Rise In Plasma Insulin Levels Research Articles

Impact of Nicotine Exposure and Withdrawal on Plasma Glucose, Insulin and Glycated Haemoglobin in High-Fat Diet Fed Wistar Rats

Background to the study: Nicotine, which is the most abundant constituent of tobacco cigarette is one of the most commonly abused drugs. The duo of obesity and tobacco smoking increases the risk of cardiometabolic disorders. Methodology: The experiment involved 48 male wistar rats separated into 4 groups of 8 rats each. All the animals were placed on high-fat diet (Margarine; blue band) in addition to the different doses of nicotine in the experimental groups. Group 1 served as control and received distilled water, Groups 2, 3 and 4 received 200µg/kg, 400µg/kg and 800µg/kg of nicotine oral solution respectively. The experimental groups were placed on their respective doses of nicotine solution for an initial four weeks. Thereafter, four animals in each group were sacrificed and blood samples collected to determine their nicotine exposure plasma levels of glucose, insulin and glycated hemoglobin. The remaining four animals in each group continued without nicotine for another four weeks after which they were sacrificed and blood samples collected to determine their nicotine withdrawal plasma levels of glucose, insulin and glycated hemoglobin. Results: The results showed that exposure to the three concentrations of nicotine (200, 400 and 800µg/kg respectively) significantly caused a rise in plasma insulin levels but dose-dependent reduction in both glucose and glycated haemoglobin compared to their control groups. Four weeks after withdrawal of initial 200µg/kg nicotine there were no significant changes in the levels of plasma glucose, insulin and glycated haemoglobin compared to the nicotine exposed groups. Withdrawal, after initial exposure to 400µg/kg of nicotine was associated with significant rise in both the plasma glucose and glycated haemoglobin but no significant change in insulin compared to their respective nicotine exposed groups. Cessation, after initial exposure 800µg/kg of nicotine resulted in significant rise in plasma levels of glucose, ..........

Neil McIntyre: professor of hepatology and author of game changing research on intestinal hormones

Credit: Wendy McIntyre In 1963 Neil McIntyre, a research fellow, joined the Royal Free Hospital in London to work for hepatologist Sheila Sherlock (read obituary: www.bmj.com/content/324/7330/174.1). He was seconded to...

Improved Postprandial Glucose Control Using the InsuPad Device in Insulin-Treated Type 2 Diabetes: Injection Site Warming to Improve Glycemic Control.

Delays in the time-action profiles of premeal boluses of rapid-acting insulin analogs contribute to early postmeal hyperglycemia in patients with diabetes. We tested whether applying local heat to skin around the injection site to increase the rate of insulin absorption reduces postprandial hyperglycemia in patients with type 2 diabetes. Fourteen patients with type 2 diabetes (4 females; age 61.6 ± 8.4 years, HbA1c 8.42 ± 1.13%; BMI 29.10 ± 5.61 kg/m(2)) on intensified insulin therapy underwent 5-hour meal tolerance tests (MTTs) with a standardized liquid meal after an overnight fast on 2 study days. Subjects injected 0.2 U/kg of insulin aspart or lispro subcutaneously into the abdominal skin on both days with and without the use of the InsuPad device. Following the premeal bolus injection of rapid-acting insulin analog, infusion site warming led to a rise in plasma insulin levels to peak concentrations that were significantly earlier than without skin warming (mean ± SD 52 ± 26.7 vs 80 ± 51.3 minutes, P < .005) as well as increase in plasma insulin levels during the first hour after injection (mean ± SD 63.5 ± 32.7 IU vs 48.0 ± 25.0 uU.min/ml, P = .019). As a result, the area under the curve of the postprandial glucose excursion during the first 2 hours (the primary study outcome) and the entire 5 hours after the meal were significantly reduced (P = .007 and P = .03, respectively) with skin warming around the injection site. Use of the InsuPad to increase the rate of insulin absorption provides an effective means to achieve better control of postmeal glucose excursions in type 2 diabetic patients receiving premeal injections of rapid-acting insulin analogs.

Effect of Citrus paradisi and Citrus sinensis on glycemic control in rats

This study was conducted to explore the effects of Citrus sinensis (orange juice) and Citrus paradisi (grapefruit juice) at three different doses alone and their two combinations on plasma insulin and blood glucose levels in healthy and diabetic rats. Diabetes was induced by alloxan after which rats were treated with C. sinensis and C. paradisi juices for six weeks, blood glucose and plasma insulin concentration was estimated. C. sinensis showed significant reduction in blood glucose and a significant rise in plasma insulin at all three doses. However C. paradisi revealed highly significant fall in blood glucose and highly significant rise in plasma insulin levels only at 0.5 ml/kg. Whereas combination dose group CSP-2 (5 + 0.3 ml/kg) showed highly significant reduction in blood glucose and highly significant rise in plasma insulin levels as compared to diabetic control. These results suggest that flavonoids and other essential nutrients present in citrus fruits juices might be responsible for these effects. Hence, it may be concluded that these juices may be used in combination to produce a synergistic effect in decreasing blood glucose and elevating plasma insulin levels. Key words: Grape fruit, orange, glucose level, insulin.

In vivo anti-diabetic, antioxidant and molecular docking studies of 1, 2, 8-trihydroxy-6-methoxy xanthone and 1, 2-dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl isolated from Swertia corymbosa

1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2- dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2) are the main constituents of petroleum ether and ethyl acetate extracts from Swertia corymbosa (Gentinaceae), a medicinal plant used in Indian traditional system for the treatment of diabetes. The present study was designed to examine the antihypoglycemic, antihyperlipidemic and antioxidant effect of compounds 1 and 2 in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (60mg/kgb.w.). The isolated compounds 1 and 2 at a dose of 50mg/kgb.w., produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 3h of the treatment. The administration of 1 and 2 (50mg/kgb.w.) daily for 28 days in STZ induced diabetic rats, resulted in a significant decrease in blood glucose, glycosylated hemoglobin, SGOT, SGPT, ALP serum urea and creatinine with significant rise in plasma insulin level. Test compounds 1 and 2 showed antihyperlipidemic activities as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage. The results of histopathology also showed 1 and 2 protected tissues (pancreas, liver and kidney) against peroxidation damage and maintained tissue integrity. Further, the molecular interaction study of the ligands 1, 2 and glibenclamide with various diabetes mellitus related protein targets like glucokinase (PDB ID: 1V4S), fructose-1, 6-bisphosphatase 1 (PDB ID: 2JJK) 11-β-hydroxysteroid dehydrogenase (PDB ID: 2BEL) and modeled protein sulfonylurea receptor 1 (SUR1) showed that ligand 1 and 2 possess binding affinity with all protein targets except for 2BEL target protein for which ligand 1 has no interaction. The ligand pose with 2BEL and SUR1 protein target of ligand 2 gave the best binding conformation. Hence 1 and 2 can be considered for developing into a potent antidiabetic drug.

Acceleration of insulin pharmacodynamic profile by a novel insulin infusion site warming device

Subcutaneously injected rapid-acting insulin analogs do not replicate physiologic insulin action due to delays in their onset and peak action resulting in postprandial glucose excursions. The InsuPatch (IP) is a novel insulin infusion site warming device developed to accelerate insulin action by increasing blood flow to the area of insulin absorption. Thirteen adolescents with type 1 diabetes (T1D, mean age 14 ± 4 yr) were enrolled in this study to investigate the effect of the IP on the pharmacodynamics and pharmacokinetics of a 0.2 unit/kg bolus dose of aspart insulin using the euglycemic clamp technique. Each subject underwent two euglycemic clamp procedures on separate occasions: one with IP and one without IP activation in random order. When the insulin bolus was given with IP activation as compared to without IP activation, time to reach maximum insulin action (T(GIRmax)) and to reach 50% maximum action (T(50%GIRmax)) were 35 and 18 min earlier (125 ± 8 min vs. 90 ± 6 min, p = 0.002 and 58 ± 5 min. vs. 40 ± 3 min, p = 0.01, respectively), and the area under curve, AUC(GIR 0-90 min), reflecting early glucodynamic action, was significantly greater (p = 0.001). IP activation also accelerated the rise in plasma insulin levels after the bolus (p = 0.03) and resulted in a higher peak (p = 0.04) and greater overall increase (p = 0.02) in plasma insulin levels. Our results show that insulin infusion site warming with IP activation accelerates the time action profile of aspart insulin which may be of benefit to current open-loop and future closed-loop insulin delivery in patients with T1D.

Antihyperglycemic and antihyperlipidemic activities of methanol:water (4:1) fraction isolated from aqueous extract of Syzygium alternifolium seeds in streptozotocin induced diabetic rats

The present study was taken up to identify potent antihyperglycemic fraction from the aqueous extract of Syzygium alternifolium (SA) seeds, using bioassay guided fractionation. The isolated fraction C at a dose of 50 mg/kg.b.w produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 6 h of the treatment. The administration of fraction C (50 mg/kg.b.w) once daily for 30 days in STZ diabetic rats resulted in a significant decrease in blood glucose, glycosylated haemoglobin with a significant rise in plasma insulin level. Further fraction C showed antihyperlipidemic activity as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic rats. A significant decrease in the activities of SGOT, SGPT, ALP and decreased levels of serum urea and creatinine in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage and non-toxic property of the fraction C. A comparison was made between the action of fraction C and antidiabetic drug glibenclamide (20 mg/kg.b.w). The effect of fraction C was more prominent when compared to that of glibenclamide.

Chestnut Astringent Skin Extract, an &amp;alpha;-Amylase Inhibitor, Retards Carbohydrate Absorption in Rats and Humans

Inhibitors of carbohydrate-hydrolyzing enzyme play an important role to control postprandial blood glucose levels. In this paper, we investigated the effect of an ethanol extract from chestnut astringent skin (CAS) on alpha-amylase. Chestnut astringent skin extract strongly inhibited human and porcine pancreatic alpha-amylase. We also investigated the effect of CAS extract on carbohydrate absorption in rats and humans. Oral administration of CAS extract to normal rats fed corn starch (2 g/kg body weight), significantly suppressed the increase of blood glucose levels after starch loading in a dose-dependent manner. The effective dose of CAS extract required to achieve 20 and 40% suppression of the rise in blood glucose level was estimated to be 40 and 155 mg/kg body weight, respectively. Chestnut astringent skin extract also suppressed the rise in plasma insulin level and the fall in plasma non-esterified fatty acid level. In the type 2 diabetic rat model, CAS extract significantly suppressed the rise in blood glucose level after starch loading in a dose-dependent manner. Chestnut astringent skin extract also suppressed the rise in plasma glucose level after boiled rice loading in a dose-dependent manner in humans. The amount of CAS extract required to achieve 11 and 23% suppression in the rise in plasma glucose level was 300 and 600 mg/person, respectively. These results suggest that CAS extract retards absorption of carbohydrate and reduces post-prandial hyperglycemia.

Changes in blood glucose and plasma insulin levels induced by bradykinin in anaesthetized rats.

1. The influence of bradykinin (BK) on blood glucose and plasma insulin levels was investigated in anaesthetized rats. 2. Blood glucose level was dose-dependently increased by intravenous infusion of BK. This effect of BK was enhanced by captopril, an inhibitor of angiotensin-converting enzyme (ACE). Des-Arg9-bradykinin (DABK), a kinin B1 receptor agonist, did not modify blood glucose levels while the effect of BK was inhibited by Hoe-140, a kinin B2 receptor antagonist. 3. The effect of BK was reduced by the NO-synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), and by the cyclo-oxygenase inhibitor, indomethacin. The effect of BK was suppressed by the association of propranolol with phentolamine or phenoxybenzamine. It was also reduced by hexamethonium, a ganglion-blocking drug. In adrenalectomized rats, the infusion of BK slightly decreased blood glucose levels. 4. The hyperglycaemic effect of adrenaline was suppressed by propranolol associated with phentolamine or phenoxybenzamine, but it was not modified by L-NAME. 5. Infusion of BK did not modify plasma insulin levels. However, after phentolamine and propranolol, BK induced a transient 2 fold rise in plasma insulin levels. The release of insulin was dose-dependent and inhibited by Hoe-140. 6. We conclude that infusion of BK induces, via a stimulation of B2 receptors, the release of NO and of prostanoids. The latter agents activate through a reflex pathway the release of catecholamines from the adrenal medulla. This release increases blood glucose levels and reduces plasma insulin levels. After adrenoceptor inhibition, BK induces a secretion of insulin, via the stimulation of B2 receptors.

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats.

This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0.13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18- and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18- and 26-month-old rats from basal values of 4.3+/-0.8, 4.7+/-0.5 and 5.6+/-1.0 ng/ml (means+/-s.e.m.) respectively, rose to 11.9+/-1.7, 29.1+/-5.5 and 27.9+/-2.7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-month-old animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3- and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values. Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups. In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance.

Effects of chronic bromocriptine (CB-154) treatment on the plasma glucose and insulin secretion response to neurocytoglucopenia in rats.

Neurocytoglucopenia has been reported to increase both parasympathetic and sympathetic tone with a predominant effect on the latter, which accounts for the major effect of plasma hyperglycemia and the inhibition of insulin secretion. The aim of this study was to determine the effects of chronic treatment with bromocriptine (0.4 mg/100 g body wt per day), a potent sympatholytic D(2)-dopaminergic agonist, on hyperglycemia and insulin secretion in response to neurocytoglucopenia induced by 2-deoxy-d-glucose (2DG). After 2 weeks of bromocriptine treatment the animals, freely moving in their cages, were submitted to 2DG administration (50 mg/100 g body wt) via atrial catheter infusion. After 2DG infusion, the plasma prolactin of vehicle-treated (VEH) rats increased rapidly, reaching a peak at 10 min (34.3+/-7.6 ng/ml; P<0.01). In contrast, 2DG infusion failed to induce any significant change in the plasma prolactin levels of bromocriptine-treated (BR) rats. BR rats showed higher resting glucose levels than control rats (8.2+/-0.28 mM (BR) vs 6.0+/-0.18 mM (VEH); P<0.01). However, the hyperglycemic response of BR rats to 2DG injection was 30% lower than that of VEH rats (P<0.05). BR rats also showed a rapid rise in plasma insulin levels reaching a peak at 30 min after 2DG injection (243% higher than basal values; P<0.01). This increased rise in the insulin response to neurocytoglucopenia of BR rats was blocked by previous intravenous injection of atropine methyl nitrate (0.2 mg/100 g body wt). The present results suggest that chronic treatment with bromocriptine determines a strong increase in the parasympathetic tone response to neurocytoglucopenia, which is responsible for the higher stimulation of insulin secretion observed in BR rats. The data also provide further evidence that D(2)-dopaminergic agonist can block neurocytoglucopenia-induced prolactin release.

Vagotomy Suppresses Cephalic Phase Insulin Release in Sheep

The effect of selective vagotomy of the abomasum, pylorus, duodenum and liver on insulin release during the cephalic phase of digestion was investigated in wethers and lactating ewes. Electrical stimulation of the cervical vagus nerves was carried out to test the completeness of the vagotomies performed. In experiment 1, using wethers, the abomasal, pyloric and duodenal branches (ADV; n = 7) or the hepatic, abomasal, pyloric and duodenal branches (HADV; n = 10) of the ventral and/or dorsal vagus nerves were cut; a third group of wethers underwent sham-operation (SO; n = 8). In experiment 2, vagotomy (ADV; n = 5) or sham-operations (SO; n = 5) were carried out in lactating ewes. Jugular blood was drawn before and after presentation of food for glucose and insulin determination (experiments 1 and 2) or before, during and after the electrical stimulation of the peripheral ends of the cut cervical vagus nerves in randomly selected lactating ewes (experiment 3: ADV = 3, SO = 3) and wethers (experiment 4: ADV = 4, HADV = 4, SO = 4), for determination of insulin only. Presentation of food caused an immediate and significant (P < 0.05) rise in plasma insulin levels in SO animals compared with ADV or HADV wethers (experiment 1) or ADV ewes (experiment 2) without any significant change in blood glucose concentrations. In comparison with the SO group the baseline-corrected areas under the insulin response curve were significantly (P < 0.05) smaller for the respective vagotomized groups for periods 1-2, 2-4 and 4-6 min (experiment 1) and 1-2 and 2-4 min (experiment 2) after presentation of food. Total area under the response curve for 10 min was significantly (P < 0.05) lower (experiment 1) and tended (P < 0.10) to be lower (experiment 2) for the vagotomized groups compared with that of the control groups. Direct electrical stimulation of the cervical vagus nerves raised plasma insulin concentrations to significantly (P < 0.05) higher levels in the SO ewes but not in the ADV ewes (experiment 3). It was also evident that in experiment 1, HADV did not have any additive effect over that achieved by ADV alone. These results indicate that the vagal innervation of the gut mediates insulin release during the cephalic phase of feeding in sheep. It is concluded that insulin secretion from the pancreatic -cells in response to either food-related reflex activation of the vagal nuclei in the hypothalamus or direct cervical vagus nerve stimulation is mediated through the vagal efferent fibres carried in the abomasal, pyloric and duodenal branches of the vagus nerves in sheep.

Treadmill Training EnhancesGlucose Tole rance More in Pregnant than in Virgin Rats

To determine whether aerobic training throughout gestation modifies glucose tolerance, female Wistar rats were mated or kept nonpregnant and run or not on a 10° slope treadmill for 5 days/week at 20 m/min, starting with a 20-min run, and with a progressive daily increase of 5 min, reaching a 75-min run on the 20th day of protocol or gestation. The exercise protocol did not modify food intake, maternal and fetal weights, litter size or blood lactic acid levels. The rise in blood glucose after an oral glucose load (2 g/kg body weight) did not differ between trained and untrained nonpregnant rats but was lower in trained than in untrained pregnant rats. In the untrained rats the rise in plasma insulin levels after the glucose load was much greater in pregnant than in nonpregnant rats; in trained rats this difference between groups was attenuated by the greater effect of exercise decreasing the plasma insulin response to the glucose load in pregnant than in nonpregnant rats. Thus, an aerobic exercise protocol that does not modify the outcome of pregnancy does significantly reduce the altered oral glucose tolerance in pregnant rats and only has a minor effect in nonpregnant rats.

Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.

The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.

Down-regulation of beta3-adrenergic receptor expression in rat adipose tissue during the fasted/fed transition: evidence for a role of insulin.

The beta3-adrenergic receptor (beta3-AR) exerts a central role in the transduction of catecholamine effects in white and brown adipose tissue (WAT and BAT). A recent report has documented that insulin strongly down-regulates beta3-AR expression and catecholamine responsiveness in 3T3-F442A adipocytes [Fève, El Hadri, Quignard-Boulangé and Pairault (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 5677-5681]. In the present report we show that the rise in plasma insulin levels elicited by the fasted/fed transition is associated with a reduction in beta3-AR mRNA levels and beta-adrenergic responsiveness in WAT and BAT. beta3-AR transcripts are also decreased in adipose tissue from animals subjected for 6 h to euglycaemic hyperinsulinaemic glucose clamps. Moreover, insulin acts directly on cultured rat white and brown adipocytes to decrease beta3-AR gene expression and adenylate cyclase activity in response to beta3-AR-selective agonists. These results suggest that there is a close relationship between food intake, plasma insulin levels and beta3-AR expression.

Impaired glucose tolerance in recipients of an intraperitoneally implanted microencapsulated islet allograft is caused by the slow diffusion of insulin through the peritoneal membrane

I NTRAPERITONEAL transplantation of microencapsulated islets has been reported to restore normoglycemia both in chemically induced and in autoimmune diabetic animal models,‘-5 and recently also in man.6 But a previous report from our laboratory showed that glucose tolerance remains disturbed in spite of normoglycemia, and that there is no increase of plasma insulin levels in response to a physiologic stimulus such as the intake of a meal5 This may be the consequence of several factors such as a gradual decrease of the number of viable and functioning islets after transplantation as a consequence of fibrotic overgrowth of the capsules, or a slow release of insulin in response to a glycemic stimulus as a consequence of overly large capsule diameters.’ The transplantation site as such may be another factor. Previous studies on the kinetics of intraperitoneal insulin absorption report a short delay between the intraperitoneal administration of insulin and rise of plasma insulin levels. *-‘i However, these studies were often performed with insulin bolus injections in unphysiologically high doses which may well be associated with a more rapid absorption of insulin than should be expected with a gradual release of insulin from encapsulated pancreatic islets. Therefore, the present study investigates whether the intraperitoneal implantation site as such interferes with optimal transport kinetics between the islets and the bloodstream.

Modulation of Insulin Secretion in Non‐insulin‐dependent Diabetes Mellitus by Two Novel Oral Hypoglycaemic Agents, NN623 and A4166

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.

The metabolic effects of oxytocin are mediated by a uterine type of receptor and are inhibited by oxytocin antagonist and by arginine vasopressin in the dog

Infusion of oxytocin (OT) into normal dogs, in doses which produced plasma levels of OT in the physiological range, has been shown to increase plasma levels of glucose, insulin and glucagon and increase rates of glucose production and uptake. This study sought to determine whether there was a correlation between these metabolic effects and the oxytocic potency of four less potent oxytocic analogues when infused into normal dogs. The rank order of oxytocic potency of all 4 correlated well with the rise in plasma glucose levels, and in 3 of the 4 with the rise in plasma insulin levels. An antagonist of the oxytocic effect of OT suppressed the usual OT-induced rise in plasma glucose, insulin and glucagon as well as the increased glucose production and uptake. Arginine vasopressin (AVP) infusion, which by itself did not produce any metabolic effects, blocked completely the effects of OT infusion to raise plasma glucose and insulin levels and increase glucose production and uptake. The data suggest that the metabolic effects of OT in the dog are mediated by OT receptors that are similar to those producing the oxytocic effects. Whether the inhibition by AVP of the metabolic and hormonal effects of OT occurs at the receptor or post receptor level or via other mechanisms remains to be determined.

Effects of pure sugar vs. mixed starch fructose loads on food intake

Using a within-subject design, we gave subjects three different 520–530 kcal preloads in the form of puddings in a randomized fashion at weekly intervals. The puddings contained either 50 g of fructose or glucose as the sole carbohydrate source in a protein and fat mixture, or 50 g fructose plus 15 g of starch. Food intake was assessed 2.25 h after the preload was completed. Blood was drawn throughout and assayed for concentrations of glucose and insulin. When the preload contained fructose alone as the sole source of carbohydrate, subjects ate significantly fewer calories and less fat than when the preload contained glucose alone. When starch was added to the fructose preload, there was no significant reduction in calorie and fat intake. Effects on food intake paralleled the rise in plasma insulin levels produced by the different preloads. Implications for use of fructose as an adjunct to weight control efforts are discussed.

Coupling of β-Cell Desensitization by Hyperglycemia to Excessive Stimulation and Circulating Insulin in Glucose-Infused Rats

Nondiabetic rats were infused with glucose for 48 h to maintain moderate or marked hyperglycemia (mean blood glucose 13.2 +/- 0.7 or 22.8 +/- 0.3 mM, respectively). The two levels of hyperglycemia increased plasma insulin levels severalfold but decreased the insulin response to 27 mM glucose by 19 and 95%, respectively, versus saline infusion. Diazoxide (5 mg.kg-1.h-1), when continuously infused during the hyperglycemia protocols, completely inhibited the glucose-induced rise in plasma insulin levels. Diazoxide transformed beta-cell insensitivity to stimulation: glucose-induced insulin release was thus increased 318% after moderate hyperglycemia and 707% after marked hyperglycemia. These stimulatory effects of diazoxide were reversed by exogenous insulin infusion (8 or 2 U/24 h) in a dose-dependent manner. It is concluded that excessive beta-cell stimulation rather than glucotoxicity underlies hyperglycemia-induced beta-cell insensitivity. Effects of hyperinsulinemia can form part of the mechanisms whereby excessive stimulation affects beta-cell secretion.