Effect of a zinc phosphate suspension of a long-acting somatostatin analog on postprandial plasma glucose, triglyceride and glucagon concentrations in alloxan diabetic dogs

The effects of a zinc phosphate suspension of a long-acting, reportedly selective somatostatin analog, Des-Ala1,Gly2 [His4,5,D-Try]-somatostatin (100 micrograms/kg) on postprandial plasma glucose, glucagon, xylose and triglyceride levels were evaluated in alloxan diabetic dogs. Compared to the analog in aqueous solution, the zinc phosphate suspension had a more gradual onset of action in suppressing plasma glucose and xylose levels but a similar onset of action on suppression of plasma triglyceride and glucagon responses. On all these responses, the zinc suspension had a duration of action (greater than 6 hrs) at least three times as long as the aqueous solution. We conclude that such a somatostatin analog in zinc phosphate suspension may have a sufficient duration of action to be useful as an adjunct to insulin in the treatment of diabetes mellitus.     

Adiponectin decreases plasma glucose and improves insulin sensitivity in diabetic Swine

To investigate the effects of recombinant human adiponectin on the metabolism of diabeticswine induced by feeding a high-fat/high-sucrose diet (HFSD),diabetic animal models were constructedby feeding swine with HFSD for 6 months.The effects of recombinant adiponectin were assessed bydetecting the change of plasma glucose levels by commercially available enzymatic method test kits andevaluating the insulin sensitivity by oral glucose tolerance test (OGTT). About 1.5 g purified recombinantadiponectin was produced using a 15-liter fermenter.A single injection of purified recombinant humanadiponectin to diabetic swine led to a 2- to 3-fold elevation in circulating adiponectin,which triggered atransient decrease in basal glucose level (P<0.05).This effect on glucose was not associated with anincrease in insulin level.Moreover,after adiponectin injection,swine also showed improved insulin sensitivitycompared with the control (P<0.05).Adiponectin might have the potential to be a glucose-lowering agentfor metabolic disease.Adiponectin as a potent insulin enhancer linking adipose tissue and glucose metabolismcould be useful to treat insulin resistance.     

Shikonin increases glucose uptake in skeletal muscle cells and improves plasma glucose levels in diabetic Goto-Kakizaki rats

Background

There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells.

Methodology/Principal Findings

Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium.

Conclusions/Significance

Shikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.     

The effect of glucagon antibodies on plasma glucose and insulin levels

The actions of glucagon and insulin are interrelated as the two hormones have opposite physiological effects and the secretion of insulin is regulated, at least in part, by the level of glucagon. We have found that rabbits which are immunized against glucagon have normal fasting levels of blood glucose but a lowered level of insulin. These rabbits are also able to rapidly utilize intravenously injected glucose butwith a much lower plasma level of insulin. These results demonstrate that in the presence of glucagon antibodies, normal blood sugar levels can be maintained with a reduced supply of insulin. It is suggested that this finding may be useful in the treatment of diabetes.     

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats (r = 0.44, P less than 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 micrograms/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 +/- 0.1 to 6.8 +/- 0.2 mM (P less than 0.05), and glucagon from 179 +/- 12 to 259 +/- 32 pg/ml (P less than 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 microgram/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to greater than 18 mM and glucagon to 249 +/- 25 pg/ml (P less than 0.05). In these rats, 10 micrograms/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 +/- 248 pg/ml) and also increased plasma ACTH. A specific oxytocin analog, Thr4,Gly7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 +/- 250 pg/ml), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15-180 min later. Plasma glucose levels dropped to less than 2.5 mM by 15 min. Oxytocin levels increased by 150-200% at 30 min; however, the effect was not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Catecholamine-induced changes in plasma glucose, glucagon and insulin in rabbits: effects of somatostatin.

The present study was conducted to determine if glucagon release is involved in the hyperglycemic response to epinephrine and isoproterenol in the fasted and fed, unanesthetized rabbit. Epinephrine produced dose-related increases in plasma glucose and glucagon levels in fed and fasted rabbits whereas isoprotereol produced modest hyperglycemia without hyperglucagonemia. Infusion of somatostatin suppressed epinephrine-induced glucagon release and this was correlated with a 50% reduction in the hyperglycemic response. These data suggest that epinephrine-induced glucagon release is the primary reason for the difference in hyperglycemic activity between epinephrine and isoproterenol in the unanesthetized rabbit.     

Effect of pinealectomy on plasma glucose, insulin and glucagon levels in the rat

In an attempt to know the role of the pineal gland on glucose homeostasis, the blood plasma concentrations of glucose, insulin and glucagon under basal conditions or after the administration of nutrients were studied in the jugular vein of conscious pinealectomized (Pn), melatonin-treated pinealectomized (Pn + Mel) and control (C) rats. Glucose levels were smaller in C than in Pn rats, while immunoreactive insulin (IRI) concentrations were significantly greater in C than in Pn rats. Contrary to this, immunoreactive glucagon (IRG) levels were significantly greater in Pn than in C animals. Melatonin treatment of Pn rats induces an increase of IRI concentrations and a reduction in IRG levels. Similar changes were obtained when hormonal determinations were carried out in portal blood plasma. Although ether anesthesia increases circulating glucagon levels in the porta and cava veins, the qualitative changes of plasma insulin and glucagon in Pn and Pn + Mel were similar to those found in conscious rats. To determine the effects of nutrients on pancreatic hormone release, intravenous arginine or oral glucose were administered to the animals of the three experimental groups. In C rats, both glucose and IRI levels reached a peak 30 minutes after glucose ingestion, decreasing thereafter. However, in Pn rats a glucose intolerance was observed, with maximum glucose and insulin concentrations at 60 minutes, while in Pn + Mel animals, glucose and IRI concentrations were in between the data obtained with the other two groups. Furthermore, glucose ingestion induced a significant reduction of IRG levels in all the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pro-opiomelanocortin-derived peptides on plasma levels of glucagon, insulin and glucose

Pro-opiomelanocortin (POMC) is a prohormone for several peptides including corticotropin, melanocyte stimulating hormones and beta-endorphin. POMC-derived peptides have been demonstrated in many tissues, including the hypothalamus and the endocrine pancreas, which play important roles in the control of plasma levels of glucagon, insulin and glucose. This article reviews the present knowledge concerning in vitro and in vivo effects of POMC-derived peptides on glucagon, insulin and glucose levels involving several possible mechanisms: direct effects on the endocrine pancreas (including endocrine, paracrine and peptidergic regulation) and glucose production, and indirect effects involving the hypothalamus, the autonomic nervous system and the adrenal gland.     

Oxytocin decreases plasma levels of thyroid-stimulating hormone and thyroid hormones in rats

Oxytocin (OXT) administered to rats induces several long-lasting physiological and metabolic effects. The aim of the present study was to investigate the effects of oxytocin treatment on plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3). For this purpose, oxytocin or NaCl was administered intracerebroventricularly (i.c.v.) (0.3 micro g) or subcutaneously (s.c.) (1 mg/kg) once a day for 5 days to male rats. Five or ten days after the last injection, rats were decapitated, blood was collected and hormone levels were analyzed by fluoroimmunoassay. The oxytocin treatment i.c.v. decreased plasma levels of TSH (p<0.05), fT3 (p<0.01) and fT4 (p<0.05) when measured at day 5 after oxytocin treatment, whereas the effect was abolished when measured at day 10. Oxytocin treatment s.c. did not affect plasma levels of TSH, fT3 or fT4. Thus, the effect seems to have been mediated within the central nervous system, and TSH and the thyroid hormones may be involved in some of the metabolic effects in response to oxytocin.     

Response of plasma and retinal somatostatin to insulin-induced hypoglycemia in diabetic and control rats

Changes in plasmatic levels and retinal content of somatostatin after insulin-induced hypoglycemia were investigated in three different groups of animals: Control group (C), Diabetic untreated group (D); and, Insulin-treated diabetic group (DI). In addition, another group of animals, not submitted to hypoglycemia, was used as control reference of retinal prehypoglycemic content of somatostatin (group B). Plasmatic basal levels of somatostatin were slightly higher in group DI, and significantly higher in group C, whereas they did not show any differences in group D and DI after hypoglycemia, being significantly higher in group C. The somatostatin retinal content is similar in animals not subjected to hypoglycemia and in the C and DI groups after hypoglycemia, where the rats of the D groups showed significantly higher values than the remainder of the experimental groups, an effect that is also evident in nontreated diabetic animals, even if they are not subjected to hypoglycemia, Summing up, the plasmatic somatostatin response to insulin-induced hypoglycemia is impaired in diabetic rats. Retinal somatostatin content is unchanged after hypoglycemia.     

Shinrin-yoku (forest-air bathing and walking) effectively decreases blood glucose levels in diabetic patients

 The influence of ”shinrin-yoku” (forest-air bathing and walking) on blood glucose levels in diabetic patients was examined. Eighty-seven (29 male and 58 female) non-insulin-dependent diabetic patients [61 (SEM 1) years old] participated in the present study. Shinrin-yoku was performed nine times over a period of 6 years. The patients were divided into two parties. They then walked in the forest for 3 km or 6 km according to their physical ability and/or the existence of diabetic complications. The mean blood glucose level after forest walking changed from 179 (SEM 4) mg · 100 ml^–1 to 108 (SEM 2) mg · 100 ml^–1 (P<0.0001). The level of glycated haemoglobin A_1c also decreased from 6.9 (SEM 0.2)% (before the first shinrin-yoku) to 6.5 (SEM 0.1)% (after the last shinrin-yoku; P<0.05). Blood glucose values declined by 74 (SEM 9) mg · 100 ml^–1 and 70 (SEM 4) mg · 100 ml^–1 after short- and long-distance walking respectively. There was no significant difference between these values. Since the forest environment causes changes in hormonal secretion and autonomic nervous functions, it is presumed that, in addition to the increased calorie consumption and improved insulin sensitivity, walking in a forest environment has other beneficial effects in decreasing blood glucose levels. Received: 9 July 1997/Accepted: 20 October 1997     

Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides

The present study has indicated that significant shifts in plasma, urinary, and tissue taurine and in non-taurine dialyzable amines occur in the STZ-induced diabetic rat, especially in the kidney. Taurine administration at relatively low dosage ameliorated only kidney taurine concentration. Anticipated alterations in plasma glucose and creatinine were observed but neither of these changes was affected by taurine administration. Similarly, urinary output of creatinine, glucose, and NAG increased significantly among diabetic rats, but none of these were detectably influenced by taurine. Increases in plasma triglycerides observed in STZ-induced diabetes appear to be attenuated by taurine administration, and although cholesterol concentrations were lower in taurine-treated rats, the differences were not statistically significant. These findings should encourage further studies of these effects in rats as a useful model for several complications of human diabetes including atherosclerosis, retinopathy, and nephropathy.     

Circadian variation in glucose tolerance and associated changes in plasma insulin and somatostatin levels in normal volunteers

The day-time variations of blood sugar and associated changes in plasma insulin and somatostatin levels in response to glucose-glucagon load were investigated in eight healthy volunteers. The glucose-glucagon test was performed in the same subjects at 9.00 a.m., at 5.00 p.m. and at midnight after 10 hrs of fasting. The blood sugar values were higher in the midnight while the corresponding plasma insulin levels were significantly lower. Plasma somatostatin levels did not differ at the different times of the day. These results suggest that the circadian variations of the glucose tolerance are correlated to a simultaneous circadian rhythmicity in the insulin response in the sense of a decreased insulin release later in the day. Somatostatin does not seem involved in the circadian variation of beta cell responsiveness observed in healthy volunteers.     

Effect of physiological increments of blood glucose on plasma somatostatin and pancreatic polypeptide levels in dogs

The present study was designed to determine the effects of physiological increments of plasma glucose levels upon basal and stimulated plasma somatostatin and pancreatic polypeptide levels. In seven conscious dogs the elevation of plasma glucose levels by 30-40 mg/dl did not change basal somatostatin and pancreatic polypeptide levels. During stimulation of these two hormones by acetylcholine and the octapeptide of cholecystokinin intravenous infusion of glucose elicited a significant decrease of somatostatin levels by 30 pg/ml and of pancreatic polypeptide levels by 300 pg/ml. The present data demonstrate that a physiological elevation of plasma glucose levels inhibits stimulated but not basal somatostatin and pancreatic polypeptide levels which may be of importance for nutrient entry and metabolism.