Sodium at high concentrations increases glucose-induced insulin secretion in the perfused rat pancreas

To study the effects of supraphysiologically high sodium concentrations on insulin secretion, the rat pancreas was perfused with normal Krebs-Ringer bicarbonate buffer (KRBB) solution and with KRBB solutions containing an additional 25 and 50 mmol/l NaCl. The first phase of insulin secretion in response to 18 mmol/l glucose was enhanced in a dose-dependent manner, from 20.8±4.0 pmol for 4 min in normal KRBB to 36.2±10.3 pmol (P<0.05) and 60.3±14.6 pmol (P<0.01) with addition of 25 and 50 mmol/l NaCl, respectively. The second phase secretion was significantly increased by the addition of 50 mmol/l NaCl (259.4±38.6 vs 170.9 ±47.4 pmol for 16 min P<0.05). The addition of 50 mmol/l isethionate Na to normal KRBB solution also increased the first and second phases of insulin secretion in response to glucose. The increase in osmolarity by the addition of mannitol to normal KRBB solution did not affect the glucose-induced insulin secretion. A high sodium concentration affected neither tolbutamide-induced nor arginine-induced insulin secretion. It is suggested that sodium concentrations have an important role in insulin secretion in response to glucose, but not to other secretagogues. Received: 29 January 1998 / Accepted in revised form: 24 June 1998     

Basal and tolbutamide-induced plasma somatostatin in healthy subjects and in patients with diabetes and impaired glucose tolerance

Peripheral levels of basal and tolbutamide-induced somatostatin have been measured in patients with diabetes or impaired glucose tolerance (IGT) and compared with those in normal individuals. Basal somatostatin was significantly higher in patients with Type 1 diabetes than in age-matched control subjects. This increase was most pronounced at diagnosis, and appeared to be related to metabolic control in insulin-treated patients. No increase was noted in patients with Type 2 diabetes or with IGT. Intravenous bolus injection of tolbutamide enhanced peripheral somatostatin levels in healthy volunteers in a biphasic manner. Patients with IGT also exhibited a biphasic response but the amplitude of the first phase was higher. No secretory response was detected in 27/29 Type 1 diabetic patients at diagnosis; a somatostatin response to tolbutamide became detectable again in Type 1 patients with normalization of their basal somatostatin levels but was then paradoxically related to poor blood glucose control. In Type 2 diabetes, basal somatostatin levels were similar to age-matched control subjects, but decreased upon intravenous tolbutamide administration.     

Ultrastructure of β-cells during the dynamic response to glucose and tolbutamide in vitro

Summary Ultrastructural changes in cells of the isolated perfused rat pancreas were observed during the dynamic response to glucose and tolbutamide. Evidence of granule secretion into the extracellular space by emiocytosis was noted during the first 60 sec of glucose stimulation, but not thereafter nor at any time during tolbutamide stimulation. Packaging of granules within the Golgi apparatus was apparent after 60 min of glucose injection, but not in the case of tolbutamide. These findings support the concept that glucose initially stimulates the release of a small labile pool of preformed insulin, while continued administration stimulates Golgi packaging activity and the provision of additional insulin for the secretory process. High tolbutamide alone, in contrast increases the Golgi complex, coated vesicles, multivesicular bodies and cytosegresomes. Thus it may stimulate packaging without insulin provision, or alternatively, increase lysosomal degradative processes.Supported in part by U.S. Public Health Service Grants AM 11182 and AM 01410.     

Insulin secretion in patients with myotonic dystrophy and their relatives

Summary Oral glucose, i.v. tolbutamide and i.v. arginine tolerance tests were performed in 11 patients with myotonic dystrophy and 9 of their clinically unaffected relatives. Five of the myotonic patients had glucose intolerance; 7 had exaggerated immunoreactive insulin (IRI) response to glucose. One of the 9 relatives demonstrated glucose intolerance and none had exaggerated insulin response to glucose. Three relatives, all obese, hyperresponded to arginine and one of them also responded excessively to tolbutamide. The results indicate that an exaggerated IRI response to glucose is common in myotonic dystrophy. Enhanced responses to other stimuli are less frequent. Although glucose intolerance occurred in half of the patients, the fact that the highest IRI levels were seen in non-diabetic patients suggests that this excessive response may protect against glucose intolerance. Our studies in relatives do not support the potential usefulness of testing for hyperinsulinemia in the early detection of myotonic dystrophy. Presented at the 9th International Diabetes Federation Congress in New Delhi, India, November 2, 1976.     

Insulin secretion in children with growth retardation

The effect of tolbutamide administration on insulin secretion was studied in 69 children with growth retardation. Diminished insulin secretion was found in all the patients, compared to the control group. This insulin deficit was most evident in patients with isolated, total GH deficiency and least evident in children with idiopathic short stature. Intermediate values were found in dwarfism due to isolated, partial GH deficiency.These results favour the hypothesis that hypoinsulinism contributes to the somatotropin deficiency in causing growth retardation.Abbreviations PD pituitary dwarfism - FSS familial short stature - GR growth retardation - GH growth hormone - ISS idiopathic short stature - tbt tolbutamide - GHtd isolated, total GH deficiency - GHpd isolated, partial GH deficiency     

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes

Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group).In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration.In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response.In the subset with a fasting blood glucose concentration of less than 8 mmol·l^–1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.     

HPLC法测定甲苯磺丁脲片的含量

目的：建立HPLC法测定甲苯磺丁脲片的含量。方法：色谱柱为VP—ODSC18（250mm×4．6mm,5μm）,甲醇一磷酸二氢铵溶液（pH：3．5）（65：35）为流动相,流速为1．0ml·min^-1,检测波长为254nm,柱温：室温,进样量：20μl。结果：甲苯磺丁脲在0．08—1．20mg·ml^-1浓度范围内与峰面积呈良好的线性（r=0．9998）。平均回收率为99．61％（RSD=0．8％,n=9）。结论：本法定量准确,可用于甲苯磺丁睬片的含量测定。     

The significance of the blood glucose level for plasma insulin response to intravenously administered tolbutamide in healthy subjects

Summary The effect of intravenous tolbutamide on insulin release in normal human subjects was investigated under various experimental conditions. The blood glucose level was either allowed to fall after i.v. tolbutamide or kept within normal limits by a concomitant glucose infusion. In other experiments, tolbutamide was given during different degrees of hypoglycaemia induced by insulin. It was found that tolbutamide provoked a rapid and short-lasting insulin release as well as a post-initial and extended insulin release, provided the blood glucose concentration was kept within normal limits. The hitherto accepted transiency of tolbutamide action in healthy subjects seems to be due to the hypoglycaemia which follows the administration of the drug. During more marked hypoglycaemia induced by exogenous insulin, the insulin releasing capacity of tolbutamide was almost blunted. Tolbutamide markedly enhanced the insulin release following glucose administration. The findings presented might clarify some of the therapeutic effects of the drug in diabetes mellitus.This study was supported by grants to E.C. and R.L. from the Swedish Medical Research Council (B69-19X-34-05A) and the Knut and Alice Wallenberg Foundation.     

C-peptide blood levels in keto-acidosis and in hyperosmolar non-ketotic diabetic coma

Summary For further evaluation of B-cell secretion in diabetic keto-acidosis (KA) and in non-ketotic hyperosmolar coma (NKHC), basal and post-i.v. tolbutamide blood CPR and IRI values were measured in 34 patients (22 KA and 12 NKHC). FFA, cortisol and HGH measurements were also performed. IRI was low in both KA and NKHC (0.07±0.01 and 0.082±0.01 nmol/l) as opposed to CPR which was significantly higher in NKHC (1.14±0.1 nmol/l) than in KA (0.21±0.03 nmol/l). After tolbutamide injection, CPR and IRI levels did not change in any of the KA cases, whereas they significantly increased in half of the NKHC cases. Cortisol and FFA values were similarly increased in both situations, as opposed to HGH which was significantly higher (6.1±1.2 ng/ml) in KA than in NKHC (1.9±0.2 ng/ml). These results suggest that B-cell function is less deficient in NKHC than in KA. Residual insulin amounts reaching the liver via the portal vein could partly account for the absence of ketosis in NKHC.     

The behaviour of the serum insulin level in non obese adult diabetics after intravenous glucose,tolbutamide and glucagon

Summary The serum insulin and blood glucose levels after the i.v. administration of three secretion stimuli, namely glucose, tolbutamide and glucagon, were investigated in 10 normal weight patients with maturity-onset diabetes and compared with the levels in a control group. The insulin values were lower in the diabetics than in the normals after each of the three stimuli. Glucose was the most potent in normals and the least potent in diabetics. The behaviour of the serum insulin level after glucose was not uniform in the diabetics; in some patients the rise was either delayed or diphasic. It may be assumed that in maturity-onset diabetes of normal body weight the biosynthesis and release of insulin are impaired by some influence exerted by the main factor, i.e. the glucose metabolism within the -cells of the Langerhans islets.

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Zusammenfassung Bei 10 normal-gewichtigen Patienten mit Alters-Diabetes wurde das Verhalten der Insulinaemie und des Blutzuckers nach i.v. Verabreichung von 3 die Insulinsekretion anregenden Substanzen untersucht: Glukose, Tolbutamid, Glukagon. Die Resultate wurden mit denjenigen der Kontroll-gruppe verglichen. Die Insulinwerte nach der Verabreichung der 3 die Sekretion stimulierenden Substanzen waren bei den Diabetikern niedriger als bei den Normalpersonen. Die Glukose erwies sich als der kraeftigste Reiz bei Nicht-Diabetikern und der schwächste bei den Diabetikern. Das Verhalten der Insulinaemie nach Verabreichung von Glukose war bei den Diabetikern nicht gleichmaessig: bei einer Anzahl von Faellen war das Ansteigen der Insulinaemie verspaetet oder zeitigte ein biphasisches Verhalten. Man darf annehmen, dass die Patienten mit Diabetes des Erwachsenenalters und Normalgewicht eine Veraenderung der Biosynthese und der Insulinfreisetzung unter dem Einfluss des Hauptfaktors, d.h. des Glukosestoffwechsels innerhalb der -Zellen der Langerhans'schen Inseln aufweisen.

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Resumen En 10 enfermos de diabetes madura, de peso normal, se ha estudiado el comportamiento de la insulinemia y de la glicemia después de haberles suministrado i.v. tres substancias estimulantes de la secreción insulínica: glucosa, tolbutamida y glicogón. Los resultados han sido comparados con los que se han obtenido en el grupo de control. Los valores insulínicos observados tras el suministro de las tres substancias estimulantes de la secreción han resultado más bajos en los individuos diabéticos que en los sanos. La glucosa ha resultado el estimulante más poderoso en la secreción de individuos normales y el más débil en los diabéticos. El comportamiento de la insulinemia tras suministro de glucosa no ha sido uniforme en los enfermos de diabetes: en una parte de ellos el aumento de la insulinemia se presentaba retrasado o con una marcha difásica. Se puede suponer que los enfermos con diabetes de la madurez y de peso normal presenten una alteración de la biosíntesis y de la liberación de insulina bajo la influencia del factor principal, es decir, del metabolismo de la glucosa dentro de las células de las islas de Langerhans.

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Resume Les AA. ont étudié 10 sujets avec diabète de la maturité, de poids normal, de point de vue de l'insulinemie et de la glycémie après administration i.v. de trois substances stimulantes la sécretion insulinique: glucose, tolbutamide et glucagone. Les résultats étaient comparés avec ceux obténus dans le groupe de contrôle. Les valeurs insulinémiques observés après l'administration des trois substances stimulates la sécretion étaient inferieurs chez les diabétiques vis à vis aux valeurs observés chez les sujets normaux. Le glucose est resulté le stimulus le plus éfficace sur la sécretion chez les sujets normaux et le moins éfficace chez les diabétiques. Le comportément de l'insulinemie après administration de glucose n'était pas uniforme chez les sujets diabétiques: dans une partie de ceux-ci l'augmentation de l'insulinemie était retardée ou démontrait une allure diphasique. On peut envisager que le sujets avec diabète de la maturité et de poids normal présentent une altération de la biosynthèse et de la libération de insuline sous l'influence du facteur principal c'est à dire du métabolisme du glucose dans les cellules beta des îles de Langerhans.

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Riassunto In 10 pazienti affetti da diabete maturo, di peso normale, è stato studiato il comportamento dell'insulinemia e della glicemia in seguito alla somministrazione i.v. di tre sostanze stimolanti la secrezione insulinica: glucosio, tolbutamide e glucagone. I risultati sono stati confrontati con quelli ottenuti nel gruppo di controllo. I valori insulinici osservati dopo la somministrazione delle tre sostanze stimolanti la secrezione sono risultati inferiori nei diabetici che nei soggetti sani. Il glucosio è risultato il più potente stimolo sulla secrezione nei soggetti normali ed il meno potente nei diabetici. Il comportamento dell'insulinemia dopo somministrazione di glucosio non è stato uniforme nei pazienti diabetici: in una parte dei casi l'aumento dell'insulinemia era ritardato od aveva andamento difasico. Si può supporre che i pazienti con diabete della maturità e di peso normale presentino un'alterazione della biosintesi e della liberazione di insulina sotto l'influenza del fattore principale, cioè del metabolismo del glucosio entro le cellule delle isole di Langerhans.