Differential effects of body weight, hyperinsulinemia and oral glucose load on serum C-peptide/insulin molar ratio.

Serum C-peptide immunoreactivity (CPR)/immunoreactive insulin (IRI) molar ratio was determined in 136 subjects without renal, hepatic and thyroid disorders, at fasting, and during the initial period of 75 g-oral glucose tolerance test. The subjects were divided into 4 groups based on their body weight and age; Group A, young (< 55 years) and normal body weight (body mass index [BMI, kg/m2] < or = 25) subjects; Group B, young and overweight (BMI > 25) subjects; Group C, aged (> or = 55 years) and normal body weight (BMI < or = 25) subjects; Group D, aged and overweight subjects. Fasting CPR/IRI ratio and absolute CPR level negatively correlated in Groups B and D but not in A and C. After oral glucose load with elevation of insulin, CPR/IRI ratio invariably declined in all groups and significant negative correlation between CPR/IRI and CPR was found in Groups A, B and D but not in C. Slope of the regression lines obtained for correlation between CPR/IRI ratio and CPR were significantly steeper at fasting compared to the post-stimulation phase. CPR/IRI ratio is affected by hyperinsulinemia and oral glucose load but not by obesity alone. Assuming that CPR/IRI ratio reflects hepatic extraction of insulin, the insulin clearance at fasting is progressively reduced with increasing insulin secretion in overweight subjects: failure to detect such phenomenon in normal body weight subjects may be due to a narrower CPR range in this population. Insulin metabolism at fasting and during glucose stimulation is likely to be regulated by distinct factors.     

Twenty-four-hour serum growth hormone, insulin, C-peptide and blood glucose profiles and serum insulin-like growth factor-I concentrations in women with polycystic ovaries.

Raised insulin levels are now recognized as a characteristic feature of women with polycystic ovaries (PCO), and hyperinsulinism has been shown to stimulate androgen production in such women. We have, however, recently shown that hyperinsulinaemia is present only in the obese subjects with PCO in whom insulin concentrations correlate with those of luteinizing hormone. We therefore studied 24-hour blood profiles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in obese and non-obese women with PCO, for comparison with their levels of insulin, C-peptide and other hormones, such as androgens which are known to be disturbed in PCO. Mean 24-hour GH levels were higher overall in PCO than in control subjects, although the difference was not significant. When, however, a separate analysis was made in obese as compared with non-obese PCO patients, GH concentrations were significantly higher in the non-obese group than in the obese (p = 0.0005). There was a significant negative correlation between body mass index and mean 24-hour GH concentrations (r = -0.641; p = 0.0006). IGF-I concentrations were however similar in the PCO group overall and in controls, as well as in the obese and non-obese PCO patients. The 24-hour blood glucose profile pattern was significantly different in PCO women from controls (p = 0.009), with absence of post-prandial peaks in blood glucose concentrations. These changes were most marked in the non-obese PCO group, who also had significantly lower blood glucose levels than either controls or obese PCO subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood glucose and serum insulin levels in lean and genetically obese mice.

Fed and 24 hour fasted lean and genetically obese mice (ob/ob) were given a fixed glucose load per gm body weight by intraperitoneal and intragastric administration. Intraperitoneal glucose injection into the obese mice produced a prolonged elevated blood glucose level with a concomitant significant decrease of circulating insulin. Possible interpretations of this observation are discussed. In those obese animals in which glucose was administered intragastrically the fed obese mice had a blood glucose concentration of 450-500 mg% for a period of one hour but there was no increase in circulating insulin, however, in the fasted obese mice in which the glucose concentration was about 350 mg% for one hour, there was a significant increase in the circulating insulin levels. The fed and fasted lean mice showed normal glucose tolerance curves and the expected increase in circulating insulin following either intraperitoneal orintragastric glucose loads. It is concluded that hyperglycaemia in the ob/ob mice is unlikely to be the principal cause of hyperinsulinaemia.     

Chronobiological study of free thyroid hormones in hypothyroid and hyperthyroid subjects

Previous reports demonstrate a circadian rhythm of the free thyroid hormones in healthy subjects. In this study we evaluated circadian variation of FT3 and FT4 in hyperthyroid and hypothyroid states. We considered six hyperthyroid patients, six hypothyroid patients and six control subjects. Blood samples were taken two hours apart from a catherterized arm vein. Data were evaluated by Halberg's cosinor analysis. The results show that FT3 and FT4 exhibit a circadian rhythm in healthy subjects, not evident in hyperthyroid and hypothyroid patients.     

Circadian oscillations of thyroid hormones and insulin in the serum of fasting rats

Adult male Wistar rats adapted to a 12:12 h light:dark regimen, fed or after a 24- or 48-h fast, were decapitated at 3-h intervals during a single day. They were deprived of food at day-time intervals ensuring that on decapitation they had fasted for the same length of time, i.e. 24 or 48 h. Thyroid hormones, insulin and glucose concentrations were determined in their serum. Fasting did not significantly affect circadian thyroxine, triiodothyronine and reverse triiodothyronine rhythms compared with the findings in fed animals; 24, but not 48 hours' fasting led to a shift in the acrophase of circadian insulin and glucose oscillations compared with fed rats. The maintenance of original circadian thyroid hormones and insulin rhythm in rats which fasted for short lengths of time testifies to a dependence of the stimulus on the time of day.     

Blood glucose and insulin levels in thymectomized rats.

The rise of blood glucose level under sugar load was much greater in thymectomized than in normal rats, whereas the insulin level remained practically unchanged. This suggests that the rise of blood sugar level is due to two factors, one being the accumulation in blood of a substance, corresponding to the blood glucose level stimulator stored in the thymus, the other the simultaneous inhibition of insulin production, or of insulin transport, into blood.     

Piperine lowers the serum concentrations of thyroid hormones, glucose and hepatic 5'D activity in adult male mice.

Piperine, the main alkaloid of Piper nigrum fruits, was evaluated for its thyroid hormone and glucose regulatory efficacy in adult male Swiss albino mice. Its daily oral administration (2.50 mg/kg) for 15 days lowered the serum levels of both the thyroid hormones, thyroxin (T (4)) and triiodothyronine (T (3)) as well as glucose concentrations with a concomitant decrease in hepatic 5'D enzyme and glucose-6-phospatase (G-6-Pase) activity. However, no significant alterations were observed in animals treated with 0.25 mg/kg of piperine in any of the activities studied except an inhibition in serum T (3) concentration. The decrease in T (4), T (3) concentrations and in G-6-Pase were comparable to that of a standard antithyroid drug, Proylthiouracil (PTU). The hepatic lipid-peroxidation (LPO) and the activity of endogenous antioxidants, superoxide dismutase (SOD), and catalase (CAT) were not significantly altered in either of the doses. It appears that the action of P. nigrum on thyroid functions is mediated through its active alkaloid, piperine. We also suggest that a higher dose of piperine may inhibit thyroid function and serum glucose concentration in euthyroid individuals.     

Rat brain insulin degrading enzyme in insulin and thyroid hormones imbalances

Rat brain insulin degrading enzyme activity and its relationship with insulin receptor were investigated in experimental hyperglycemia, hyperinsulinemia, hypothyroidism and hyperthyroidism. Insulin degrading enzyme activity was assessed in synaptosomes and high speed cytosol using [125I]insulin. Levels of insulin degrading enzyme were changed in high speed cytosol in insulin and thyroid hormone imbalances. These results suggest that insulin degrading enzyme in brain is predominantly active in cytosol and is subject to regulation by insulin and thyroid hormones. Probably it plays some role in long term effects of insulin in brain.     

Intravenous glucose tolerance, insulin response to glucose, peripheral sensitivity to insulin, and serum lipoproteins in post-myocardial infarct patients with normal fasting blood glucose

Intravenous glucose tolerance (IVGTT), basal insulin and insulin response to glucose infusion (GIT), insulin sensitivity, and lipoprotein patterns were determined in non-obese post-coronary subjects, 3-6 months after myocardial infarction. Twelve had decreased and 31 normal IVGTT. The control group comprised 31 subjects with normal IVGTT, who did not display any signs of coronary disease. The post-coronary patients were not taking any drugs except for furosamide, which was shown not to influence insulin response to GIT or glucose tolerance. Decreased IVGTT in the post-coronary patients could be ascribed to decreased insulin response and insulin resistance. These two derangements are considered as hereditary markers in glucose intolerance and type 2 diabetes. Accordingly, our findings suggest that glucose intolerance in subjects with myocardial infarcts has the same background. The post-coronary patients demonstrated elevated triglycerides (TG) and cholesterol in total serum and in very low density lipoproteins (VLDL), the lipoprotein patterns being almost identical in post-coronary patients with or without decreased IVGTT. No relationship was found in the control and post-coronary groups between IVGTT, basal insulin, stimulated insulin (KI, IP), and insulin sensitivity (KG), on the one hand, and total or VLDL TG or any other lipoprotein particle, on the other. Thus, the derangements in glucose, insulin, and serum triglyceride metabolism were independent abnormalities (risk factors) in these non-obese post-coronary patients.     

Reduced levels of thyroid hormones, insulin, and glucose, and lower body core temperature in the growth hormone receptor/binding protein knockout mouse

The mechanisms that are responsible for the extension of lifespan in the mouse with targeted disruption (knockout [KO]) of the growth hormone (GH) receptor/binding protein (GHR-KO) are unknown. However, in the long-living Ames dwarf mouse, blood glucose and body core temperature (Tco) are consistently lower than in normal mice. In addition, insulin levels are reduced and corticosterone levels are elevated in male dwarfs. These functional alterations, similar to those seen in animals under caloric restriction, have not been proven to be causally related to the extension of lifespan, but they do provide some insight into what traits may be necessary for long life. Therefore, to investigate which of these parameters are similarly affected in two genetically unrelated, yet similarly long-living mouse models, we measured Tco, thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), and insulin, in addition to morning and afternoon levels of glucose and corticosterone, in young adult male and/or female GHR-KO mice and their normal siblings. Tco in GHR-KO mice was numerically reduced throughout the 24-hr period; however, these differences were only significant 4 hr prior to lights-off (14:00 hr), immediately after lights-off (18:00 hr), and during the 3 hr preceding lights on (03:00 to 06:00 hr). GHR-KO mice had significantly reduced levels of T3 and T4, while the ratio of these hormones was similar to that in normal mice. Insulin levels in GHR-KO mice were lower than in normal mice; levels in male GHR-KO mice were below the detectable limits of the assay used. Glucose levels in GHR-KO mice (male and females) were lower than in normal mice in measurements taken in both morning and afternoon; however, these differences arose from consistent reductions in males, as morning glucose levels in GHR-KO females were similar to those of normal mice. Corticosterone levels measured in blood plasma collected under basal (nonstressed) conditions showed sex-related alterations. Basal corticosterone levels in female GHR-KO mice were similar to normal females, while those in male GHR-KO mice were higher than in normal males in the afternoon. Corticosterone levels in stressed GHR-KO females were similar to those measured in stressed normal females. These data show that the long-living GHR-KO mouse shares a reduction in glucose, insulin, thyroid hormones, and Tco with the Ames dwarf mouse. Reductions in these parameters may be important to the underlying mechanisms of delayed aging in these animals.     

Effects of glucose,exogenous insulin,and carbachol on C-peptide and insulin secretion from isolated perifused rat islets

Isolated perifused rat islets were stimulated with glucose, exogenous insulin, or carbachol. C-peptide and, where possible, insulin secretory rates were measured. Glucose (8-10 mm) induced dose-dependent and kinetically similar patterns of C-peptide and insulin secretion. The addition of 100 nm bovine insulin had no effect on C-peptide release in response to 8-10 mm glucose stimulation. The addition of 100 nm bovine insulin or 500 nm human insulin together with 3 mm glucose had no stimulatory effect on C-peptide secretion rates from perifused rat islets. Stimulation with carbachol plus 7 mm glucose enhanced both C-peptide and insulin secretion, and the further addition of 100 nm bovine insulin had no inhibitory effect on C-peptide secretory rates under this condition. Perifusion studies using pharmacologic inhibitors (genistein and wortmannin) of the kinases thought to be involved in insulin signaling potentiated 10 mm glucose-induced secretion. The results support the following conclusions. 1) C-peptide release rates accurately reflect insulin secretion rates from collagenase-isolated, perifused rat islets. 2) Exogenously added bovine insulin exerts no inhibitory effect on release to several agonists including glucose. 3) In the presence of 3 mm glucose, exogenously added bovine or human insulin do not stimulate endogenous insulin secretion.     

Responses of plasma insulin C-peptide and proinsulin-like components to glucose and glucagon in the pig.

This study was undertaken to evaluate the relative contribution of insulin, proinsulin-like components (PLC) and C-peptide toward plasma levels of immuno reactive insulin (IRI) and C-peptide immunoreactivity (CPR) in the pig and to elucidate the mode of secretion of PLC in the early phase of insulin release. Following the intravenous glucose loads, the concomitant secretion of CPR with that of IRI occured rapidly and the maximum plasma level of IRI was observed at an earlier time than that of CPR. Following the intravenous glucagon injection, the maximum plasma levels of IRI and CPR were observed at the same time in the early phase. After the gel filtration of acid alcohol extracts of plasma in a fasted state, a very small amount of PLC and a small amount of C-peptide as well as a small amount of insulin were detected. The results obtained from the gel filtration of extracts revealed that the increased amounts in IRI and CPR after the injection of glucose or glucagon consisted mostly and respectively of insulin and C-peptide in the pig, because the concentration of PLC increased only slightly in the early phase. In fact, plasma levels of CPR and IRI were essentially and respectively paralleled to those of insulin and C-peptide which were assayed after the gel filtration of extracts. In addition, the slight elevation of PLC in the early phase after these stimulations indicated that PLC was elicited into blood circulation at the same time of the secretion of insulin and C-peptide.     

Independent influence of insulin, catecholamines, and thyroid hormones on metabolic syndrome

The objective of this study was to examine whether metabolic syndrome, defined according to adult treatment panel III criteria, is associated with insulin, catecholamines, and thyroid hormones, independently of age and gender. A cohort of 651 euthyroid overweight and obese patients, 440 women and 211 men, aged 18-68 years, were examined. Central fat accumulation (indirectly measured by waist circumference), fasting thyroid-stimulating hormone (TSH), FT(3), FT(4), insulin, glucose, and lipid (cholesterol, HDL-cholesterol, and triglyceride) serum concentrations, 24-h urinary catecholamines, and the level of insulin resistance (estimated by homeostasis model assessment for insulin resistance (HOMA(IR))) were measured. Patients with metabolic syndrome showed higher insulin (P < 0.001) and FT(3) (P < 0.001) serum levels and higher 24-h urinary noradrenaline (P < 0.001) than subjects without this syndrome. The number of metabolic syndrome parameters was directly associated with insulin (P < 0.001) and FT(3) (P < 0.05) serum levels, and with 24-h urinary noradrenaline (P < 0.001) in the whole population. When a multiple regression analysis was performed with the metabolic syndrome as the dependent variable, and age, gender, and insulin, and TSH, FT(3), FT(4) serum levels, and 24-h urinary noradrenaline and adrenaline as independent variables, the metabolic syndrome maintained an independent positive association with age (P < 0.001), male sex (P < 0.001), insulin (P < 0.001), and 24-h urinary noradrenaline (P < 0.001). In conclusion, this study suggests that insulin and noradrenaline cooperate independently to the development of the metabolic syndrome.     

Development of a radioimmunoassay for plasma C-peptide in sheep: kinetics of C-peptide and effects of exogenous growth hormone and glucose on insulin and C-peptide

An antiserum to purified bovine C-peptide was used to develop a sensitive radioimmunoassay for C-peptide in sheep. The assay was used to measure kinetics of C-peptide and insulin in non-pregnant and non-lactating sheep. Injected, purified C-peptide was distributed in pools comprising c. 11.4% of liveweight, the half time of C-peptide was estimated as 13.7 min and its clearance rate was c. 5 ml kg-1 min-1. In lactating ewes exogenous recombinant bovine growth hormone (rebGH) increased both plasma insulin and C-peptide as did glucose challenge given before and during administration of rebGH. Estimates of insulin secretion rate in lactating ewes were c. 7 x 10(-3) and 8.5 x 10(-3) nmol kg-1 min-1 before and after glucose challenge prior to injections of rebGH. After 4 days of injection of rebGH, corresponding values were c. 8 x 10(-3) and 10 x 10(-3) nmol min-1 kg-1.     

Increase of serum somatomedin C in hyperthyroid patients with pregnancy.

In thyrotoxic women with pregnancy, serum somatomedin C (SmC) concentration was markedly elevated (mean +/- SD 13.57 +/- 4.66 U/ml) compared to thyrotoxic women without pregnancy (1.24 +/- 1.09 U/ml), non-pregnant euthyroid women previously treated for hyperthyroidism (0.87 +/- 0.30 U/ml), normal subjects with pregnancy (6.08 +/- 3.36 U/ml) and pregnant euthyroid women previously treated for hyperthyroidism (5.98 +/- 1.52 U/ml). Since SmC/growth hormone ratio was significantly more in thyrotoxic pregnant women than in normal pregnant women and euthyroid pregnant women previously treated for hyperthyroidism, and since human placental lactogen (HPL), human chorionic gonadotropin (HCG) and prolactin (PRL) do not crossreact with SmC antibody, it is suggested that excess thyroid hormone during pregnancy results in excessive hepatic somatomedin C production.     

Glucose, immunoreactive insulin and C-peptide immunoreactivity in patients with acute viral hepatitis

Carbohydrate intolerance with high insulin levels are a consistent finding in acute and chronic liver diseases. It has been recently clarified that in cirrhotic patients hyperinsulinism is related to decreased hepatic clearance, but the role of liver cell damage or portal systemic shuntings is still unclear. Therefore, we assessed glucose, immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR), in the basal state and after oral and intravenous glucose load, in fifteen patients with acute viral hepatitis (AVH), a liver disease where cell necrosis is prominent. CPR is a useful tool for investigation of hyperinsulinism as, according to previous reports, it is not - or is only to a limited degree - metabolised by the liver. Our results confirm the carbohydrate intolerance, with high IRI levels, in the early stage of AVH. CPR levels were significantly increased before and after glucose load. This study suggests that liver cell damage plays a key role in the pathogenesis of hyperinsulinism in liver diseases and high CPR values seem also to be related to liver damage.     

Effects of coffee consumption on glucose tolerance, serum glucose and insulin levels--a cross-sectional analysis.

OBJECTIVE: Coffee has several metabolic effects that could reduce the risk of type 2 diabetes. Our objective was to examine the effects of coffee consumption on glucose tolerance, glucose and insulin levels. RESEARCH DESIGN AND METHODS: A subsample of subjects aged 45 to 64 years in 1987 and in 1992 from the population-based FINRISK study (12,287 individuals) was invited to receive the standard oral glucose tolerance test at baseline. Plasma samples were taken after an overnight fast, and a two-hour oral glucose tolerance test was administered. Fasting and two-hour plasma glucose and insulin were measured in 2434 subjects with data on coffee use and potential confounders. RESULTS: After adjustment for potential confounding factors (age, body mass index, systolic blood pressure, occupational, commuting and leisure time physical activity, alcohol and tea drinking, smoking), coffee consumption was significantly and inversely associated with fasting glucose, two-hour plasma glucose, and fasting insulin in both men and women. Coffee consumption was significantly and inversely associated with impaired fasting glucose, impaired glucose regulation, and hyperinsulinemia among both men and women and with isolated impaired glucose tolerance among women. CONCLUSIONS: In this cross-sectional analysis, coffee showed positive effects on several glycemia markers.     

Effects of acetazolamide on insulin release, serum glucose and insulin, glucose tolerance, and alloxan sensitivity of mice

Isolated pancreatic islets exposed to 100 mM acetazolamide (AZM) and low glucose concentration exhibited increased insulin release, whereas those subjected to AZM and high glucose concentration exhibited decreased secretion of insulin. A slight transient hyperglycaemia was found 24 h after administration of 1.5 g/kg b.wt. of AZM to fed mice, whereas no such response was seen in starved mice. The serum insulin concentration was increased in the 24 h after AZM injection. Pretreatment with AZM caused decreased glucose tolerance and protection against alloxan toxicity. Inhibited carbonic anhydrase activity and ionic alterations might have played a role in the development of these effects of AZM in mice.