In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: Possible relevance to the maladaptive responses to chronic hyperglycaemia

Summary We tested the hypothesis that glucosamine, a putative activator of glucose toxicity in vitro through acceleration of the hexosamine pathway, may determine in vivo the two key features of glucose toxicity in diabetes, namely, peripheral insulin resistance and decreased insulin secretion. Two groups of awake rats were studied either with intraarterial administration of glucosamine (5 mol·kg^–1· min^–1) or saline. Insulin secretion was determined after arginine, glucose (hyperglycaemic clamp), and arginine/glucose infusions, while insulin-mediated glucose metabolism was assessed by the euglycaemic hyperinsulinaemic clamp in combination with [3-³H]-glucose infusion. Glucosamine had no effects on arginine-induced insulin secretion both at euglycaemia and hyperglycaemia, but significantly (40–50%) impaired glucose-induced insulin secretion (both first and second phases). During euglycaemic hyperinsulinaemic clamp studies, glucosamine decreased glucose uptake by 30%, affecting glycolysis (estimated from ³H₂O rate of appearance) and muscle glycogen synthesis (calculated from accumulation of [³H]-glucosyl units in muscle glycogen) to a similar extent. Muscle glucose 6-phosphate concentration was markedly reduced in the glucosamine-infused rats, suggesting an impairment in glucose transport/phosphorylation. Therefore, an increase in hexosamine metabolism in vivo: 1) inhibits glucose-induced insulin secretion, and 2) reduces insulin stimulation of both glycolysis and glycogen synthesis, thereby mimicking in normal rats the major alterations due to glucose toxicity in diabetes.Abbreviations GFAT Glutamine:fructose 6-phosphate amidotransferase - UDP-N-acetylglucosamine uridine-diphospho-N-acetylglucosamine     

Reversibility of the acute toxic effect of Cyclosporin A on pancreatic B cells of Wistar rats

Summary. This study investigated if and to what extent the acute toxic effect of Cyclosporin A on pancreatic Wistar rat B cells is reversible. After 2 weeks of treatment rats developed marked glucose intolerance accompanied by reduced pancreatic insulin content due to a loss of B cells, diminished islet DNA synthesis and decreased B-cell insulin content. Cyclosporin A had accumulated in the pancreas. Three weeks after withdrawal of Cyclosporin A, pancreatic tissue concentrations of Cyclosporin A were still 100 times larger than in serum. Glucose tolerance, however, had already improved, associated with an increase of B-cell insulin content and apparent islet replication, and the insulin response of isolated islets was reduced. Five weeks after the withdrawal of Cyclosporin A, glucose tolerance was normal, but pancreatic insulin content and relative B-cell volume were still diminished in comparison to vehicle-treated controls. Eight weeks after withdrawal, the morphometric parameters had also been normalized. The results suggest that the loss of pancreatic B cells is caused by a toxic destruction, possibly combined with an apparent decrease of replicatory activity. The acute toxic effects of Cyclosporin A in pancreatic B cells are stepwise reversible.     

On the effects of human galanin in man

Summary Human galanin was recently isolated and sequenced and was found to differ from porcine galanin, hitherto used for studies in humans, in several important respects. We therefore synthesized and purified human galanin and infused it i.v. at a rate of 74 pmol · kg^–1· min^–1 into six healthy volunteers for 60 min during a hyperglycaemic clamp. The clamp was achieved by i. v. infusion of glucose at a rate which in a control experiment had been demonstrated to maintain the plasma glucose level at 12–13 mmol/l for 90 min. Galanin concentrations reached a plateau of approximately 1500 pmol/l throughout the infusion as opposed to pre-infusion and control levels of 20–30 pmol/l. The glucose levels obtained in the two experiments were indistinguishable. Plasma levels of C-peptide and insulin increased significantly in both experiments and the dynamic concentration curves were almost identical. Glucagon concentrations in plasma decreased significantly and similarly. Growth hormone levels, however, increased eight-fold during galanin infusions. Galanin was eliminated from plasma with a half-life of 3.7±0.4 min, similar to that of porcine galanin. It is concluded that human galanin powerfully stimulates growth hormone secretion in man, but has no effect on pancreatic endocrine secretion or glucose metabolism in the concentrations obtained in this study.     

B-cell function and blood glucose control in insulin dependent diabetics within the first month of insulin treatment

Summary Seventeen insulin dependent diabetics were studied after two to four weeks of insulin treatment in a situation approximating to their normal daily life. Some endogenous insulin secretion, assessed by plasma C-peptide determinations, was present in all. Plasma C-peptide concentration was positively correlated with the blood glucose concentration and increased after breakfast, lunch and dinner (p<0.01); both peak values and relative increases were lower than those observed in normal subjects (p<0.01). The highest insulin secretory capacity was found in subjects with the least unstable blood glucose concentration (r=0.57, p <0.03), and these patients required the smallest insulin doses (r=0.54, P<0.04). These findings demonstrate the metabolic importance of a preserved B-cell function.     

Effects of feeding and fasting on the insulin secretory response to glucose and sulfonylureas in intact rats and isolated perfused rat pancreas

Summary In intact rats 16 h of fasting reduced the plasma insulin response to i.v. stimulation with either glucose, tolbutamide or glibenclamide by 50–80 %, without affecting the extractable insulin content of the pancreas. In subsequent studies with the isolated perfused rat pancreas two distinct patterns of insulin release could be discerned during the secondary phase. In thefed state, glucose 1.5 mg/ml induced a more or less constant elevation of the insulin secretion rate over 30 min (type I). At glucose concentrations of 2 and 3 mg/ml the release pattern was characterized by progressively increasing secretion rates (type II pattern). Infusion of tolbutamide (0.2 mg/ml) lowered the threshold for glucose stimulation and induced both patterns of secretion at lower glucose concentrations.Fasting for 24 h caused a 70–80 % inhibition of insulin secretion per 30 min at glucose levels of 1.5 and 2 mg/ml. Decreased glucose sensitivity was indicated by a shift to the right of the entire dose-response curve for glucose and by reduced inhibition (30 %) at a glucose level of 3 mg/ml. The effect of tolbutamide was also strongly diminished. The percent inhibition of the response to tolbutamide at different levels of glucose showed a pattern of inhibition similar to that observed with glucose alone. These findings suggest that the glucose-dependent release mechanism is highly sensitive to relatively short periods of fasting.Presented in part at the Sixth Annual Meeting of the European Association for the Study of Diabetes, Warsaw, September 1970.Supported by a grant from the Netherlands Organization for the Advancement of Pure Research (Z.W.O.).     

Simple empirical assessment of Beta-cell function by a constant infusion of glucose test in normal and Type 2 (non-insulin-dependent) diabetic subjects

Summary The plasma insulin or C-peptide response to a 90-min constant glucose infusion 5 mg · kg ideal body weight^–1·min^–1 provides Beta-cell assessment comparable to more intensive methods. In 14 diet-treated Type 2 (non-insulin-dependent) diabetic subjects and 12 non-diabetic subjects, plasma insulin and C-peptide concentrations gave near linear plots against simultaneous glucose values. The glucose-insulin and glucose-C-peptide vectors (G-I and G-C vectors), could be extrapolated to predict insulin and C-peptide levels during a 12 mmol/l hyperglycaemic clamp. Predicted concentrations correlated with clamp concentrations, r = 0.94 and r = 0.98 respectively, p<0.001, validating the vectors as empirical glucose dose-response curves. The vector slopes correlated highly with % Beta, a mathematical model-derived measure of Beta-cell function using constant infusion of glucose model assessment, Spearman r = 0.95 and 0.93 for insulin and C-peptide, respectively. G-I vector slopes in 21 diet-treated Type 2 diabetic subjects with fasting glucose (mean +1 SD) 7.5±2,3 mmol/1, were lower than in 28 non-diabetic subjects, (geometric mean, 1 SD range, 8.4 pmol/mmol (3.3–21.0) and 25.1 pmol/mmol (14.3–44.1), p<0.001, respectively), indicating an impaired Beta-cell response. The G-I vector slopes correlated with obesity in both groups (r = 0.54 p<0.02 and 0.72, p<0.001 respectively), and, in 15 non-diabetic subjects, correlated inversely with insulin sensitivity as measured by a euglycaemic clamp (r = –0.66, p<0.01).Thus,Beta-cell function needs to be interpreted in relation to obesity/insulin resistance and, taking obesity into account, only 4 of 21 diabetic patients had Betacell function (G-I vector slope) in the non-diabetic range. The fasting plasma glucose in the diabetic subjects correlated inversely with the obesity-corrected G-I and G-C vector slopes (partial r = –0.57, p <0.01 and –0.86, p<0.001, respectively). The insulin or C-peptide response to the glucose infusion provides a direct empirical measure of the Beta-cell function, which can be interpreted in relation to obesity or to insulin resistance to assess underlying pancreatic responsiveness.     

Effects of diet supplementation with olive oil and guar upon fructose-induced insulin resistance in normal rats

Exposure of normal rats to fructose-containing drinking water represents a current model of insulin resistance. The major aim of the present study was to assess the possible effect of diet supplementation with either olive oil or guar upon the metabolic consequences of exposure to exogenous fructose. For this purpose, the changes in body weight, plasma d-glucose and insulin concentrations, and d-glucose infusion rate during a hyperinsulinemic-euglycemic clamp were measured after 65 days exposure to exogenous fructose and either olive oil- or guar-enriched diet. The results were compared to those previously collected in control animals exposed for the same period to either tap water or the fructose-containing drinking water and a standard diet. Diet supplementation with olive oil or guar failed to affect the increase in the insulinogenic index and the decrease in insulin sensitivity and fasted/fed ratio for plasma insulin concentration caused by exogenous fructose. In the rats exposed to exogenous fructose, the olive oil-fed rats differed from other animals by the absence of a decrease in food intake and body weight gain, whilst the guar-fed rats differed from other animals in a lower plasma d-glucose concentration in fed state and an absence, at day 65, of a higher plasma d-glucose concentration than that at day 0 measured in after overnight fasting state. These findings argue in favour of guar, rather than olive oil, to oppose the effect of exogenous fructose on glucose homeostasis.     

Irreversible loss of normal beta-cell regulation by glucose in neonatally streptozotocin diabetic rats

Summary Animals with NIDDM display abnormal glucose regulation of insulin secretion and biosynthesis. We tested reversibility of abnormal regulation by normoglycaemia using an islet transplantation technique. Inbred non-diabetic and neonatally STZ diabetic rats (n-STZ) were used. Transplantations insufficient to normalize the blood glucose levels (200 islets under kidney capsule) were performed from diabetic to normal (D-N) and from diabetic to diabetic (D-D), as well as from normal to normal (N-N) and from normal to diabetic (N-D) rats. Four weeks after transplantation, graft bearing kidneys were isolated and perfused with Krebs-Henseleit bicarbonate buffer to measure insulin secretion in response to 27.8 mmol/l glucose and 10 mmol/l arginine. Four weeks of normoglycaemia failed to restore glucose-induced insulin secretion from n-STZ islets (glucose induced increment:-1.7±2.5 fmol/min in D-N, 1.2±7.1 fmol/min in D-D). In contrast to normal islets, normoglycaemia reduced insulin mRNA contents (60±24 in D-N, 496±119 in D-D; O.D.-arbitrary units). However, arginine-induced secretion was markedly enhanced by diabetic environment in both normal and n-STZ islet grafts. These results indicate that selected aspects of glucose recognition are irreversibly damaged by a long-term diabetic state or, alternatively, by a lasting effect of STZ administration.Abbreviations NIDDM non-insulin-dependent diabetes mellitus - STZ streptozotocin - O.D. optical density - IRI immunoreactive insulin     

The effect of serotonin on in vitro insulin secretion and biosynthesis in mice

Summary The effect of serotonin on insulin secretion and biosynthesis was studied using isolated islets of mice. Serotonin produced a small stimulatory effect on insulin secretion when glucose was present in the incubation medium at a low concentration. On the other hand, an inhibition of insulin secretion was obtained with serotonin when glucose in the medium reached 3.0 mg/ml concentration. No significant effect of serotonin was obtained on insulin biosynthesis, neither in the presence of low nor with a high glucose concentration. These results suggest that the effect of this monoamine on insulin secretion is not mediated via its effect on insulin biosynthesis.Supported by Deutsche Forschungsgemeinschaft Bonn-Bad Godesberg, SFB 87 Ulm     

Effect of high sucrose diet on insulin secretion and insulin action: a study in the normal rat

Summary The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in normal male rats. As compared to the standard chow diet, the high sucrose diet induced excess in vivo insulin response to an intravenous glucose load; the high sucrose diet also slightly improved glucose tolerance, as demonstrated by significantly higher rate of glucose disappearance (p<0.02). The increased insulin secretion in response to glucose in vivo seems to be related to an hyper-reactivity of the pancreatic B cell to glucose, since it was still observed in vitro with the isolated perfused pancreas preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a normal response to arginine and a significantly lowered (p<0.05) response to acetylcholine. The insulin action in the sucrose-fed rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilization were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilization was found significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies the glucose utilization induced by submaximal (400 U/ml) or maximal (7500 U/ml) insulin levels was significantly more important (p<0.02) in the sucrose-fed rats than in the chow-fed rats. This suggests that insulin-mediated glucose uptake is enhanced over a large range of plasma insulin levels in the sucrose-fed rats. In the basal state hepatic glucose production was significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies, the suppression of glucose production induced by submaximal or maximal insulin levels was significantly less effective (p<0.05) in the sucrose-fed rats as compared to chow-fed rats, thus suggesting that the liver becomes resistant to insulin action after sucrose feeding.     

Effect of high sucrose diet on insulin secretion and insulin action. A study in rats with non-insulin-dependent diabetes induced by streptozotocin

Summary The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in rats with non-insulin-dependent diabetes. As compared to the standard diet, the high sucrose diet induced an increase of the in vivo insulin response to an intravenous load and deteriorated the glucose tolerance as attested by significantly lower rates of glucose disppearance (K values, p<0.001). The increased insulin secretion in response to glucose in vivo seems to be related to a slight increase of the pancreatic B-cell reactivity to glucose, since it was still observed in vitro with the isolated perfused pancreas preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a significantly lowered (p<0.01) response to acetylcholine and arginine. The insulin action in the sucrose-fed diabetic rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilisation were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilisation was found significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies the glucose utilisation induced by submaximal (450 mU/l) insulin level was significantly less important (p<0.01) in the sucrose-fed rats than in the chow-fed rats. Following a maximal hyperinsulinaemia (5000 mU/l) the glucose utilisation was similar in both groups. This suggests that insulin-mediated glucose uptake is decreased over the range of submaximal plasma insulin levels in the sucrose-fed diabetic rats. In the basal state hepatic glucose production was significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies, the suppression of glucose production induced by submaximal or maximal insulin levels was significantly less effective (p<0.01) in the sucrose-fed rats as compared to chow-fed rats, thus suggesting that the liver becomes resistant to insulin action after sucrose feeding. Finally, these results suggest that restriction of complex carbohydrates in favor of sucrose in insulin-deficient rats leads to metabolic events likely to develop insulin resistance in target tissues.     

Effects of postnatal feeding on the functional maturation of pancreatic islet B-cells of neonatal rats

Summary The insulin response to glucose stimulation has been investigatedin vivo andin vitro in suckling rats from small or large litters. In two day old animals from small litters there was a marked increase in serum insulin levels after an intraperitoneal glucose injection, while the insulin response to glucose in animals from large litters was low and sluggish. The weak insulin response to glucose in the two day old rats from large litters was further substantiated in studiesin vitro in which the insulin release of isolated pancreatic glands was measured after incubation in a low or a high glucose concentration. On the third and fourth postnatal days there was an increased insulin secretion in response to the glucose challenge bothin vivo andin vitro in the two groups of animals. The results indicate that postnatal feeding modulates the development of the glucose-mediated insulin release.

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Die Wirkung der postnatalen Fütterung auf die funktionelle Reifung der B-Zellen der Pankreasinseln neonataler Ratten

Zusammenfassung Die Insulinsekretion nach Glucosestimulation wurdein vivo undin vitro an kleinen und großen Würfen säugender Ratten untersucht. Bei 2 Tage alten Tieren aus kleinen Würfen war ein starker Anstieg des Seruminsulinspiegels nach intraperitonealer Glucoseinjektion festzustellen, während die Insulinantwort auf Glucose bei Tieren eines großen Wurfs langsam und gering war. Die schwache Insulinsekretion nach Glucose bei 2 Tage alten Ratten eines großen Wurfs wurdein vitro weiter untersucht und die Insulinsekretion in geringer und hoher Glucosekonzentration gemessen. Am dritten und vierten postnatalen Tag wurde eine erhöhte Insulinsekretionin vivo undin vitro bei beiden Tiergruppen beobachtet. Die Ergebnisse deuten darauf hin, daß die Entwicklung der glucoseinduzierten Insulinsekretion von der postnatalen Fütterung beeinflußt ist.

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Effet de la nutrition post-natale sur la maturation fonctionnelle des cellules B des îlots pancréatiques chez le rat nouveau-né

Résumé La réponse de l'insuline à une stimulation par le glucose a été étudiéein vivo etin vitro chez des rats nouveau-nés de petites ou de grandes portées. Chez les animaux des petites portées, âgés de deux jours, il y avait une nette augmentation des taux de l'insuline du sérum après une injection de glucose intrapéritonéale, tandis que la réponse de l'insuline au glucose était faible et lente chez les animaux des grandes portées, âgés de deux jours. La faible réponse de l'insuline au glucose chez les animaux des grandes portées, âgés de deux jours, a été confirmée par l'étudein vitro dans laquelle a été mesurée la sécrétion d'insuline par les glandes pancréatiques isolées après incubation dans une concentration faible ou forte de glucose. Le 3^e ou le 4^e jour après la naissance, il y a une augmentation de la sécrétion d'insuline en réponse à une charge de glucosein vivo etin vitro dans les deux groupes d'animaux. — Les résultats indiquent que la nutrition post-natale influence le développement de la sécrétion d'insuline provoquée par le glucose. La possibilité d'une influence des facteurs extra-pancréatiques sur le procédé de maturation est discutée.

     

Hypophysis and function of pancreatic islets

Summary Insulin secretion and biosynthesis of proinsulin and insulin were determined in isolated pancreatic islets of hypophysectomized rats. Control rats were of both same age and weight. Hypophysectomy was performed either 13 or 5 weeks prior to the investigation, the weight of the animals being either 80 or 170 g. Biosynthesis of insulin was estimated from the amounts of radioactivity incorporated into proinsulin and insulin after incubation of isolated islets at 50 or 300 mg% glucose in the presence of³H-leucine for 3 h. Islet proteins were separated on Sephadex G 50 fine. — Hypophysectomy resulted in a significant decrease of both glucose stimulated secretion and biosynthesis of insulin. It was found that this reduction was 1) more significant when compared with controls of same age 2) more marked in rats which had been hypophysectomized 13 weeks before than in rats after an interval of 5 weeks and 3) less in rats which had been hypophysectomized at a weight of 170 g than in rats in whom pituitary ablation was performed at a weight of 80 g. At basal glucose concentrations, no significant changes of both secretion and biosynthesis of insulin were apparent. The relation of radioactivity incorporated into proinsulin and insulin was unchanged under all conditions. Insulin content of the isolated islets used was found within about the same range in all rats, apart from the animals which had been hypophysectomized 13 weeks before. In islets of these rats, a reduction to 84% was observed. — Our findings may be explained by reduced sensitivity of the pancreatic B-cell to glucose and a slower rate of insulin biosynthesis after hypophysectomy.Alexander von Humboldt-Fellow 1970–1972.H.S. was on leave from the 2nd Medical Clinic, University of Vienna, Austria.Supported by Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, SFB Ulm 87, Proj. 11.     

用高胰岛素-正葡萄糖钳夹实验探讨增龄对Wistar大鼠胰岛素敏感性的影响

目的探讨增龄对Wistar大鼠体重、空腹血糖、空腹胰岛素、空腹游离脂肪酸(FFA)水平及胰岛素敏感性的影响。方法将雄性Wistar大鼠45只分为4月龄组、14月龄组和24月龄组,每组15只,行高胰岛素-正葡萄糖钳夹实验,观察空腹血糖、空腹胰岛素、血清FFA和胰岛素敏感性的变化。结果 3组大鼠的体重差异有统计学意义(P<0.05,P<0.01)。与4月龄组比较,14月龄组和24月龄组大鼠空腹胰岛素、胰岛素抵抗指数明显升高(P<0.01),24月龄组大鼠血清FFA明显高于4月龄组(P<0.01);与4月龄组比较,14月龄组和24月龄组大鼠稳态葡萄糖输注速率明显降低,差异有统计学意义(P<0.01)。多元线性回归分析显示,增龄与胰岛素敏感性呈负相关。结论随着年龄的增加,大鼠空腹血糖无明显差异,空腹胰岛素和FFA均明显增加,胰岛素的敏感性降低,胰岛素抵抗加重。脂肪、肌肉和肝脏可能参与了增龄介导的胰岛素抵抗。     

Effects of intravenous neuropeptide Y on insulin secretion and insulin sensitivity in skeletal muscle in normal rats

Summary Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia, insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin. We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition, the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-³H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal was significantly increased in the rats given neuropeptide Y compared with controls (27.8 ± 1.3 vs 24.3 ± 1.6 mg · min^–1· kg^–1; p < 0.05) as was the glycolytic flux (18.9 ± 1.6 vs 14.4 ± 0.8 mg · min^–1· kg^–1; p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats, accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to hyperglycaemia. [Diabetologia (1998) 41: 1361–1367] Received: 4 March 1998 and in revised form: 27 May 1998     

Apparent discrepancy between the insulin secretory responses in vivo and in vitro in carbohydrate-intolerant sand rats

Summary A subpopulation (n=27) of normoglycaemic Sand rats was characterized as carbohydrateintolerant by intraperitoneal glucose loading. Five of these animals did not show any rise in peripheral insulin concentrations when injected with glucose. However, when isolated by collagenase digestion their islets still exhibited a significant enhancement of insulin secretion in response to glucose, glyceraldehyde, mannose and theophylline. The in vitro secretory responses were comparable to those of islets from carbohydrate-tolerant Sand rats. The results underline the importance of the natural environment for the B-cell response in vivo.     

In vitro pancreatic B-cell response of hyperinsulinemic rats. Differences between pregnancy and VMH-lesions

Summary We investigatedin vitro the pancreatic B-cell response of hyperinsulinemic animals compared to that of controls with the aim of clarifying if the hyperinsulinemia is related to an alteration of the islet insulin secretion. Hyperinsulinemia was induced by pregnancy (observation at 19.5 days) and electrolytic lesions of the hypothalamic nucleus ventromedialis (2 days after lesion). The kinetics of the glucose dose/response curves (measured during a 60 min incubation period) differed markedly in the two hyperinsulinemic conditions. Whereas the islets from pregnant rats were characterized by a lowered glucose threshold, an enhanced half-maximal and maximal secretion rate, those of lesioned rats showed only an increased half-maximal and maximal secretion response in spite of a comparable islet insulin content. When culturing islets of hyperinsulinemic animals up to 6 days, the insulin secretion of those prepared from VMH-lesioned rats behaved identically to controls, whereas the islets of pregnant rats maintained their enhanced sensitivity at a glucose concentration of 5 mmol/l. These results confirm that the pancreatic B-cell response contributed significantly to the hyperinsulinemia, but different mechanisms are likely to be responsible for the altered B-cell secretion.     

Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance

Summary The relative importance of insulin resistance and abnormal insulin secretion as risk factors for the development of impaired glucose tolerance (IGT) is controversial. Few prospective data are available on metabolic precursors of IGT. We examined the relation of fasting serum insulin level (as a marker of insulin resistance) and change in insulin/glucose ratio (ΔI ₃₀/ΔG₃₀) over the first 30 min after glucose ingestion (as a marker of insulin secretion) as predictors of the 7-year development of IGT in 839 Mexican Americans and non-Hispanic whites with normal glucose tolerance at baseline from the San Antonio Heart Study. IGT eventually developed in 148 subjects. When modelled separately, fasting serum insulin (odds ratio (OR)=2.60,95 % confidence interval (CI)=1.58,4.28,p<0.005), but not ΔI ₃₀/ΔG₃₀ (OR=0.80, 95 % CI=0.50,1.27,p=0.339) predicted the development of IGT. However, when both variables were included in the same logistic regression model, fasting serum insulin (OR=3.50, 95 % CI=1.97,6.21,p<0.001) and low ΔI ₃₀/ΔG₃₀ (OR=0.48, 95 % CI=0.28,0.82,p=0.008) both predicted IGT. These results were basically unchanged after further adjustment for obesity, body fat distribution and fasting plasma glucose level. We conclude that both decreased insulin secretion (as assessed by low ΔI ₃₀/ΔG₃₀) and increased insulin resistance (as assessed by fasting serum insulin) predict the development of IGT and are thus early precursors of non-insulin-dependent diabetes mellitus; further studies of insulin secretion should take into account the level of basal insulin resistance.     

Effects of synthetic rat C-peptide in normal and diabetic rats

Summary The effects of synthetic rat C-peptide 1 and C-peptide 2 on plasma insulin and blood glucose concentrations in the rat were studied. Infusion of rat C-peptide (500g·h^-1· kg^-1) diminished glucose induced increase of plasma insulin by 56% (15.2±0.9 versus 6.6± 0.6 ng/ml, p<0.01, mean±SEM). Somatostatin infused at a rate of 50 g·h^-1·kg^-1 body weight inhibited glucose-induced insulin secretion by 33%. In the presence of a mixture of both C-peptides or somatostatin, blood glucose after intravenous glucose was higher than in the control experiments. In alloxan-diabetic rats, C-peptide (160 g/kg) significantly increased and prolonged the hypoglycaemic effect of exogenous insulin. It is suggested that C-peptide may not be a biologically inert substance.     

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.