Raised plasma somatomedin activity and cartilage metabolic activity (35S sulphate uptake in vitro) in the fetus of the mildly diabetic pregnant rat

Summary A mildly diabetic state was induced in pregnant rats following treatment with streptozotocin the day after mating. On day 21 of gestation, these rats had a lower plasma insulin (55±9 versus 107±23 mU/l for control rats; p<0.05, mean ±SEM) and a reduced pancreatic area occupied by insulincontaining cells compared with control animals (0.40±0.04 versus 1.03±0.08%; p<0.001), but hyperglycaemia was not apparent. Fetuses from mildly diabetic animals were longer but not heavier than those from control rats. Plasma somatomedin activity measured by fetal rat cartilage bioassay was higher in fetuses from mildly diabetic rats (1.12±0.07 versus: 0.74±0.05 U/ml for control fetuses; p<0.001) as was cartilage metabolic activity in basal culture medium (³⁵S sulphate uptake) (1 883±141 versus 1473±104 c.p.m./mg for control rats; p<0.05), but plasma insulin levels and the pancreatic area occupied by insulin-containing cells did not differ between the two groups of fetuses. Fetal plasma somatomedin activity, measured by fetal cartilage assay, showed a significant positive correlation with both body weight and length. It is concluded that by day 21 of gestation a small body overgrowth had occurred in the fetus of the mildly diabetic rat and this was associated with an increase in plasma somatomedin activity, but not with any abnormality of circulating insulin levels or volume density of B cells in the pancreatic islets.     

Effects of partially purified preparations with nonsuppressible insulin-like activity (NSILA-S) on sulfate incorporation into rat and chicken cartilage

Summary Several partially purified preparations of NSILA-S were tested for sulfation activity on rat and chicken embryo cartilage. A clearcut stimulation was obtained with as little as 0.1 U/ml and a near maximal effect with 10 U/ml. In no instance could sulfation activity be dissociated from NSILA-S. It is, therefore, likely that NSILA-S and sulfation activity are exerted by one and the same molecule. It is, however, compatible with our results and those from other laboratories that still other substances with sulfation activity besides NSILA-S may be present in serum. Morell's findings [7, 8] according to which NSILA-S stimulates growth and metabolism of chicken embryo fibroblasts and our results on NSILA-S stimulation of sulfate incorporation into cartilage point to a possible physiological role of NSILA-S as a growth factor.This work was supported by a grant (3.85.69) from the Schweizerische Nationalfonds.     

Human plasma fractions inhibit the action of insulin on adipocytes and somatomedin on cartilage

Summary Since human immunoglobulins exert an insulinlike stimulatory effect on adipocyte lipogenesis at concentrations markedly lower than those found in vivo, and since human serum or plasma are only mildly stimulatory, we predicted that human serum probably contains an inhibitor of adipocyte lipogenesis. Supernatant preparations, obtained from the precipitation of immunoglobulins from plasma in 2.5 mol/1 ammonium sulphate, were extensively dialysed and tested for their activity on bioassay systems commonly used for measuring insulin. The supernatants produced a marked inhibition of basal and insulin- or IgG-stimulated lipogenesis and glucose oxidation by adipocytes at protein concentrations of 10 mg/1. The supernatants were further purified through ultrafiltration to demonstrate two main inhibitory fractions, 10 to 30 K and 30 to 50 K, which again produced marked inhibition of basal and insulin- or IgG-stimulated adipocyte lipogenesis and glucose oxidation. These fractions were then tested for basal and serum somatomedin-stimulated ³⁵S sulphate uptake by porcine cartilage: both basal and serum somatomedin-stimulated ³⁵S uptake were significantly inhibited (p < 0.01). Therefore, normal human serum contains at least two peptides which are markedly inhibitory to glucose metabolism and insulin action on adipocytes and ³⁵S transport and somatomedin action on cartilage.     

Testosterone metabolism in prepubertal rabbit cartilage

Using thin-layer chromatography, celite column chromatography and recrystallization methods, articular (AR) and growth plate (GP) cartilage tissues and cells from prepubertal rabbits were shown to convert testosterone (T) into at least three main metabolites: dihydrotestosterone (DHT), delta 4-androstenedione and androstanediols. In tissue incubation experiments the amount of each newly formed metabolite per mg of tissue was always greater in AR than in GP cartilage. After a 24 h incubation with AR or GP cartilage tissues, T was mainly converted to DHT and delta 4-androstenedione in approximately equal amounts. The amount of androstanediol metabolites formed was much lower. In a time-course experiment, the conversion of T to DHT and delta 4-androstenedione was shown to increase in a linear fashion, while the conversion to androstanediols was more variable. Using cultured AR cartilage cell incubations, similar results were obtained. In addition, DHT was shown to be the sole metabolite which accumulated in the cellular pool during the first 3 h incubation, as well as during the 24 h incubation when maximum cellular uptake of radioactivity was observed. At this time, the intracellular amount of unmetabolized [3H]T (88 pmoles/100 micrograms DNA) was similar to the amount of [3H]DHT (70 pmoles/100 micrograms DNA) accumulated in the chondrocytes. For both delta 4-androstenedione and androstanediols, 99% of radioactivity was extracted from the incubation medium.     

Human somatomedin A and longitudinal bone growth in the hypophysectomized rat

A somatomedin A preparation, when given at total doses of 14 and 70 U did not increase the longitudinal bone growth in hypophysectomized rats. Growth hormone (WHO) significantly increased the longitudinal bone growth.     

Growth hormone receptors in rat liver membranes: effects of fasting and refeeding, and correlation with plasma somatomedin activity

The effects of fasting and refeeding on hepatic growth hormone receptors, on insulin receptors and on plasma somatomedin activity were studied. Female rats were either subjected to fasting for 4 days, refed for 3 days after a 4-day fasting, or allowed free access to food (controls). The specific binding of 125I-labelled bovine growth hormone was low in liver microsomal membranes (45% that of controls) and in plasma membranes (52% that of controls) of fasted rats. The number of somatotropic sites rather than the affinity of the binding was decreased. Lactogenic sites as judged by the binding of 125I-labelled human growth hormone were not significantly reduced in liver membranes of fasted rats. 125I-labelled insulin specific binding was enhanced in microsomal (184% that of controls) and plasma membranes (136% that of controls) of fasted rats; these modifications were associated with a decreased insulinemia. But immunoreactive rat growth hormone levels were not different in plasma of fasted, refed and control animals. Decreased plasma bioassayable somatomedin was associated with the low number of somatotropic binding sites in liver membranes of fasted rats. Somatomedin activity of refed animals was comparable to controls. A significant correlation between the plasma bioassayable somatomedin and the hepatic level of somatotropic binding sites was found. It is proposed that, in fasting, the loss of somatotropic binding sites in the liver is one of the possible causes of the decreased plasma somatomedin bioactivity.     

Cellular and molecular correlates of the decline in responsiveness of cartilage and thymus to growth hormone in aged animals

The responses in vitro of cartilage to somatomedin and of thymocytes to growth hormone have been studied in tissues derived from rats of various ages. The basal and somatomedin stimulated incorporation of radioactive proline into proteins and of sulphate into mucopolysaccharides diminishes markedly with age. Chondrocytes per unit area in cartilage of old rats are about 4- to 5-fold reduced in number as compared to those in cartilage from 1-day old rats. The organ size and yield of thymocytes are reduced in aged rats. Besides the fall in number of cells, the average metabolic activity of cells as measured by uridine incorporation into RNA in vitro is also diminished. There is a progressive decline in stimulation by growth hormone of uridine incorporation in isolated thymocytes with age. Immunocytochemical studies reveal the location of the hormone along the membrane. The amount of the hormone bound by thymocytes, estimated by immunoenzymatic methods is 3- to 9-fold lower in thymocytes from 14-months old rats as compared to similar preparations from 4-week old rats. Thymocytes from both young and old rats are composed of subpopulations, one of which binds growth hormone. The proportion of the hormone binding cells is higher in thymocytes from young rats as compared to those from aged animals.     

The effect of acute and chronic insulin administration on insulin-like growth factor-I expression in the pituitary-intact and hypophysectomised rat

Summary Although growth hormone is known to be the main regulator of insulin-like growth factor-I, insulin has also been shown to play a role in regulating serum insulin-like growth factor I levels in diabetic animals. While this effect is thought to be due to correction of metabolic perturbations, some studies have suggest that insulin may have a direct effect on growth and/or insulin-like growth factor-I levels. We have examined the effects of acute and chronic insulin administration to non-diabetic, pituitary-intact and hypophysectomised rats. Rats were injected intraperitoneally with insulin as an acute bolus (10 U) or a chronic subcutanious infusion (low dose; 2.4 U/day, high dose; 12 U/day) over 5 days. Insulin-like growth factor-I mRNA was quantitated by Northern and slot blots of RNA from various tissues. A small (less than 2-fold) but significant increase (p<0.05) was seen in hepatic insulin-like growth factor-I mRNA abundance in pituitary-intact rats following acute insulin injection and chronic low dose insulin infusion. An increase in insulin-like growth factor-I mRNA levels was also seen in other tissues including diaphragm, lung, kidney and heart. A significant increase (p<0.05) in serum insulin-like growth factor-I levels was also observed 6 h after insulin injection. In contrast, in pituitary-intact rats which received high dose insulin infusion and were hypoglycaemic at the time of death, tissue levels of insulin-like growth factor-I mRNA were reduced compared to saline-treated control groups. Similarly in the hypophysectomised rats neither acute nor chronic insulin administration had any consistent effect on insulin-like growth factor-I mRNA abundance in any of the tissues examined. This data suggests that insulin has no direct effect in regulating insulin-like growth factor-I gene expression. The small effects demonstrable in pituitary-intact rats may result from a synergistic action of insulin with growth hormone or other pituitary factors.     

Decrease in the insulin of rabbit pancreas in late pregnancy

Summary Plasma insulin levels and extractable insulin of the pancreas of normal and pregnant rabbits have been studied. — The mean plasma insulin of non-pregnant controls was 25U/ml (range 18 to 33); extractable pancreas insulin was 3.56g/100 mg tissue (3.33 to 3.76). — The insulin level in the blood increases during late pregnancy to 56U/ml (range 37 to 81) and the extractable pancreatic insulin decreases to 1.17g/100 mg tissue (0.65 to 1.73). — The fine structure of B and A-cells has been studied in pregnancy: insulin stored in B granules decreases and the A-cells show definite signs of increased activity. — The above findings might be interpreted as suggesting that in late pregnancy an increased synthesis and secretion of glucagon augment the insulin secretory activity of the pancreas.

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Abnahme des Pancreas-Insulins beim Kaninchen während der fortgeschrittenen Schwangerschaft

Zusammenfassung Bei normalen und graviden Kaninchen wurden die Plasma-Insulinspiegel und das aus dem Pancreas extrahierbare Insulin gemessen. — Die mittleren Insulinspiegel der normalen Kontrolltiere lagen bei 25E/ml (zwischen 18–33), das Pankreasinsulin bei 3.56g/100 mg Gewebe (3.33–3.76). Die Seruminsulin-spiegel steigen während der späten Schwangerschafts-stadien auf 56E/ml (37–81) an und das extrahierbare Pancreas-Insulin nimmt auf 1.17G/100 mg Gewebe (0.65–1.73) ab. — Wir untersuchten die Feinstruktur der Alpha- und Beta-Zellen während der Schwangerschaft: Dabei nahm das in den Beta-Granula gespeicherte Insulin ab und die Alpha-Zellen zeigten eindeutige Zeichen gesteigerter Aktivität. Die oben skizzierten Befunde könnten daraufhin deuten, daß während der späten Schwanger-schaftsstadien eine gesteigerte Glucagon-Synthese und Sekretion die insulinsekretorische Aktivität der Bauchspeicheldrüse erhöht.

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Diminution de l'insuline dans le pancréas du lapin pendant la gestation avancée.

Résumé Le contenu en insuline du plasma de lapins normaux et en gestation a été étudié par rapport à la quantité d'insuline qui pouvait être extraite de leurs pancréas. — Le contenu plasmatique moyen en insuline des lapins normaux, utilisés comme témoins, était de 25U/ml (entre 18 et 33) et l'insuline extraite de leurs pancréas était de 3.56g/100 mg de tissu (entre 3.33 et 3.76). — Lorsque la gestation était à un stade avancé, le contenu en insuline dans le sang s'élevait à 56U/ml (entre 37 et 81), alors que l'insuline extraite du pancréas tombait à 1.17g/100 mg de tissu (entre 0.65 et 1.73). — L'ultrastructure des cellules A et B pendant la gestation a également été étudiée. La teneur des granules B en insuline diminue et les cellules A présentent des signes évidents d'une haute activité. — Les observations précédentes suggéreraient que lors de la gestation avancée, une synthèse et une sécrétion de glucagon accrues augmentent l'activité sécrétrice du pancréas en insuline.

     

Increased intestinal absorption of insulin in a micellar solution: Water-in-oil-in-water insulin micelles

Summary Water-in-oil-in-water (W/O/W) insulin micelles were prepared, and the possibility of insulin absorption in a micellar form was examined. In this preparation, insulin was trapped in oil droplets of oleic acid in glyceryl-α-monooleate. (1) W/O/W insulin micelles were absorbed from the ligated jejunal loop of rabbits to the order of 12.3 to 58.5% of the dose given (10 U/kg body weight) during the 3-h experimental period. (2) Alloxan diabetic rats were treated with intrajejunal administration of W/O/W insulin micelles at a dosage of either 25 or 50 U/100 g body weight, three times daily for as longs as 14 days. During treatment, a significant reduction in the daily excretion of urinary glucose was observed, concomitant with a decrease in fasting blood glucose. Quantitative estimates suggested that the effectiveness of 25 U/100 g of intrajejunal W/O/W insulin micelles was comparable to that of regular insulin at a dosage of 1 U/100 g i.m. These results would indicate that W/O/W insulin micelles, when given enterally, are more effective in lowering blood and urinary glucose levels than W/O/W insulin emulsions in which insulin was trapped in oil droplets of triglyceride.     

A comparison of the activity and disposal of semi-synthetic human insulin and porcine insulin in normal man by the glucose clamp technique

Summary The activity of semi-synthetic human insulin has been compared with porcine insulin in normal man using an euglycaemic glucose clamp at two different insulin infusion rates. In a two hour infusion insulin levels plateaued for both types of insulin at 44–48 mU/l (infusion rate 0.05 U kg body weight^-1 h^-1) and 22–24 mU/l (0.02 U kg^-1 h^-1), giving identical metabolic clearance rates. The glucose delivery required to maintain euglycaemia in the second hour of insulin infusion was 13.9±2.1 g (mean±SEM) and 14.7±1.5 g (NS) at the lower dose for porcine and human insulins respectively, and 27.1±2.5 and 28.0±2.9 g (NS) at the higher dose. The potency ratio for human, compared with porcine, insulin was 1.06 ±0.12. No differences were seen in the time of onset of action of the insulins, serum half-life or distribution space. The responses of blood lactate, pyruvate, alanine, glycerol and 3-hydroxybutyrate were identical. No untoward reactions occurred. The activity and disposal of this semi-synthetic human insulin are indistinguishable from porcine insulin in normal euglycaemic man.     

Metabolic changes by acute insulin deficiency in rabbits injected with anti-insulin serum

Summary Acute insulin deficiency was produced in rabbits treated with anti-insulin guinea pig serum. The changes in the levels of blood sugar, free fatty acids, aceto-acetate, SGOT, SGPT, liver glutamicoxaloacetic and glutamic-pyruvic transaminases, and liver lactate dehydrogenase were examined. A significant increase of the blood glucose level and the free fatty acids as well as glycosuria was observed. The other examined parameters remained unchanged. The results confirm the statement that acute insulin deficiency causes a prompt impairment of glucose and fat metabolism.

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Zusammenfassung Ein akuter Insulin-Mangelzustand wurde in mit anti-Insulinserum vom Meerschweinchen behandelten Kaninchen hervorgerufen. Es wurden die Veraenderungen des Blutzuckerspiegels, der freien Fettsaeuren, des Azetoazetats, der SGOT, SGPT, der Glutaminsaeure-Oxalessigsaeure-Transaminase und der Glutaminsaeure-Pyruvat-Transaminase, sowie der LDH in der Leber untersucht. Es wurde eine signifikante Steigerung des Blutzuckers, der freien Fettsaeuren und auch des Harnzuckers festgestellt. Die anderen untersuchten Parameter blieben unveraendert. Die Resultate bestaetigen den Tatbestand, dass der akute Insulinmangelzustand eine sofortige Stoerung des Kohlenhydrat- sowie des Fettstoffwechsels ausloest.

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Resumen Una carencia insulínica aguda ha sido provocada en los conejos tratados con suero de cobayo anti-insulina. Han sido estudiadas las variaciones en los niveles de la glucemia, de los ácidos grasos libres, del acetoacetato, de la SGOT, de la SGPT, de las transaminasas glutámico-oxaloacética y glutámico-pirúvica hepáticas y de la láctico-dehidrogenasa hepática. Ha sido puesto de manifiesto un aumento significativo de la glucemia y de los ácidos grasos libres, y también de la glucosuria. Los otros parámetros examinados han quedado invariados. Los resultados ratifican el hecho de que la carencia aguda de insulina provoca una alteración inmediata en el metabolismo de los glúcidos y de los lípidos.

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Resume On a provoqué une carence en insuline aïgue chez des lapins traités au sérum de cobaye antiinsuline. On a étudié les variations de taux de glycémie, des acides gras libres, d'acéto-acétate, de SGOT, de SGPT, des transaminases glutamique oxalacétique et glutamico-pyruvique hépatiques ainsi que de la déshydrogénase lactique hépatique. On a observé une augmentation significative de la glycémie et des acides gras libres, et même de la glycosurie. Les autres paramètres étudiés sont restés inchangés. Les résultats confirment le fait que la carence aïgue en insuline provoque une perturbation immédiate du métabolisme des glucides et des lipides.

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Riassunto Una carenza insulinica acuta è stata provocata nei conigli trattati con siero di cavia anti-insulina. Sono state studiate le variazioni del livello della glicemia, degli acidi grassi liberi, dell'acetoacetato, della SGOT, della SGPT, delle transaminasi glutammico-ossalacetica e glutammico-piruvica epatiche e della lattico deidrogenasi epatica. E' stato rilevato un aumento significativo della glicemia e degli acidi grassi liberi, ed anche della glicosuria. Gli altri parametri esaminati sono rimasti invariati. I risultati confermano il fatto che la carenza acuta di insulina provoca un disturbo immediato del metabolismo glucidico e lipidico.

     

Effect of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with Type 1 (insulin-dependent) diabetes mellitus

Summary These studies were undertaken to assess the influence of storage temperature of insulin vials on pharmacokinetics and pharmacodynamics of a mixture of lente insulin (Monotard HM) and regular insulin (Actrapid HM) injected subcutaneously. Seven subjects with Type 1 (insulin-dependent) diabetes mellitus were studied twice after overnight normalization of plasma glucose. A mixture of lente insulin (0.22 U/kg) and regular insulin (0.11 U/kg) was prepared from insulin vials kept either refrigerated (4 °C) or at room temperature (18 °C) and injected subcutaneoulsy (abdomen). Euglycaemia was maintained for the following 16 h by glucose infusion at variable rate. With refrigerated insulin, the plasma free insulin peak was greater (53±5 versus 45±6 mU/l) and occurred earlier (2.5±0.2 versus 6±0.3 h), and the glucose infusion rate showed a greater (16.5±1.2 versus 14.5±0.9 mol·kg^–1·min^–1) and earlier peak (3.2±0.2 versus 6±0.4 h) as compared to that occurring with the non-refrigerated insulin (p<0.05). However, 6 h after insulin injection, both plasma free insulin and glucose infusion rate were 30% lower with the mixture of refrigerated as compared to that of non-refrigerated insulin (p<0.05). In contrast, when NPH-insulin (Protaphane HM) was mixed with regular insulin and injected in 4 out of the 7 diabetic patients, the storage temperature of insulin vials had no effect on the pharmacokinetics and pharmacodynamics of the mixture. Thus, the storage temperature of insulin vials profoundly influences the effects of the mixture lente/regular insulin, but does not affect the pharmacokinetics and pharmacodynamics of the mixture NPH/regular insulin.     

Growth hormone regulation of DNA replication,but not insulin production,is partly mediated by somatomedin-C/insulin-like growth factor I in isolated pancreatic islets from adult rats

Summary We have investigated whether the previously demonstrated stimulatory actions of growth hormone on DNA synthesis and (pro)insulin biosynthesis and release of isolated adult rat islets of Langerhans are mediated by an autocrine release of somatomedin-C/insulin-like growth factor I (SM-C/IGF I). In medium containing 1% fetal calf serum, the presence of 16.7 mmol/l glucose, or 2.7 mmol/l glucose supplemented with a concentrate of essential amino acids, caused a significant increase in ³H-thymidine incorporation and insulin release compared to 2.7 mmol/l glucose alone but no increase in SM-C/IGFI release. Further supplementation with 1 g/ml growth hormone increased ³H-thymidine incorporation and SM-C/IGF I release within all groups, and insulin release in the 16.7 mmol/l glucose and 2.7 mmol/l plus amino acid groups. The ability of growth hormone to increase ³H-thymidine incorporation in the presence of 16.7 mmol/l glucose, but not its action on insulin release, was partly inhibited by a monoclonal antibody against SM-C/IGF I (control cultures 100%; growth hormone alone 261±27%, mean±SEM; growth hormone+anti-SM-C/IGFI 179±21%; p<0.05, n=18). Growth hormone, but not 100 ng/ml SM-C/IGF I, increased insulin biosynthesis assessed as immunoprecipitable ³H-labelled insulin by 45%, but this was accompanied by a similar increase in overall protein synthesis. Similarly growth hormone, but not SM-C/IGF I caused a 75% increase in glucose oxidation by islets. Both growth hormone and SM-C/IGF I failed to increase the cellular uptake of -aminoisobutyric acid or 3-O-methyl glucose over a 90 min period. The results suggest that while the stimulatory effect of growth hormone on islet cell insulin biosynthesis and release, glucose oxidation and general protein synthesis is probably direct, its action on B-cell replication is partly mediated by a paracrine release of SM-C/IGF I. This may provide a mechanism for increasing B-cell mass and consequently total insulin output during times of increased metabolic demands on insulin secretion.     

Serum levels of insulin-like growth factor (IGF) I, II and IGF binding protein in diabetic adolescents treated with continuous subcutaneous insulin infusion

IGF-I and IGF-II as well as the low molecular type of IGF binding protein (IGFPB) were determined in serum from 11 adolescents with insulin-dependent diabetes mellitus (IDDM) during a cross-over study with conventional and continuous subcutaneous insulin infusion (CIT and CSII) therapy. At the onset of the study the mean IGF-I level, 127 +/- 15 ng ml-1, was significantly decreased (P less than 0.001) in comparison with age-matched controls, whereas the mean IGF-II level, 1024 +/- 48 ng ml-1, was increased. A significant correlation (r = 0.70, P less than 0.05) was found between IGF-II and HbA1c levels. The mean morning level of IGFBP, 75 +/- 17 ng ml-1, at the onset of the study, was increased threefold above that in age-matched controls (P less than 0.01). There was a significant correlation between IGFBP and blood glucose values (r = 0.66, P less than 0.05). During CSII therapy a significant decrease (P less than 0.05) of the IGFBP levels was seen in subjects with a decrease in glucose levels, whereas no change was observed in IGF levels. The findings of elevated IGF-II and IGFBP levels and correlations between IGFBP and blood glucose concentration as well as IGF-II and HbA1c levels in adolescents with IDDM indicate that both IGF-II and IGFBP reflect a deranged metabolism caused by inadequate insulin administration.     

The role of glucose and insulin in the metabolic regulation of growth hormone secretion

The exact physiological basis for the suppression of growth hormone secretion by oral glucose intake remains unknown, despite the widespread use of the oral glucose tolerance test in endocrinology. Lack of growth hormone suppression by glucose occurs in about a third of patients with acromegaly, as well as in other disorders. It is currently known that the secretion of growth hormone is affected by various factors, such as age, gender, body mass index, and the redistribution of adipose tissue. There is also evidence of the impact of overeating as well as being overweight on the secretion of growth hormone. It is known that both of these conditions are associated with hyperinsulinemia, which determines the possibility of its predominant role in suppressing the secretion of growth hormone. The purpose of this review is to discuss the accumulated data on the isolated effects of hyperglycemia and hyperinsulinemia on growth hormone secretion, as well as other metabolic regulators and conditions affecting its signaling. Understanding of the pathophysiological basis of these mechanisms is essential for further research of the role of glucose and insulin in the metabolic regulation of growth hormone secretion. However, the studies in animal models are complicated by interspecific differences in the response of growth hormone to glucose loading, and the only possible available model in healthy people may be the hyperinsulinemic euglycemic clamp.     

Melatonin–insulin interactions in patients with metabolic syndrome

Abstract:  Metabolic syndrome (MS) as a group of risk factors is strongly associated with diabetes type 2 and cardiovascular disease. Insulin resistance plays a key role in the pathogenesis of MS. Recent studies have shown that melatonin may influence insulin secretion and glucose homeostasis. Therefore, the present study analyzed the relationships between the melatonin and the insulin in patients with MS and controls. The melatonin rhythm, insulin and lipid levels were studied in 40 subjects (21 patients and 19 controls) in reproductive age. The night melatonin–insulin ratio was correlated negatively with low-density lipoprotein cholesterol ( r  = −0.370, p  = 0.024) and total cholesterol ( r  = −0.348, p  = 0.030), and positively with high-density lipoprotein cholesterol levels ( r  = +0.414, p  = 0.010). Night-time melatonin levels were related to night-time insulin concentrations ( r  = +0.313, p  = 0.049). The correlation was pronounced in patients with MS ( r  = +0.640, p  = 0.002), but did not reach statistical significance in controls ( P  > 0.05). In the patients with MS unlike the controls the night–day melatonin difference (%) correlated negatively with the fasting glucose ( r  = −0.494, p  = 0.023) and positively to daily insulin ( r  = +0.536, p  = 0.012). Our results show that melatonin–insulin interactions may exist in patients with MS, as well as relationships between melatonin–insulin ratio and the lipid profile. Pineal disturbances could influence the pathogenesis and the phenotype variations of the MS. Larger studies are needed to confirm or reject this hypothesis and to clarify the role of the melatonin in the metabolic disturbances.