23.5 kg m-2 (17.2-29.9), IGT 26.0 kg m-2 (19.8-33.9), diabetic 24.2 kg m-2 (19.3-32.2)) and with a greater waist-hip ratio (controls 0.83 (0.70-0.98), IGT 0.88 (0.75-0.98), diabetic 0.89 (0.75-1.00)). Blood pressure was significantly higher in both IGT (systolic 127 mmHg (108-162), diastolic 84 mmHg (66-99)) and diabetic patients (systolic 130 mmHg (104-160), diastolic 84 mmHg (66-102)) compared to non-diabetic controls (systolic 120 mmHg (100-151), diastolic 80 mmHg (60-94)). Univariate analysis showed that in diabetic patients systolic blood pressure was related to age (r = 0.17, p < 0.05), BMI (r = 0.23, p < 0.01) and plasma immunoreactive insulin (fasting and post glucose, r = approximately 0.25, p < 0.01) but not to C-peptide concentrations; diastolic blood pressure to BMI (r = 0.35, p < 0.001), waist-hip ratio (r = 0.23, p < 0.01) and plasma immunoreactive insulin (fasting r = 0.30, p < 0.001, post glucose r = approximately 0.20, p < 0.05) but not to C-peptide concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance.

Conventional immunoassays to quantify insulin concentration do not differentiate between insulin and proinsulin. Thus, previous conclusions as to the relationship between the development of hyperglycemia in patients with noninsulin-dependent diabetes mellitus (NIDDM) and pancreatic insulin secretory function may have been confounded by not being able to determine the contribution made by plasma proinsulin to the putative measurements of plasma insulin concentration in these patients. The current study was initiated to address this issue by making specific measurements of plasma insulin, proinsulin, and C-peptide concentrations in 42 individuals: 14 with normal glucose tolerance, 12 with impaired glucose tolerance (IGT), and 16 with NIDDM. The study population was further subdivided into a nonobese (body mass index, < 30 kg/m2) and an obese (body mass index, > 30 kg/m2) group. Mixed meals were given at 0800, 1200, and 1800 h, and blood was removed at 0800 h (before the meal) and at hourly intervals from then until 1600 h. Plasma glucose concentrations throughout the sampling period were slightly, but significantly (P < 0.01), greater in patients with IGT than in normal individuals. Patients with NIDDM had markedly elevated glycemic excursions, greater than either of the other two groups (P < 0.002). Both plasma immunoreactive insulin and C-peptide concentrations from 0800-1600 h were higher (P < 0.002-0.001) in patients with either IGT or NIDDM than in the group with normal glucose tolerance. Although day-long plasma immunoreactive insulin and C-peptide concentrations were higher, on the average, in patients with IGT compared to those with NIDDM, the difference was not statistically significant. Plasma proinsulin concentrations were highest in patients with NIDDM (P < 0.002), lower in those with normal glucose tolerance (P < 0.002), and intermediate in patients with IGT. When the calculated "true" insulin concentration was determined by taking the proinsulin content into consideration, patients with IGT had the highest day-long levels, with the lowest values found in the control population (P < 0.002). Although absolute values varied as a function of obesity, the generalizations outlined above were found in both weight groups. These results show that ambient plasma proinsulin concentrations increase as glucose tolerance declines. However, true plasma insulin concentrations in response to mixed meals remain highest in patients with IGT, lowest in normal individuals, and intermediate in patients with NIDDM. Thus, previous conclusions that absolute day-long plasma insulin concentrations are not lower than normal in patients with NIDDM do not appear to result from an inability to differentiate true insulin from proinsulin.

Seasonal changes in CSF insulin levels in marmots: insulin may not be a satiety signal for fasting in winter

Plasma insulin (PI) reportedly crosses the blood-brain barrier in mammals and acts with the central nervous system (CNS) to reduce food intake. Animals that hibernate (hibernators) eat little or no food from early winter (November) to spring (April). This lack of food intake may be due to elevated PI concentrations acting within the CNS. In this study, we determined whether hibernators have altered insulin levels within the CNS at different times during the circannual cycle of metabolism and feeding. Plasma and cerebrospinal fluid (CSF) immunoreactive insulin concentrations were measured in marmots (Marmota flaviventris) during the feeding phase of the body weight cycle and during the fasting period (hibernation). Basal plasma and CSF samples were collected in September, November, January, and April. In addition, plasma and CSF insulin levels were monitored during a 2-h intravenous infusion of glucose (20% wt/vol) that stimulated pancreatic B-cell production of insulin. During the spring feeding period, we found that as PI levels rise, so do CSF insulin concentrations. However, in fall and winter when marmots are fasting, very little insulin entered the CSF even when PI levels were significantly elevated. Furthermore, the longer the fast, the lower was the CSF insulin under both basal and infusion conditions. These results lead us to conclude that elevated CSF insulin is not a likely cause of suppressed food intake in fasting marmots.

Insulin and C-peptide levels following oral administration of insulin in intestinal-enzyme protected capsules

1. 1. Crystalline beef insulin was administered orally in capsules composed of a methacrylic acid copolymer which prevented breakdown of the insulin by enteric and pancreatic peptidases. 2. 2. In studies performed in 3 individuals blood was sampled before oral ingestion of the insulin (40–144 units), and at 15 or 30 min intervals thereafter for 5.5 hr for measurement of immunoreactive insulin and C-peptide concentrations. 3. 3. Following the administration of oral insulin, plasma immunoreactive insulin concentrations became elevated 4–5 hr after ingestion. 4. 4. The rise in plasma insulin concentrations was associated with a corresponding fall in the concentration of C-peptide. 5. 5. The data suggest that this preparation of oral insulin can produce significant enteric absorption of the peptide, and that further investigation of agents that facilitate insulin absorption from the gut might render the use of methacrylic acid copolymer coated capsules a physiologically sound and a commercially feasible method of oral insulin administration.

Decrease of liver glycogen content in golden hamsters infected with plerocercoids ofSpirometra erinacei

Liver glycogen content decreased in golden hamsters experimentally infected with plerocercoids of Spirometra erinacei. The activity of glycogen synthase a decreased significantly in infected animals, whereas that of glycogen phosphorylase a was not significantly affected. These observations suggest that changes in glycogen content were not attributable to increased glycogenolysis, but rather resulted from suppressed glycogenesis. Plasma immunoreactive insulin (IRI) concentrations in infected animals were slightly lower than those in controls, but the differences were not statistically significant. Plasma glucagon concentrations were significantly higher in infected animals. These results suggest that the suppression of glycogen synthase activity in S. erinacei-infected hamsters was attributable to enhanced levels of glucagon and that enhanced secretion of glucagon was caused by parasite-induced hypoglycemia.

Absorption kinetics of regular insulin in dogs with alloxan-induced diabetes mellitus

SUMMARY The absorption kinetics of porcine regular insulin following iv, im, and sc administration were evaluated in 10 dogs with alloxan-induced diabetes mellitus. Plasma immunoreactive insulin (iri) concentrations were evaluated immediately prior to and at 10, 20, 30, 45, 60, 90, 120, 180, and 240 minutes following iv administration; and immediately prior to and every 30 minutes for 2 hours and then every hour for 6 hours following im and sc administration of 0.55 U of porcine regular insulin/kg of body weight. Model-independent pharmacokinetic analysis was performed on each data set. Plasma iri concentration declined rapidly after iv administration of regular insulin and then returned to baseline iri concentration by 3.2 ± 0.8 hours. The absorption kinetics following iv administration of regular insulin were similar to those found in earlier studies in healthy dogs and human beings. The im and sc routes of regular insulin administration resulted in a pharmacologic concentration of iri at 30 minutes. The peak mean (± SD) plasma iri concentration was significantly (P &lt; 0.05) greater following sc administratin than it was following im administration of regular insulin (263 ± 185 and 151 ± 71 IμU/ml, respectively). The time of the peak plasma iri concentration (68 ± 31 minutes and 60 ± 30 minutes) and the time to return to baseline plasma iri concentration (5.8 ± 1.2 hours and 5.8 ± 1.3 hours) were not significantly different following sc and im administration of regular insulin, respectively. The absorption kinetics following sc administration of regular insulin were similar to those found in earlier studies in healthy dogs and human beings. The absorption kinetics following im administration of regular insulin differed from those found in earlier studies and was similar to the absorption kinetics of regular insulin administered sc in this study. The reasons for this similarity were not readily apparent.

The role of α‐ and β‐adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1). 7. The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by alpha 2- and beta 2-adrenoceptors, whereas alpha,- or beta l-adrenoceptors do not appear to be involved.

Modulation of baroreflex by varying insulin and glucose in conscious dogs

We developed a conscious, chronically instrumented canine preparation (n = 5 dogs) in which insulin concentration was precisely controlled to study the effects of controlled variations of plasma insulin and glucose concentrations on cardiac responses to bilateral carotid occlusion and dobutamine. Endogenous insulin secretion was reduced to negligible levels using alloxan and then replaced by continuous, constant intravenous insulin infusion at a rate (0.625 +/- 0.115 U/h) sufficient to maintain fasting normoglycemia (85 +/- 9 mg/100 ml); plasma immunoreactive insulin (IRI) in this basal "normal insulin, normal glucose" (NI,NG) condition was 0.362 +/- 0.45 ng/ml (NS vs. prealloxan fasting concentration). A fivefold increase of IRI from NI,NG levels with normoglycemia maintained (5 x NI,NG) reduced (P less than 0.05) the maximal first time derivative of left ventricular pressure (LV dP/dtmax) from 3,010 +/- 62 to 2,398 +/- 91 (SE) mmHg/s but had no effect on LV dP/dtmax when plasma glucose was elevated to 298 +/- 25 mg/100 ml (5 x NI,HG). The LV dP/dtmax increase during bilateral carotid occlusion (BCO) in the NI,NG state of 124 +/- 17 mmHg/s was significantly reduced (P less than 0.05) in the 5 x NI,HG state to 58 +/- 18 mmHg/s but was not altered in the 5 x NI,NG state. Reduction of plasma insulin to one-fifth of the normal fasting level had no effect on basal cardiac function or the responses to BCO. There were no other statistically significant effects of insulin or glucose concentration on cardiovascular responses to BCO or to infusion of dobutamine. Our data indicate that physiologically realistic variations in plasma IRI and glucose concentrations interact and may modulate cardiovascular responses to changes in autonomic nervous activity, even though previously reported effects of pharmacological doses of insulin were not observed.

Induction of Diabetes in PVG/c Strain Rats by Manipulation of the Immune System

A combination of thymectomy and sublethal irradiation (Tx-X) consistently induced diabetes in female rats of the PVG/c strain. The incidence of diabetes varied from 10.7% to 53.4% in seven successive Tx-X groups (mean 29.7%). Both clinical and subclinical disease was observed with the majority of affected animals developing the former condition. This was acute in onset, rapidly fatal (1-4 days) and characterized by ketosis and lipidemia. Overtly diabetic rats had markedly raised plasma glucose concentrations compared to normal rats of the same strain and plasma immunoreactive insulin concentrations were correspondingly depressed in this group. Histopathological change within the islets of Langerhans correlated with clinical status and ranged from diffuse atrophy in the majority of the acutely diabetic rats to mild and focal lymphocytic insulitis in a proportion of the non-diabetic rats. Islet cell autoantibodies were demonstrated by indirect immunofluorescence in approximately 25% of clinically diabetic animals. The majority of diabetic rats were found to be responsive to insulin and the clinical signs could be reversed by daily parenteral insulin administration. These observations implicate the immune system in diabetes generation and are consistent with an immune mediated pathogenesis as the underlying cause of the islet cell destruction. This syndrome may thus be a potentially useful animal model for type 1 (insulin dependent) diabetes in man.

Reduced insulin removal and erythrocyte insulin binding in obese children.

To study the relationship between childhood obesity, weight loss, hyperinsulinaemia and the erythrocyte insulin receptor, we measured the plasma concentrations of immunoreactive insulin (IRI) and C-peptide and the binding of 125I-insulin to erythrocytes in 12 obese children with a mean age +/- SD of 11.4 +/- 2.5 years and a mean relative weight score +/- SD of 4.8 +/- 1.4 and 12 age-matched normal-weight children. Eight obese children were re-evaluated after 1 year's participation in a weight reduction programme. The obese children had higher fasting plasma concentrations of IRI (P less than 0.01) and C-peptide (P less than 0.05) and a lower C-peptide to IRI molar ratio (P less than 0.01) than the normal-weight children. The obese children had in addition a reduced erythrocyte insulin binding (P less than 0.05 or less) over the physiological range of circulating insulin concentration. There was a negative correlation (r = -0.60; P less than 0.01) between the insulin tracer binding and the relative weight. The weight reduction programme resulted in a decrease of 1.0 SD (P less than 0.05) in the mean relative weight score. At the end of the therapy the obese children had lower fasting blood glucose levels (P less than 0.05) and lower plasma IRI concentrations at 90 min (P less than 0.05) after an oral glucose load than at the onset of therapy. There were no significant differences between the insulin binding characteristics at the commencement and at the end of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

A study of beta-cell function after glucagon stimulation in thalassaemia major treated by high transfusion programme.

An increased incidence of diabetes mellitus and glucose intolerance has been reported in thalassaemia major treated with a high transfusion programme (HTP). To investigate beta-cell function, serum immunoreactive insulin (IRI), C-peptide (CP) and glucose were measured fasting and at 3, 6 and 10 min after i.v. administration of 1 mg glucagon in 20 thalassaemia patients treated by many transfusions and in nine healthy control subjects. Fasting C-peptide concentrations (mean +/- SEM) were higher in the thalassaemic group (2.15 +/- 0.17 ng/ml) than in the controls (1.41 +/- 0.13 ng/ml). After stimulation with glucagon, C-peptide concentrations were consistently higher (P less than 0.01) by approximately 50% in the thalassaemic than in the control group (5.29 +/- 0.31 vs 3.36 +/- 0.21 ng/ml, at 3 min; 5.22 +/- 0.30 vs 3.53 +/- 0.21 ng/ml at 6 min and 4.69 +/- 0.27 vs 3.30 +/- 0.17 ng/ml after 10 min). Plasma IRI concentrations increased in both groups after glucagon stimulation but were not significantly different. The glucose values were approximately 15% higher at each sampling time in the thalassaemic group than those of the normal subjects. It is concluded that disturbances in carbohydrate metabolism in thalassaemia major treated with HTP are the consequence of hepatic cirrhosis which accompanies secondary haemosiderosis, and possibly iron deposition in the beta-cells of the pancreas.

Aberrant insulinoma in the duodenum

A rare case of aberrant insulinoma in the duodenum is described. Hyperinsulinemia with typical hypoglycemic symptoms was induced by prolonged fasting. Selective angiography demonstrated a tumor supplied from the first branch of the jejunal artery, and duodenoscopy revealed a submucosal tumor at the third portion of the duodenum. An increase in venous plasma immunoreactive insulin concentration was evident in the vein draining from the tumor, by sampling through percutaneous transhepatic catheterization. Hypoglycemia was ameliorated after the removal of the submucosal tumor of the duodenum. Histologic and immunocytochemical characterization of the tumor showed an insulinoma, predominantly composed of cells with typical B-cell-like granules. The acid extract of the tumor contained 1.2 U/g of insulin, and this insulin, analyzed by reverse-phase high-pressure liquid chromatography, revealed that it had the same amino acid structure as that of human insulin.

Differential insulin responses to oral and intravenous glucose in the transplantable rat insulinoma — a role for GIP

We have previously demonstrated an impaired insulin response to intraperitoneal glucose and arginine by the transplantable NEDH rat insulinoma. The nature of this tumour B-cell defect has been further studied by investigating the response of insulinoma-bearing rats to intravenous and intragastric glucose. Intravenous glucose failed to stimulate plasma immunoreactive insulin (IRI) above high basal levels (14.5 ± 1.1 μg/L). However, significant elevation of the plasma IRI concentration was observed following an intragastric glucose load (17.1 ± 1.5 μg/L; P < 0.02). In view of the different effects of oral and intravenous glucose on insulin secretion in the RIN, implicating an involvement of incretin factors from the gut, the response of the tumour to GIP was investigated. Plasma IRI concentrations rose significantly in these animals (20.6 ± 2.5 μg/L at 5 min, P < 0.02). We conclude that (a) the transplantable rat insulinoma is responsive to GIP, and (b) that whilst the tumour B-cell has lost its insulin responsiveness to hyperglycaemia produced by intraperitoneal or intravenous glucose, it retains its ability to respond to intragastric glucose. This could be due to incretin factors from the gut of which GIP is currently the strongest candidate.

Spontaneous hyperglycemia and impaired glucose tolerance in athymic nude BALB/c mice.

Basal plasma glucose, glucose tolerance, and insulin secretion were investigated in young and mature athymic nude BALB/c mice and in age-matched controls. Basal plasma glucose levels in male athymic nude mice were similar to those of controls at 1, 3, and 4 wk of age. At 6, 8, and 12 wk of age, male athymic nudes had significantly higher basal plasma glucose levels when compared with controls (P less than 0.01). Plasma immunoreactive insulin concentrations were similar in athymic nudes and controls at 1 wk of age, but at 3 wk of age and subsequently at 6, 8, and 12 wk athymic nude mice had significantly decreased insulin levels when compared with their age-matched controls (P less than 0.05). We found impaired glucose tolerance in male athymic nude mice at all age groups when compared with both female athymic nudes and control BALB/c mice. The discovery of a spontaneous diabetic syndrome (hyperglycemia, impaired glucose tolerance, and decreased insulin secretion) in a colony of athymic nude mice may provide an excellent model for studying the genetics and interactions between the immune and endocrine systems.

Effects of inhibitors of 5-hydroxytryptamine uptake on plasma glucose and their interaction with 5-hydroxytryptophan in producing hypoglycaemia in mice

The effects of various inhibitors of 5-HT uptake on plasma glucose have been studied in normal and monoamine oxidase inhibitor pretreated mice. Additionally their interaction with 5-hydroxytryptophan (5-HTP) in producing hypoglycaemia was studied. Clomipramine, fenfluramine, fluoxetine, ORG 6582 (dl-8-chloro-11-anti-amino-benzo-(b)-bicyclo[3.3.1]nona-3, 6α(10α)-diene hydrochloride), ORG 6997 (dl-4-exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6α(10α)-diene hydrochloride), MK 212 and mazindol did not modify the plasma glucose in normal mice but produced hypoglycaemia in mice pretreated with either nialamide or pargyline. Dexamphetamine did not influence plasma glucose in either normal or monoamine oxidase inhibitor pretreated mice. Each of the above drugs except ORG 6997 but including dexamphetamine augmented the hypoglycaemic effect of 5-HTP in normal mice. These responses did not appear to be mediated by insulin since none of the drugs increased the plasma immunoreactive insulin concentration or augmented the hyperinsulinaemic effect of 5-HTP. Moreover, fenfluramine, fluoxetine and ORG 6582 did not augment the hypoglycaemic action of injected insulin although such an augmentation was produced by mazindol.

Glucose intolerance following cis-platinum treatment in rats

cis-Dichlorodiammineplatinum ( cis-Pt) is a heavy metal complex used in cancer chemotherapy. Since this drug has been shown to induce hyperglycemia in rats, these studies were initiated to elucidate the effects of cis-Pt on carbohydrate tolerance and insulin and glucagon secretion. Two days following i.v. cis-Pt (2.5 or 7.5 mg/kg, 5 ml/kg) or vehicle administration to male F-344 rats, plasma glucose, immunoreactive insulin (IRI) and glucagon (IRG) concentrations were determined in the basal state and serially following a glucose load (2 g/kg, i.p.). Since cis-Pt induces a dose-related anorexia, a pair-fed control group was also studied. Admnistration of 7.5 mg/kg cis-Pt was associated with plasma glucose concentrations 2.5–5 time greater than ad-libitum and pair-fed controls at every time point during the 2-h glucose tolerance test. Although basal plasma IRI concentrations of the 7.5-mg/kg group were comparable to ad-libitum fed controls, they were significantly greater than those of pair-fed partners. Furthermore, ther appropriate IRI response to a glucose stimulus observed in both controls and the 2.5-mg/kg group was absent in the 7.5-mg/kg group. Basal plasma IRG concentrations of the 7.5-mg/kg group were approximately 3–4 times greater than ad-libitum and pair-fed controls and were not suppressed following a glucose load. These results suggest that cis-Pt induces marked glucose intolerance in association with an impaired IRI response and abnormal glucagon response to a glucose stimulus.

Further studies on the effects of 5-hydroxytryptophan on plasma glucose and insulin in the mouse

The effects of 5-hydroxytryptophan on plasma concentrations of glucose and immunoreactive insulin were examined in conscious mice. Blood samples were obtained after anaesthetizing the mice lightly with ether at the desired time. Large doses of L-5-hydroxytryptophan (5HTP) (200-400 mg/kg IV) produced a dose-dependent hypoglycaemic response in fasted mice (e.g. control 5.7 +/- 0.2 mmol/l, 5HTP 400 mg/kg 2.6 +/- 0.3 mmol/l). This response was preceded by a significant elevation in the plasma immunoreactive insulin concentration (e.g. control 6 +/- 2 mU/l; 5HTP 400 mg/kg 53 +/- 7 mU/l). Induction of diabetes with alloxan (80 mg/kg IV 72 h previously) prevented the hypoglycaemic effect of 5HTP. Alloxan diabetes abolished the hyperinsulinaemic response to 100 mg/kg of 5HTP and reduced by 66% the response to 400 mg/kg of 5HTP. In alloxan diabetic mice 5HTP produced a marked hyperglycaemic response (control 17.9 +/- 2.0 mmol/l; 5HTP 100 mg/kg 36.1 +/- 2.3 mmol/l). In normal mice pre-treated with nialamide, a monoamine oxidase inhibitor, much lower doses of 5 HTP (5-10 mg/kg) were required to produce hypoglycaemia. There was no detectable elevation in the plasma insulin concentration accompanying the hypoglycaemic response to smaller doses of 5HTP in nialamide treated mice. The hyperinsulinaemic and hypoglycaemic actions of 5HTP in normal mice were prevented completely by pretreatment with benserazide, an inhibitor of aromatic amino acid decarboxylase. 5-hydroxytryptamine did not modify the plasma glucose concentration in either normal or nialamide-treated animals. It is concluded that the hypoglycaemic response to 5HTP in normal mice is mediated at least partly through an elevation in the plasma insulin concentration, although it is likely that additional mechanisms are involved.

Insulin Secretion and Metabolism during the Perinatal Period in the Rat

To better understand why plasma immunoreactive insulin (IRI) concentration is high in the rat fetus during the last 3 d of gestation and why fetal hyperinsulinemia abruptly subsides after birth, insulin secretion and metabolic clearance rates were estimated in fetuses and nursed pups. Intravenously injected [(125)I]monoiodoinsulin was cleared from the plasma of prematurely delivered pups at least as rapidly as from that of 7- to 10-d-old pups, suggesting that fetal hyperinsulinemia is not a result of slow clearance of the hormone. The fetal liver bound 35% of the injected label within 3 min, and binding was saturable. The uptake of radioactivity by the fetal kidney was nonsaturable and much lower than that of adult rat kidney. Isolated fetal islets were already reactive to glucose on the 19th d of gestation. Pancreatic insulin secretory capacity was estimated by measuring (a) the insulin release of isolated islets incubated in the presence of 2.8 mM glucose, (b) the insulin content of the same islets, and (c) the total insulin extracted from the pancreas, using the formula (a x c)/b. 2 d before birth, the pancreatic insulin secretory capacity was high, accounting for fetal hyperinsulinemia. It was even higher after birth, not accounting for the postnatal decrease in plasma IRI concentration. Pups delivered by caesarian section 1 d before term exhibited a brisk decrease in plasma IRI concentration when the cord was cut. By contrast, if the feto-placental unit was removed from the dam, maintaining fetal blood circulation through the placenta, fetal plasma IRI concentration remained as high as in utero. These experiments suggest that a placental factor stimulates fetal insulin secretion. After birth, when the cord is cut, insulin secretion is rapidly turned off, and the pups switch from a state of unlimited fuel supply by the mother to a state of fuel saving.

The effects of levodopa on plasma glucose in two strains of rat

The effects of levodopa on plasma glucose were examined in two strains of rats. In fasted Wistar rats levodopa produced a dose-dependent hyperglycaemic response which was augmented by pretreatment with nialamide. This response in nialamide-treated rats was prevented by pretreatment with phentolamine and converted to a hypoglycaemic response. Phentolamine increased the plasma concentration of immunoreactive insulin (IRI). In phentolamine-pretreated rats levodopa produced a further marked increase in the plasma IRI concentration. It is suggested that the prevention of levodopa hyperglycaemia by phentolamine is due to the marked increase in the plasma IRI concentration produced by pretreatment with phentolamine. Moreover the fall in the plasma glucose concentration produced by levodopa in phentolamine-pretreated rats is likely to be due, at least in part, to the additional increase in the plasma IRI concentration produced by levodopa under these conditions. In contrast, in fasted Sprague-Dawley rats pretreated with nialamide, levodopa produced either no effect on plasma glucose, or in larger doses, a marked hypoglycaemic effect followed by death. This hypoglycaemic effect was accompanied by a decrease in the plasma IRI concentration.

Normalization of the Paradoxic Secretion of Glucagon in Diabetics Who Were Controlled by the Artificial Beta Cell

Since it is important to elucidate the precise significance of pancreatic A-cell hypersecretion in the pathogenesis of diabetes mellitus, the change in the immunoreactive glucagon (IRG) response to 100 g oral glucose challenges was studied in diabetics whose blood glucose responses and plasma immunoreactive insulin concentrations (IRI) simulated those in normal subjects with the aid of the artificial beta cell system that we developed originally. In six nonobese adult-onset and four insulin-dependent diabetics whose blood glucose responses and plasma insulin concentrations after 100 g oral glucose load were made equivalent to those seen in normal subjects by the artificial beta cell, the glucagon release was similar to the response in normal subjects. In one insulin-dependent diabetic with high anti-insulin-binding capacity, the blood glucose response after an oral glucose challenge was not normalized by the artificial beta cell and the glucagon secretion was paradoxically increased. This fact suggested that the paradoxic rise in glucagon, seen in response to an oral glucose load in some diabetics, is secondary to insulin deficiency.