Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study.

In a study of retinopathy during one year of tight blood glucose control 45 type I (insulin dependent) diabetics without proliferative retinopathy were randomised to receive either continuous subcutaneous insulin infusion, multiple insulin injections, or conventional insulin treatment (controls). Near normoglycaemia was achieved with continuous infusion and multiple injections but not with conventional treatment. Blind evaluation of fluorescein angiograms performed three monthly showed progression of retinopathy in the control group, transient deterioration in the continuous infusion group, and no change in the multiple injection group. Half the patients receiving continuous infusion and multiple injections developed retinal cotton wool spots after three to six months. These changes regressed in all but four patients after 12 months. Control patients did not develop cotton wool spots. Patients who developed cotton wool spots are characterised by a larger decrement in glycosylated haemoglobin and blood glucose values, more frequent episodes of hypoglycaemia, a longer duration of diabetes, and more severe retinopathy at onset. A large and rapid fall in blood glucose concentration may promote transient deterioration of diabetic retinopathy.     

Insulin effect on in vivo gluconeogenesis from [3-14C]pyruvate in the starved rat

During a 24 hr fast rats received 4 subcutaneous injections of insulin, and 15 min after the last injection they were given an intravenous pulse of [3-14C]pyruvate. The amount of [14C]glucose in blood 2 min after the tracer did not differ between insulin treated and control animals, whereas at 5 and 10 min values were significantly lower in the former group. At 10 min after the tracer, liver [14C]glycogen specific activity and [14C]fatty acid amount were higher in the insulin treated animals than in controls while plasma concentration of gluconeogenic amino acids was lower in the first group. Similar changes but less pronounced and more retarded were found in 24 hr fasted rats given only one insulin dose 15 min before the [3-14C]pyruvate pulse. Results indicate that gluconeogenesis from pyruvate is not directly modified by insulin treatment. Effects found at 5 and/or 10 min after the tracer and reported effects after prolonged insulin treatments may be caused by one or all of the following possibilities: enhanced utilization of the new-formed glucose, reduced availability of gluconeogenic substrates, and counteracting action on gluconeogenic hormones.     

Effect of near normoglycaemia for two years on progression of early diabetic retinopathy,nephropathy, and neuropathy: the Oslo study.

Forty five insulin dependent diabetics were randomised to treatment with continuous subcutaneous insulin infusion (CSII), multiple insulin injections (five or six daily), or conventional twice daily insulin injections. Near normoglycaemia was obtained with CSII and multiple injections but not with conventional treatment (p less than 0.01). Hypoglycaemic coma was observed less frequently with CSII than with multiple injections and conventional treatment (p less than 0.001), but blood glucose concentrations below 2.5 mmol/l (45 mg/100 ml) were more common. After two years fewer retinal microaneurysms and haemorrhages had developed in the patients given CSII and multiple injections compared with those given conventional treatment, in whom the number had increased significantly (p less than 0.01). Motor nerve conduction velocity deteriorated in the patients given conventional treatment; in those given CSII it was unchanged during the first year but had improved after two years (p less than 0.01). Glomerular hyperfiltration was reduced with CSII, but no change occurred in urine albumin excretion rates. Long term near normoglycaemia may prevent the progression of early stages of late diabetic complications.     

Treatment of diabetic coma with small intravenous insulin boluses.

The clinical efficacy of small intravenous boluses of insulin in treating diabetic decompensation was tested in 23 patients presenting in either a ketoacidotic or a nonketotic diabetic coma. In addition to the usual ionic and fluid replacement, the patients received hourly intravenous injections of insulin 5 IU. This dose lowered blood glucose levels in all but two patients. In the patients who responded the percentage decrease in glycaemia was similar whatever the initial glucose concentration and averaged (+/-SE of mean) 50+/-3% in five hours. Close monitoring of insulin and glucose concentrations after intravenous insulin in three patients showed that despite the short half life of insulin the effect of the intravenous bolus lasted for about 60 minutes. The overall clinical effectiveness of this type of treatment is comparable to that of the other low-dose regimens. Owing to its simplicity, this technique of insulin administration seems most suitable for the routine treatment of diabetic coma.     

Circadian Neuroendocrine Role in Age-Related Changes in Body Fat Stores and Insulin Sensitivity of the Male Sprague-Dawley Rat

A role for circadian neuroendocrine rhythms in the age-related development of obesity and insulin resistance was investigated in the male Sprague-Dawley rat. The phases and amplitudes of the plasma rhythms of several metabolic hormones (i.e. corticosterone, prolactin, insulin, and triiodothyronine) differed in lean, insulin-sensitive (3-week-old rats). insulin-resistant (8-week-old rats) and obese, insulin-resistant (44-week-old rats) animals. Simulation of the daily rhythms of endogenous corticosterone and prolactin by daily injections of the hormones at times corresponding to the peak levels found in 3-week-old rats reversed age-related increases in insulin resistance and body fat in older (5-6-month-old) rats. Ten such daily injections of corticosterone and prolactin in 12-14-week-old rats produced long-term reductions in body fat stores (30%). plasma insulin concentration (40%'). and insulin resistance (60%) (determined by a glucose tolerance test) measured 11-14 weeks after the treatment. Alterations in circadian neuroendocrine rhythms may account for age-related changes in carbohydrate and lipid metabolism in the male Sprague-Dawley rat, and resetting of these rhythms by appropriately timed daily injections of corticosterone and prolactin may help maintain metabolism characteristic of younger animals.     

Thyroid status,but not insulin status,affects expression of avian uncoupling protein mRNA in chicken

The aim of this study was to investigate the hormonal regulation of the avian homolog of mammalian uncoupling protein (avUCP) by studying the impact of thyroid hormones and insulin on avUCP mRNA expression in chickens (Gallus gallus). For 3 wk, chicks received either a standard diet (control group), or a standard diet supplemented with triiodothyronine (T(3); T3 group) or with the thyroid gland inhibitor methimazole (MMI group). A fourth group received injections of the deiodinase inhibitor iopanoic acid (IOP group). During the 4th wk of age, all animals received two daily injections of either human insulin or saline solution. The results indicate a twofold overexpression of avUCP mRNA in gastrocnemius muscle of T3 birds and a clear downregulation (-74%) in MMI chickens compared with control chickens. Insulin injections had no significant effect on avUCP mRNA expression in chickens. This study describes for the first time induction of avUCP mRNA expression by the thermogenic hormone T(3) in chickens and supports a possible involvement of avUCP in avian thermogenesis.     

Circadian Neuroendocrine Role in Age-Related Changes in Body Fat Stores and Insulin Sensitivity of the Male Sprague-Dawley Rat

A role for circadian neuroendocrine rhythms in the age-related development of obesity and insulin resistance was investigated in the male Sprague-Dawley rat. The phases and amplitudes of the plasma rhythms of several metabolic hormones (i.e. corticosterone, prolactin, insulin, and triiodothyronine) differed in lean, insulin-sensitive (3-week-old rats). insulin-resistant (8-week-old rats) and obese, insulin-resistant (44-week-old rats) animals. Simulation of the daily rhythms of endogenous corticosterone and prolactin by daily injections of the hormones at times corresponding to the peak levels found in 3-week-old rats reversed age-related increases in insulin resistance and body fat in older (5-6-month-old) rats. Ten such daily injections of corticosterone and prolactin in 12-14-week-old rats produced long-term reductions in body fat stores (30%). plasma insulin concentration (40%″). and insulin resistance (60%) (determined by a glucose tolerance test) measured 11-14 weeks after the treatment. Alterations in circadian neuroendocrine rhythms may account for age-related changes in carbohydrate and lipid metabolism in the male Sprague-Dawley rat, and resetting of these rhythms by appropriately timed daily injections of corticosterone and prolactin may help maintain metabolism characteristic of younger animals.     

Amino acids and insulin are both required to regulate assembly of the eIF4E. eIF4G complex in rat skeletal muscle

The respective roles of insulin and amino acids in regulation of skeletal muscle protein synthesis and degradation after feeding were examined in rats fasted for 17 h and refed over 1 h with either a 25 or a 0% amino acid/protein meal. In each nutritional condition, postprandial insulin secretion was either maintained (control groups: C(25) and C(0)) or blocked with diazoxide injections (diazoxide groups: DZ(25) and DZ(0)). Muscle protein metabolism was examined in vitro in epitrochlearis muscles. Only feeding the 25% amino acid/protein meal in the presence of increased plasma insulin concentration (C(25) group) stimulated protein synthesis and inhibited proteolysis in skeletal muscle compared with the postabsorptive state. The stimulation of protein synthesis was associated with increased phosphorylation of eukaryotic initiation factor (eIF)4E binding protein-1 (4E-BP1), reduced binding of eIF4E to 4E-BP1, and increased assembly of the active eIF4E. eIF4G complex. The p70 S6 kinase (p70(S6k)) was also hyperphosphorylated in response to the 25% amino acid/protein meal. Acute postprandial insulin deficiency induced by diazoxide injections totally abolished these effects. Feeding the 0% amino acid/protein meal with or without postprandial insulin deficiency did not stimulate muscle protein synthesis, reduce proteolysis, or regulate initiation factors and p70(S6k) compared with fasted rats. Taken together, our results suggest that both insulin and amino acids are required to stimulate protein synthesis, inhibit protein degradation, and regulate the interactions between eIF4E and 4E-BP1 or eIF4G in response to feeding.     

Psychomotor performance during insulin-induced hypoglycemia

Subjects were given intravenous injections of insulin and/or saline on separate occasions and then tested on a pursuit-tracking task. Seven subjects showed clear clinical signs of hypoglycemia which were accompanied by a plasma glucose concentration of 32 mg/dl or less and by impaired tracking performance. Seven subjects showing no hypoglycemic signs despite insulin, and seven subjects receiving saline injections, showed no impairment in tracking. Impairment lasted from about the 15th to the 60th minute following injection, and was more readily apparent in response execution than response selection. There were no changes in accuracy of performance. Possible explanatory mechanisms, including neuroglycopenia, are discussed, and some implications for driving performance are noted.     

Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction.

Diabetes mellitus is associated with a high mortality after myocardial infarction. To see whether this may be decreased by improved diabetic control the effect of an insulin infusion regimen was studied in patients with acute myocardial infarction. From April 1982 to April 1983, 33 diabetics were admitted with acute myocardial infarction. Those being treated with diet alone or oral hypoglycaemic drugs continued with this unless control was poor, when they were changed to a "sliding scale" regimen of subcutaneous insulin injections thrice daily. Those already receiving insulin were maintained on thrice daily subcutaneous injections. From April 1983 to April 1984, 29 diabetics had acute myocardial infarction. Those receiving treatment with oral hypoglycaemic drugs or insulin were changed to continuous intravenous infusion of insulin, the aim being to maintain the blood glucose concentration at 4-7 mmol/I (72-126 mg/100 ml). Those being treated with diet alone continued with this if blood glucose concentrations were acceptable. Total mortality fell from 42% in the first year to 17% in the second (p less than 0.05). Over the same period mortality among non-diabetic patients with myocardial infarction did not change significantly. There was a significant fall in cardiac arrhythmias (expressed as the percentage of patients in whom arrhythmias were recorded) from 42% to 17% (p less than 0.05). The most significant fall in the incidence of complications occurred in those who had been receiving oral hypoglycaemic drugs on entry to the study (87% to 50%, p less than 0.05).     

Comparison of high fibre diets,basal insulin supplements,and flexible insulin treatment for non-insulin dependent (type II) diabetics poorly controlled with sulphonylureas.

OBJECTIVE--To compare high fibre diet, basal insulin supplements and a regimen of insulin four times daily in non-insulin dependent (type II) diabetic patients who were poorly controlled with sulphonylureas. DESIGN--Run in period lasting 2-3 months during which self monitoring of glucose concentration was taught, followed by six months on a high fibre diet, followed by six months'' treatment with insulin in those patients who did not respond to the high fibre diet. SETTING--Teaching hospital diabetic clinics. PATIENTS--33 patients who had had diabetes for at least two years and had haemoglobin A1 concentrations over 10% despite receiving nearly maximum doses of oral hypoglycaemic agents. No absolute indications for treatment with insulin. INTERVENTIONS--During the high fibre diet daily fibre intake was increased by a mean of 16 g (95% confidence interval 12 to 20 g.) Twenty five patients were then started on once daily insulin. After three months 14 patients were started on four injections of insulin daily. ENDPOINT--Control of diabetes (haemoglobin A1 concentration less than or equal to 10% and fasting plasma glucose concentration less than or equal to 6 mmol/l) or completion of six months on insulin treatment. MEASUREMENTS AND MAIN RESULTS-- No change in weight, diet, or concentrations of fasting glucose or haemoglobin A1 occurred during run in period. During high fibre diet there were no changes in haemoglobin A1 concentrations, but mean fasting glucose concentrations rose by 1.7 mmol/l (95% confidence interval 0.9 to 2.5, p less than 0.01). With once daily insulin mean concentrations of fasting plasma glucose fell from 12.6 to 7.6 mmol/l (p less than 0.001) and haemoglobin A1 from 14.6% to 11.2% (p less than 0.001). With insulin four times daily concentrations of haemoglobin A1 fell from 11.5% to 9.6% (p less than 0.02). Lipid concentrations were unchanged by high fibre diet. In patients receiving insulin the mean cholesterol concentrations fell from 7.1 to 6.4 mmol/l (p less than 0.0001), high density lipoprotein concentrations rose from 1.1 to 1.29 mmol/l (p less than 0.01), and triglyceride concentrations fell from 2.67 to 1.86 mmol/l (p less than 0.05). Patients taking insulin gained weight and those taking it four times daily gained an average of 4.2 kg. CONCLUSIONS--High fibre diets worsen control of diabetes in patients who are poorly controlled with oral hypoglycaemic agents. Maximum improvements in control of diabetes were achieved by taking insulin four times daily.     

Management of severely brittle diabetes by continuous subcutaneous and intramuscular insulin infusions: evidence for a defect in subcutaneous insulin absorption.

Severely brittle diabetes is defined as a rare subtype of insulin-dependent diabetes with wide, fast, unpredictable, and inexplicable swings in blood glucose concentration, often culminating in ketoacidosis or hypoglycaemic coma. To assess the role of inappropriate type, amount, or timing of insulin treatment and the route of administration as a cause of severe brittleness six patients with continuous subcutaneous insulin infusion, which provides a high degree of optimisation of dosage with exogenous insulin in stable diabetics. The glycaemic control achieved during continuous subcutaneous insulin infusion was compared with that during continuous intramuscular insulin infusion. Six patients with non-brittle diabetes were also treated by continuous subcutaneous insulin infusion. These patients achieved the expected improvement in glycaemic control (mean +/- SD plasma glucose concentration 5.1 +/- 2.3 mmol/l (92 +/- 41 mg/100 ml)), but not the patients with brittle diabetes remained uncontrolled with continuous subcutaneous infusion (13.6 +/- 5.8 mmol/1 (245 +/- 105 mg/100 ml) compared with 10.3 +/- 4.1 mmol/l (186 +/- 74 mg/100 ml) during treatment with optimised conventional subcutaneous injections). During continuous intramuscular infusion, however, glycaemic control in five of the patients with brittle diabetes was significantly improved (7.7 +/- 2.6 mmol/l (139 +/- 47 mg/100 ml). The remaining patient with brittle diabetes, previously safely controlled only with continuous intravenous insulin, did not respond to continuous intramuscular infusion. It is concluded that in five of the six patients with brittle diabetes studied here impaired or irregular absorption of insulin from the subcutaneous site played a more important part in their hyperlability than inappropriate injection strategies. This absorption defect was presumably bypassed by the intramuscular route.     

Fetal rat islet insulin deficiency following maternal administration of streptozotocin

Pancreatic islets were isolated from the fetuses of normal rats and rats made diabetic by the iv administration of streptozotocin (STZ) on either Day 3 or 5 of pregnancy. Of the rats made diabetic on Day 3, one group also received insulin injections at the appearance of glucosuria. Maternal blood glucose on Day 20 of gestation was significantly different in the diabetic rats (405 +/- 27 mg/dl) from the normal (97 +/- 1 mg/dl) and insulin-treated diabetic rats (69 +/- 9 mg/dl). While fetal weight was significantly decreased in the STZ-treated rats (2.64 +/- 0.13 g vs 3.52 +/- 0.05 g for the control group, P less than 0.005), fetal glucose was significantly higher in the STZ-treated than in normal pups (342 +/- 11 vs 35 +/- 1 mg/dl, P less than 0.005). Both fetal weight and glucose were normalized by insulin treatment: 3.16 +/- 0.18 g and 31 +/- 7 mg/dl, respectively. Insulin release from fetal islets of diabetic dams was blunted after a week in culture both in basal and stimulated conditions. After 2 weeks in culture, there was partial recovery in the insulin response to glucose but it did not equal to that measured in fetal islets from the normal and insulin-treated diabetic rats. These data suggest maternal hyperglycemia severely impairs fetal weight and insulin release from fetal rat islets in vitro, and correction of the hyperglycemia by insulin treatment not only improves fetal weight and glucose concentrations, but it also normalizes insulin release from fetal rat islets in vitro.     

Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: a comparison study in type 2 diabetes with conventional insulin regimen failure.

OBJECTIVE: To compare the effectiveness of two intensified insulin regimens, i.e., pump delivery versus multiple daily injections in patients with type 2 diabetes not optimally controlled with conventional insulin therapy. RESEARCH DESIGN AND METHODS: Seventeen type 2 diabetes patients uncontrolled by two daily injections of regular plus NPH were randomly assigned in a cross-over fashion to either three daily injections of lispro plus NPH or pump device delivering lispro. HbA1c, 6 points capillary blood glucose, 24-hour continuous glucose monitoring system tracings and global satisfaction score were evaluated at the end of each 12-week treatment period. RESULTS: HbA1c decreased from 9.0+/-1.6% to 8.6+/-1.6% with multiple injections and 7.7+/-0.8% with pump device (p<0.03). Capillary blood glucose was lowered at all time-points with pump, but only at morning with multiple injections (p<0.01). Compared to conventional therapy, pump reduced hyperglycemic area under curve by 73% (p<0.01), but multiple injections by only 32% (p=0.08). Rate of hypoglycemia was not increased and patient's satisfaction was comparable with both intensive treatments. CONCLUSIONS: Pump therapy provides a better metabolic control than injection regimens, and seems to be safe and convenient in patients with type 2 diabetes who fail to respond to conventional insulin therapy.     

Plasma constituents and mortality in rat pups given chronic insulin via injection, pellet, or osmotic minipump

Two studies compared the glucose responses of 9-day-old rats given subcutaneous insulin, either continuously or via daily injection, for 10 days. In Experiment 1, implanted pellets released a total of 0, 1.9, or 5.7 U insulin/kg the first 24 h. Injected doses were larger, 0 or 8 U/kg. Injections caused no deaths, but insulin-releasing pellets caused high mortality within 24 h. Pups surviving the pellets were normoglycemic by treatment day 8. In Experiment 2, pups received 0.184 U of insulin daily, approximately 8 U/kg at 9 days, via either injection or osmotic minipump. All pups survived. Injected pups were hypoglycemic 2 h postinjection through treatment day 10, whereas pups with insulin minipumps were normoglycemic by day 5. Insulin injections, but not minipumps, lowered plasma triglycerides on day 10. To examine age differences in response to insulin, additional pups and adults received daily injections of 0 or 8 U/kg for 10 days. All survived. Insulin lowered plasma glucose more in pups than in adults and reduced triglycerides in pups but not in adults. The rapid development of normoglycemia in pups with insulin minipumps, compared with pups injected daily with the same dose, suggests that continuous early insulin may produce insulin resistance.     

Effects of HCG or gonadoreline on seminal parameters and plasma testosterone levels in young male rabbits

The effect of successive HCG or Gonadoreline injections on some reproductive parameters in 21 young male rabbits, aged from 4 to 4.5 months, has been studied. Animals were randomly allocated in three groups of seven to receive weekly (on each Monday) i.m. injections of 20 mg Gonadoreline, 50 IU HCG, or 0.5 ml Saline solution, respectively. The ejaculate from each male was collected and analysed twice a week (Tuesday and Friday). Higher sperm volumes were observed on the first week after Gonadoreline administration compared to the other groups (p < 0.05), and lower values during the second week in the Control group vs. Gonadoreline group (p < 0.05). Sperm volume increases after the 3rd week in Control animals (p < 0.05). When considering the global period studied, mean sperm volumes achieved after Gonadoreline treatment were higher than in HCG or Control group. Despite the random distribution of the animals to each treatment, and although throughout the experiment more ejaculates were discarded in the Gonadoreline group, the final number of doses obtained per ejaculate was higher in this group followed by HCG treated animals. Globally, the mean sperm concentration of the Control group during the entire studied period was significatively lower compared to the other groups (p < 0.001). No sperm motility differences were detected among the groups (p < 0.1174). HCG injections caused a significative increase in plasma testosterone concentration during the first and second week (p < 0.001) and similar plasma levels were observed in all groups afterwards. No direct plasma testosterone increasing levels owed to Gonadoreline injections were detected, probably due to the frequency of blood sampling (once a week).     

Decreased response of plasma catecholamine to stress in diabetic rats

Previously we reported that the heart norepinephrine concentration was markedly increased in diabetic rats. To further study the relationship between a disturbance in the autonomic nervous system and catecholamine metabolism in diabetes mellitus, the plasma catecholamine response to stress and catecholamine concentration of heart and adrenals were measured. Wistar male rats were made diabetic by streptozotocin and kept for 13 weeks. A silicon catheter was placed in the superior V. cava 1 week prior to the experiment. Insulin was injected subcutaneously for 3 days once daily. After an overnight fast and without anesthesia, 1 ml of blood, a control sample, was obtained and then the animals were exsanguinated. The blood was mixed with 1 mM EGTA at a final concentration and centrifuged. The tissue was homogenized with 0.4 N perchloric acid containing 1 mM EGTA and centrifuged at 10,000 x g for 20 minutes. Catecholamines were determined by high performance liquid chromatography. Normal rats responded to blood withdrawal stress, and plasma catecholamines were markedly increased, but almost no increase or an actual decrease was observed in diabetic rats. These abnormal responses were improved by insulin treatment. Heart norepinephrine was increased significantly in the diabetic rats compared with the control rats and was reduced significantly by insulin injections. Adrenal epinephrine was also significantly increased in the diabetic rats compared with the control rats, but was not significantly reduced by insulin. These result suggest a possible disturbance of catecholamine secretion in the diabetic rats.     

Clenbuterol-Induced Insulin Resistance in Calves Measured by Hyperinsulinemic,Euglycemic Clamp Technique

Hyperinsulinemic, euglycemic clamp tests were performed on calves before and after clenbuterol treatment. Clenbuterol was given as 2 intramuscular injections with an interval of about 12 h. The dose used was 1 μg/kg b.w. The treatment resulted in increased plasma levels of insulin and glucose. The results of the clamp tests showed that clenbuterol induced a transient decrease in insulin sensitivity. Both insulin mediated glucose disposal (M), expressed as μmol/kg live b.w./min. and the M/I-index (M divided by the average insulin concentration at steady state) were significantly reduced after treatment. The effect of clenbuterol on carbohydrate metabolism seemed to be rather short-lived, since significant changes occurred only in animals treated 5-6 h prior to the test. According to the literature, the metabolic effects of clenbuterol have been studied only after the high doses used for growth promoting purposes. The results from the present study showed that similar changes occur also after doses at the therapeutic level. The hyperinsulinemic, euglycemic clamp test was considered to be a valuable tool for the study of insulin sensitivity in cattle.     

Secretion of glucagon and insulin in hypophysectomized rats: effect of tolbutamide.

Normal and hypophysectomized (hypox) rats, fed ad libitum, received intraperitoneal injections of tolbutamide (75 mg/kg/day) or of saline for 6 weeks. 24 h after the last injection, blood samples were taken for glucose, insulin and glucagon determinations. In normal rats, tolbutamide treatment did not alter serum glucose, insulin and glucagon, although it suppressed the secretion of insulin and glucagon by the pancreatic islets. In hypox rats, tolbutamide decreased serum glucose and insulin, elevated serum glucagon and stimulated the secretion of glucagon, but not that of insulin by the pancreatic islets. In addition, tolbutamide treatment increased the glucagon response to arginine in normal, but not in hypox rats. The serum glucose response to arginine was decreased by tolbutamide treatment and by hypophysectomy and, thus, appeared independent of the glucagon rise or preexisting glucagon level. We conclude that tolbutamide treatment decreased the secretion of glucagon and insulin in normal rats and stimulated that of glucagon in hypox rats, perhaps because of the low levels of insulin in the serum and in the pancreas of the latter. Our results are compatible with the hypothesis that the pancreatic action of tolbutamide is influenced by the pituitary.