β-lipotropin increases plasma insulin immunoreactivity

Porcine β-lipotropin increased plasma insulin immunoreactivity and glycerol levels in the rabbit. These effects could not be reversed by the opioid antagonist naloxone suggesting that these in vivo effects are not mediated by an opiate receptor. Since serum glucose concentrations remained unaffected despite the increase of insulin a simultaneous release of glucagon is suggested. We conclude that β-lipotropin might be of physiological importance for the regulation of glucose metabolism.     

Reducing plasma membrane sphingomyelin increases insulin sensitivity

It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency- or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity.     

Leptin acts peripherally to limit meal-induced increases in plasma insulin concentrations in mice: a brief communication

Leptin inhibits food intake and lowers plasma insulin concentrations. This study was designed to determine whether leptin acts independent of food-intake regulation to affect meal-induced increases in plasma insulin concentrations. Leptin-deficient, Lep(ob)/Lep(ob) mice were administered 1 microg leptin intracerebroventricularly (ICV) or intraperitoneally. Food intake and plasma insulin concentrations of mice administered leptin ICV before a meal were lower, as expected, than were intakes and plasma insulin concentrations of mice administered vehicle ICV. However when food intake was controlled, meal-induced increases in plasma insulin were unaffected by ICV administration of leptin. Intraperitoneal administration of 1 microg leptin before a meal lowered meal-induced increases in plasma insulin concentrations without influencing the size of the meal. We conclude that plasma leptin concentrations can affect meal-induced insulin secretion independent of the central nervous system actions of leptin associated with food-intake regulation.     

Acute stress increases plasma concentrations of atrial natriuretic peptides

5 min exposure of inbred Maudsley Reactive male rats to intermittent foot-shock resulted in an approximate doubling of plasma atrial natriuretic peptides ANP (Control grp mean = 62.12 +/- 8.74; Stressed grp mean = 128.70 +/- 26.63 pg/ml) and 25 min exposure resulted in a three-fold increase (Stressed grp mean = 187.88 +/- 39.24 pg/ml). In the second experiment exposure of genetically heterogeneous Wistar male rats to 15 min of intermittent foot-shock produced a 10-fold increase in plasma ANP (Control grp mean = 45.76 +/- 6.05; Stressed grp mean = 471.20 +/- 58.49 pg/ml). The magnitude of the increase in plasma ANP produced by acute stress is as large as the increase caused by volume expansion and administration of various pharmacological agents and therefore delineation of biological role of ANP must take account of its potential role as a stress-hormone.     

Roles of insulin resistance and obesity in regulation of plasma insulin concentrations

Plasma glucose, insulin, and C-peptide concentrations were determined in response to graded infusions of glucose, and insulin secretion rates were calculated over each sampling period. Measurements were also made of insulin clearance, resistance to insulin-mediated glucose, uptake, and the plasma glucose, insulin, and C-peptide concentrations at hourly intervals from 8:00 AM to 4:00 PM in response to breakfast and lunch. Plasma glucose, insulin, and C-peptide concentrations were significantly (P < 0.01) higher in obese women in response to the graded intravenous glucose infusion, associated with a 40% (P < 0.005) greater insulin secretory response. Degree of insulin resistance correlated positively (P < 0.05) with the increase in insulin secretion rate in both nonobese (r = 0.52) and obese (r = 0.58) groups and inversely (P < 0.05) with the decrease in insulin clearance in obese (r = -0.46) and nonobese (r = -0.39) individuals. Weight loss was associated with significantly lower plasma glucose, insulin, and C-peptide concentrations in response to graded glucose infusions and in day-long insulin concentrations. Neither insulin resistance nor the insulin secretory response changed after weight loss, whereas there was a significant increase in the rate of insulin clearance during the glucose infusion. It is concluded that 1) obesity is associated with a shift to the left in the glucose-stimulated insulin secretory dose-response curve as well as a decrease in insulin clearance and 2) changes in insulin secretion and insulin clearance in obese women are more a function of insulin resistance than obesity.     

Oscillations of circulating plasma insulin concentrations in the rat

In previous studies, we found that insulin is secreted in a pulsatile fashion in vitro in isolated rat pancreatic islets. This study evaluated whether similar plasma insulin fluctuations occur in the rat in vivo. Freely moving rats were implanted with a chronic jugular catheter and serial blood samples were obtained 48-72 hrs post surgery. Blood was sampled at 3 min intervals for 60 mins with volume replacement using a red cell preparation. Plasma insulin concentrations were observed to fluctuate around a mean of 10.6 +/- 1.1 uU/ml, with an amplitude of 4.7 +/- 0.5 uU/ml and a period of 13.3 +/- 1 mins (n = 6). This was similar to the cycling observed in isolated islets at similar glucose concentrations. Sampling during the dark phase of the light-dark cycle in the rat was associated with an increase in the mean plasma level, amplitude and period of insulin oscillations compared with values obtained during the light phase (n = 3). These data are the first in vivo demonstration of oscillatory circulating insulin concentrations in the rat and show that the pulsatility in this species is similar to that observed in other mammals including man. We conclude that the chronically catheterised rat is a useful model for the evaluation of oscillating insulin concentrations in vivo, and may provide interesting insights by comparison with in vitro data in the same species.     

Moderate physical training increases brain insulin concentrations in experimental diabetic rats

Insulin is an important modulator of growth and metabolic function in the central nervous system. The aim of this study was to investigate the influence of swimming physical training (at 32 degrees +/- 1 degree C, 1 hr/day, 5 days/week, with an overload equivalent to 5% of the body weight, for 4 weeks) on brain insulin concentrations in alloxan induced type 1 diabetic rats. Training attenuated hyperglycemia but had no effect on insulinemia in diabetic rats. Hematocrit and blood albumin values remained without changes. Brain insulin did not change in diabetic rats. However, physical training increased the concentration in both control and diabetic rats. It is concluded that in the present experimental conditions, diabetes had no influence on brain insulin, however moderate physical training increased the hormone in both control and diabetic animals.     

A rapid radioimmunoassay for determining plasma concentrations of LH in dogs

A heterologous dog LH radioimmunoassay was modified to provide accurate results for LH concentrations in blood plasma of dogs within 3-4 h. This assay utilizes radioiodinated ovine LH (LER-1056-C2), antiserum against ovine LH (GDN-15) at a final dilution of 1:48,000 and dog LH (LER-1685-1) as standard. A 60-min incubation, including a 30-min delay in the addition of tracer, was carried out at 37 degrees C. The free and antibody-bound hormone were separated by addition of a Micro Sepharose bead suspension containing anti-gamma-globulin, followed by incubation at room temperature for 30 min. The minimum detectable concentration in this assay, calculated from the precision profile, was 1.5 micrograms/l. The amount of dog LH needed to cause 50% reduction of the initial binding was 1.57 +/- 0.13 ng/tube (15.7 micrograms/l for 100-microliters samples). Daily blood samples were collected in heparinized tubes from the cephalic vein of 5 pointer and 7 beagle bitches from the onset of pro-oestrus until 3-4 days after either the last mating or artificial insemination with frozen semen or until metoestrus. Samples were assayed for LH content by the short and normal incubations as well as for progesterone and oestradiol-17 beta content. In all bitches plasma concentrations of progesterone increased rapidly within 1 week after the LH peak which indicates that they had ovulated. Comparison of the short (1.5 h) with the normal (24 h) incubation system resulted in a regression equation: y = 1.0 + 0.7 x (r = 0.95, n = 153 samples).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of glucose and insulin concentrations in macaque sera and plasma

The glucose and insulin concentrations in blood from Macaca nigra and M. mulatta were determined after an overnight fast and 3 min after a glucose infusion. Blood treatment included clotting for serum or additions of fluoride, heparin, or heparin plus fluoride. Samples were centrifuged at 0 min or after being held at 22 degrees C for 20, 40, or 60 min. Levels of glucose and insulin generally agreed within 1 SD at all times examined for samples removed at 0 or 3 min.     

Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects.

Metformin has been widely used in clinical type 2 diabetes treatment and prevention. The present study was designed to explore the effect on people with a sedentary lifestyle at therapeutic doses. Twenty-two physically-inactive volunteers with normal glucose tolerance were studied. Escalating doses of metformin in low-dose (250 mg), intermediate-dose (500 mg), and high-dose (750 mg) treatment three times per day were administrated into each subject for a three-week treatment period. Fasting plasma glucose, A1C, HOMA-IR for insulin resistance, lipid profile, and plasma beta-endorphin-like immunoreactivity (BER) were measured before treatment and weekly at the end of each dosing period. Metformin significantly reduced fasting plasma glucose and HOMA-IR in healthy humans after receiving this treatment at therapeutic doses including low-dose (5 %, 17 %), intermediate-dose (6 %, 25 %) and high-dose treatment (6 %, 21 %). Plasma BER was also increased from 135.46 +/- 61.73 pg/ml to 137.52 +/- 66.11 pg/ml by low-dosing (p = 0.39), to 139.17 +/- 64.08 pg/ml by intermediate-dosing (p = 0.32), and to 149.59 +/- 63.32 pg/ml by high-dosing (p < 0.05). Also, serum cholesterol decreased significantly using metformin at therapeutic doses including low-dose (4 %), intermediate-dose (8 %) and high-dose treatment (7 %). However, metformin failed to modify levels of serum HDL-cholesterol and C-reactive protein (CRP) in healthy subjects. Also, the reduction of serum cholesterol by metformin did not correlate to the increase in insulin sensitivity. In conclusion, metformin causes a significant parallel increase in insulin sensitivity and plasma beta-endorphin level in human subjects.     

Loss of mPer2 increases plasma insulin levels by enhanced glucose-stimulated insulin secretion and impaired insulin clearance in mice

The existence of peripheral oscillators has been shown, and they are critically important for organizing the metabolism of the whole body. Here we show that mice deficient in mPer2 markedly increase circulatory levels of insulin compared with wild type mice. Insulin secretion was more effectively stimulated by glucose, and alloxan, a glucose analogue, induced more severe hyperglycemia in mPer2-deficient mice. Hepatic insulin degrading enzyme (Ide) displayed an obvious day and night rhythm, which was impaired in mPer2-deficient mice, leading to a decrease in insulin clearance. Deficiency in mPer2 caused increased Clock expression and decreased expression of Mkp1 and Ide1, possibly underlying the observed phenotypes and suggesting that mPer2 plays a role in regulation of circulating insulin levels.     

Alpha-melanocyte stimulating hormone increases plasma levels of glucagon and insulin in rabbits

Intravenous injections of 25 and 2.5 micrograms alpha-melanocyte stimulating hormone (alpha-MSH) increased plasma levels of glucagon, insulin and free fatty acids in fasted and fed rabbits. 45 micrograms beta-melanocyte stimulating hormone (beta-MSH) had similar effects, whereas 22 micrograms gamma-2-melanocyte stimulating hormone (gamma-MSH) was inactive. The alpha-MSH-induced increases in the plasma levels of glucagon, insulin and free fatty acids were not inhibited by alpha- or beta-adrenergic blocking drugs. The alpha-MSH-induced increases in the plasma levels of insulin were, however, augmented by phentolamine (an alpha-adrenergic receptor blocking drug). The plasma levels of glucose were increased by 25 micrograms alpha-MSH in fed rabbits, only, and were decreased by alpha-MSH during alpha-receptor blockade. The acute in vivo effects of alpha-MSH and beta-MSH on the plasma levels of glucagon, insulin and free fatty acids were rather similar to those previously reported for corticotropin (ACTH). It is possible that the 4-10 ACTH sequence, present in alpha-MSH, beta-MSH and ACTH, but not in gamma-MSH, is a message sequence for the observed effects. However, ORG 2766, a 4-9 ACTH analogue, was inactive. The mechanism by which alpha-MSH increased the plasma levels of glucagon and insulin in rabbits remains to be determined. It is possible, that the effects were mediated by both a central nervous action and a direct action on the endocrine pancreas.     

The effect of porcine Orexin A on insulin plasma concentrations in pigs

Orexin A is a member of a wider family of orexigenic neuropeptides that have been recently discovered. They are produced by a small group of neurons located in the area of the brain, round the nucleus of the fornix (posterior hypothalamus), in the paraventricular nucleus, the dorsomedial nucleus, the ventromedial hypothalamus, as well as in the lateral hypothalamic region; these are sites that are known to be involved in regulating feeding in mammals. Orexin A is a neuropeptide, which is involved in appetite regulation and energy homeostasis. An intracerebroventricular (i.c.v.) injection of Orexin A in the brain of rats causes an impressive increase in food consumption. In addition, a subcutaneous or intravenous (IV) injection of Orexin A produces changes on insulin plasma concentrations in rats. Recent research suggests that Orexin A is also involved in regulating many other physiological functions. In this study, we examined the potential effects of the central administration of porcine Orexin A on insulin plasma concentrations in pigs, and whether these changes are connected with the possible effect of the neuropeptide on the enteroinsular axis.     

Stimulation of hepatic mitochondrial calcium transport by elevated plasma insulin concentrations.

The effect of insulin (injected intraperitoneally) on the transport of Ca2+ by hepatic mitochondria from rats was investigated. 2. Elevated concentrations of plasma insulin within the physiological range (10-100muunits/ml) stimulate the initial rate of Ca2+ transport into mitochondria at 4 degrees C by about 75% and prolong by approx. tenfold the time for which the mitochondria retain the accumulated Ca2+. 3. The prolonged retention of Ca2+ is observed under the conditions where hypoglycaemia is significantly decreased by the simultaneous injection of glucose and insulin. 4. A good correlation is observed between the effects on Ca2+ transport and the decrease in blood glucose concentration when the amount of insulin injected was varied. 5. The effects of insulin on mitochondrial Ca2+ transport are apparent at about 30 min after the injection, and are inhibited by cycloheximide. 6. There is little change in mitochondrial energy transduction after the administration of insulin. 7. The results are briefly discussed in relation to the mechanisms of Ca2+ transport across the inner mitochondrial membrane and the role of mitochondria in modifying intracellular Ca2+ concentrations with reference to the mechanism(s) by which insulin affects cellular metabolism.