Lateral modulation of the hypoglycemic action of insulin

The results of the experimental investigation on 15 rabbits are presented here. Hypoglycemic action of the standard exogenic insulin dose strengthened after performing transcerebral lateral electrostimulation on the right side with the weak current impulse.     

The discovery of hypoglycemic sulfonamides

In 1933 Auguste Loubatières started to work at the Physiological Laboratory of the Montpellier Medical School, famous for the scientific work of Emmanuel Hédon and then Louis Hédon on experimental diabetes mellitus. Auguste Loubatières was particularly interested in the study of a new preparation of long-lasting insulin (insulin-protamine-zinc: IPZ) in the totally pancreatectomized dog. In 1938, he observed that high doses of IPZ induced a severe and protracted hypoglycemia entailing convulsive attacks and even irreversible coma. The story of hypoglycemic sulfonamides started in France in spring 1942. During the second world war, because of the food shortage in Montpellier, a lot of people ate rotting food or even food contaminated with bacteria, such as shellfish. Many cases of thyphoid fever were diagnosed and treated by Marcel Janbon at the Clinic of the Montpellier Medical School with a new sulfonamide (VK 57 or 2254 RP). Adverse reactions were observed: in some patients, convulsions and even prolonged coma occurred; in some others a major drop in blood glucose was observed. M. Janbon informed the physiologists about these observations questioning them for an interpretation. A. Loubatières was particularly interested and immediately undertook animal trials. On June 13, 1942, he observed that repeated oral administration of 2254 RP in the normal fasting conscious dog induced a progressive, marked and long-lasting decrease in glycemia. He continued his experiments and definitively established the hypoglycemic effect of this sulfonamide. However the mechanism of action remained to be established. The pattern of some graphs reminded him that of some others he could previously observe in the study with IPZ; it occurred to him that 2254 RP could lower the blood glucose concentration by stimulating insulin secretion. He had then to establish the validity of his hypothesis. From 1942 to 1946, A. Loubatières performed a systematic study of the effects of 2254 RP and structural analogs and investigated the mechanism involved in the hypoglycemia. These results are reported in his "Doctorat ès-Sciences" thesis (1946). He observed that 2254 RP was ineffective on glycemia in totally pancreatectomized dogs but was effective in partially pancreatectomized ones. The hypoglycemic effect in normal dog was dependent on the plasma sulfonamide concentration; this effect appeared whatever the route of administration and was unaffected by vagotomy. Furthermore, Loubatières performed cross-circulation experiments. In these experiments, the pancreatico-duodenal vein of a normal dog was anastomosed to the jugular vein of a receiver dog made diabetic by alloxan; in this case, the injection of 2254 RP into the donor induced a decrease in blood glucose levels in the receiver. In early 1946, Auguste Loubatières proposed that the hypoglycemic property of 2254 RP was due to its ability to stimulate insulin secretion through a direct action on pancreatic islets; he wrote in his thesis "A notre avis, le para-amino-benzène-sulfamido-isopropylthiodiazol (2254 RP) est donc un corps essentiellement insulino-sécréteur; son action s'exerce directement sur les ?lots de Langerhans". He also proposed to use such hypoglycemic sulfonamides in certain forms of diabetes "que l'on peut qualifier de fonctionnels et qui sont la conséquence d'une paresse des mécanismes insulino-sécréteurs". In 1992, Jean-Claude Henquin demonstrated that the sequence of events triggered by 2254 RP at the level of islet beta-cells was similar to that induced by sulfonylureas of the first or second generation. Thus, the 2254 RP, proposed by Auguste Loubatières in the treatment of certain forms of diabetes, was the first of oral hypoglycemic sulfonamides currently used in the treatment of type 2 diabetes mellitus.     

Species-specific hypoglycemic activity of triphenylphosphoranylideneacetophenones.

The species-specific hypoglycemic activity of two 2-triphenylphosphoranylideneacetophenones is described. 2-Triphenylphosphoranylideneacetophenone (SK&F 45359) and 2-triphenylphosphoranylidene-m-trifluoromethyl-acetophenone (SK&F 62775) were hypoglycemic in various rat models, but failed to exhibit hypoglycemic activity in other species.     

Catecholamines in the rat brain during hypoglycemic convulsions and coma

The purpose of the study was to investigate the relation between the catecholamines: noradrenaline and dopamine in the rat brain on one hand and hypoglycemic convulsions and coma on the other. Concentrations of noradrenaline in the hypothalamus, brain stem and cerebral cortex were decreased during hypoglycemic convulsions and were lower during coma than those during convulsions. Dopamine concentration in the striatum was decreased during convulsions and coma. It was shown that the decrease in concentration of catecholamines was a result of hypoglycemia but not of insulin action itself. Clonidine- alpha 2 agonist accelerated occurrence and prolonged duration of hypoglycemic convulsions. Haloperidol-dopamine receptor blocker had no effect on the time of occurrence or duration of convulsions and coma. The results indicate that noradrenaline may exert an inhibitory influence on hypoglycemic convulsions. No evidence has been provided to support involvement of dopamine in the control of hypoglycemic convulsions and coma.