Insulin release in the isolated perfused rat panereas was measured after stimulation with B-Hydroxy Butyrate, Acetoacetate and Palmitate. Tbe perfusion medium contained either 2.75,5.5 or 11 mM glucose or was glucose free. Neither Palmitate, B-Hydroxy Butyrate, nor Acetoacetate was capable of inereasing insulin release when perfused in the absence of glucose. With glucose (5.5 mM) Palmitate, Acetoacetate and B-Hydroxy Butyrate produced a significant inerease in the insulin seeretion. A greater inerease was seen with Acetoacetate and Palmitate than with B-Hydroxy-Butyrate. However, in every case, there was a deerease in the insulin seeretion before reaching the end of the ketone bodies and Palmitate infusions.Our results indicate that the mechanism through which these substances promote insulin seeretion are glucose dependent and glucose 11 mM potentiates the action of BHydroxy Butyrate.

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 (500 micrograms X h-1 X kg-1) diminished glucose induced increase of plasma insulin by 56% (15.2 +/- 0.9 versus 6.6 +/- 0.6 ng/ml, p less than 0.01, mean +/- SEM). Somatostatin infused at a rate of 50 micrograms X h-1 X 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 micrograms/kg) significantly increased and prolonged the hypoglycaemic effect of exogenous insulin. It is suggested that C-peptide may not be a biologically inert substance.

Insulin and glucagon release in the isolated perfused rat pancreas was measured after stimulation with tolbutamide. The perfusion medium contained either 5.5 mM of glucose or was glucose free. During the first ten min of perfusion with tolbutamide, insulin output rose rapidly while glucagon release was signiticantly depressed After aperiod of prolonged stimulation glucagon began rising again but did not return to initial levels. Following destruction of insulin-producing Bcells by streptozotocin, tolbutamide still caused identical inhibition of glucagon secretion, as in the presence of intact islets. A signiflcant inverse relationship between insulin and glucagon output seemed to be established Yet, despite the fact that considerably higher insulin levels were kept in the presence of S.S mM glucose in the perfusate, tolbutamide effected about the same depression of glucagon quantitatively

Hyperglycemia was recently described in diabetic mutant mice (Laube, Fußgänger, Maier and Pfeiffer 1973). In obese hyperglycemic mice, however, hypertrophy of the alpha cells has already been noted in 1953 (Mayer, Andrus and Silides), while significantly elevated levels of total pancreatic glucagon (IMG) were only found 20 years later (Findlay, Rookledge, Beloff Chain and Lever 1973). In view of rather conflicting results in obese patients (Kalkhoff. Matute and GosS4in 1972, Paulsen and lAwrence 1968, Wise, Hendler and Felig 1973, the present report deals with the dynamics of glucagon release in obese hyperinsulinemic-hyperglycemic mice (ob/ob).Lean Iitter controls and obese hyperglycemic mice (Jackson Laboratory, Bar Harbour, USA) approximately 6 months old, weighing 50-65 gm, were used. Fasting blood sugar levels were ranging between 75-88 and 150-180 mg% respectively. The pancreas was dissected and perfused in an analogous way to that described for rats (Sussman, Vaughan and Timmer 1966). Glucose (2.75 and 8.25 mM) and arginine (8.25 mM) were used as substrate. Glucagon was measured immunologically, details of the assay were described elsewhere (Laube et al. 1973).

Pancreozymin stimulates glucagon and insulin release independently of the autonomous nervous system in the isolated perfused rat pancreas in vitro. Dynamics of secretion show primary release of insulin and secondary secretion of glucagon. Presence or absence of glucose in the perfusion medium influences this pattern inversely: ~uc~se concentrations of about 100 mg % potentiate msulin release and decrease glucagon secretion, whereas absence of glucose is accompanied by augmentation of glucagon, and depression of insulin secretion.Honn. Metab. Res. 1: 224-227 (1969) K e y -W 0 r d s: Pancreozymin -Insulin Secretion in vitro -Glucagon Secretion in vitro -Isolated Perfused Rat Pancreas Stimulation of insulin release by pancreozymin (CCK-PZ) has been repeatedly observed in vivo as weIl as in vitro (cf. Pfeif/er and Raptis, 1968). Augmentation of plasma glucagon levels following pancreozymin was found in men and dogs by Unger, Ketterer, Dupre and Eisentraut (1967); Bucha'}On, Vance, Morgan and Williams (I 968); Dupre, Olms, Unger, Waddell and Beck (I 969). On the other hand, Buchanan, Vance and Williams (1969) were unable to demonstrate any effect of pancreozymin on glucagon secretion of isolated islets of rats in vitro. Moreover, Lazarus, Voyles, Devrim, Tanese and Recant (1968) as weIl as Malaisse and Malaisse-Lagae (1968) and Turner (1969) failed to confirm in vitro effectiveness of pancreozymin on incubated pieces and islets of rat and rabbit pancreas as regards stimulation of insulin secretion. Conceming the action of pancreozymin on the exocrine pancreas, Foreli, Stahlheber, Otte and Görlich (I969) suggested a linkage with a vagus reflex mechanism initiated by the contact of bile with duodenal mucosa, resulting from cholecystokinin activity. On account of this, one might • Supported by Deutsche Forschungsgemeinschaft, Bad Godesberg.assurne effectiveness of pancreozymin on islets of Langerhans in vivo only. Experiments in dogs showed an instantaneous secretion of glucagon accompanied simultaneously by an increase of insulin. In view of the known insulinogenic action of glucagon (Samols, Marri and Marks, 1965; Turner and McIntyre, 1966; Grodsky, Bennett, Smith and Schmid, 1967, a chain reaction resulting in the successive secretion of pancreozymin -glucagon -insulin was considered by Unger, Ohneda, Valverde, Eisentraut and Exton (1968) and Marks and Samols (1968). At variance to the fmdings given above, our studies report insulinogenic and glucagonogenic activities of pancreozymin on the isolated perfused rat pancreas in vitro, too. However, an inverse sequence of secretory reactions was observed. Materials and MethodsMale 250 g Wistar-albino-rats (Fa. Thomae, Biberach) were fasted 15 hours before operation, which was carried out under anesthesia with Nembutal ®. Preparation ot the isolated pancreas was performed according to Sussman, Vaughan and Timmer (I966) Le. the pancreas was separated from all surrounding tissue. The gland was perfused with an 02/C02 saturated, blood-free 1 % albumin (bovine serum albu...

Wistar albino male rats with a body weight between 80-100 g and an age of 36-40 days were submitted to a subtotal pancreatectomy (95 %). The subtotal pancreatcctomy is followed by a prediabetic period of 3-4 weeks duration, where the basal blood glucose is normal, the i.v. glucose tolerance test pathological, basal IMI lower than normal and no insulin release after i.v. glucose load. One group of rats was treated orally immediately after operation with HD 419 (Glybenclamid) I mg/kg body weight, dissolved in water. Resu!ts: 1) The increase in body weight of partially pancreatectomized rats can be normalized by administration of HB 419. 2) 14 days after operation in partially pancreatectomized rats there is an increase in blood glucose level 7 hours after food intakc. 3) The amount of immunlogical measurable insulin in blood decreases to about half of the initial value after 3 weeks, and after a 4-weeks-treatment the IMI-Ievel amounts to almost double the initial level. 4) In partially pancreatcctomized rats after i.v. glucose injection there is no reactive insulin response. Treatment with HB 419 does not affect these phenomena. Dur rcsults indicate that HD 419 as weil as the other sulfonylurea have an influence on the islet cell system, however, on the whole they stimulatc only basal insulin secretion. Reactivity of B-cells to an increase in glucmc concentration in arterial blood is not changed.

No abstract

Normal male rats were made hyperglycemic for 24 hours by the infusion of high amounts of glucose and the effect of mannose, glucose and glucose plus glucagon on insulin biosynthesis and release was studied in the isolated islets. Saline infused animals served as controls. It was found that all stimuli markedly enhanced the pro-/insulin biosynthesis in islets from hyperglycemic rats in comparison with saline infused animals. Maximal insulin release was observed in the control group with 300 mg/dl glucose plus 10 microgram/ml glucagon, while submaximal stimulation with 100 mg/dl mannose or glucose resulted in a higher insulin secretion rate in B-cells from hyperglycemic animals at 60 min, when compared with the saline infused animals. The results show that elevation of the blood glucose results in an overall stimulation of insulin biosynthesis and secretion, while lowering of the blood sugar as in starvation predominantly decreases the glucose dependent mechanisms for both insulin synthesis and release.