Diabetogenic effect and inhibition of insulin secretion induced in normal rats by ammonium infusions

Abstract

Summary. In order to explain the abnormalities of glucose metabolism previously observed in patients with blood ammonia elevation, the effect of a transitory hyperammonemia on I. V. glucose tolerance was investigated in rats. An I. V. glucose tolerance test was performed in 3 groups of 15 rats 60 min after the beginning of a 95 rain infusion of either a 2 ml isotonic NaC1 solution (control group) or ammonium acetate solutions at low (0.50 gmol/kg/min. NI-I4+ ) or high doses (1.70 ~tmol/kg/min NH4+ ). The "high" NH4+ infusion produced an increase of blood ammonia to levels near 1000 ~tg/100 ml, a significant decrease in the K coefficient for glucose disappearance (2.53 x 10-24-0.20 compared to 4.92 x 10 -a 4-0.13 in control group) and a suppression of the radioimmunological plasma insulin (I. R. I.) response to glucose.With the "low" NH 4 -/-infusion the hyperammonemia was less pronounced (200-300 gg/100 ml), but the decrease in K(3.02 x 10 -2 4-0.15) and in the first phase of I.R.I. release remained significant. The decrease in glucose disappearance rate could be accounted for by the proportional decrease in insulin secretion. Thus glucose intolerance induced by ammonium acetate infusions may be due to a direct effect of NI"I 4 "1-on the pancreas. These abnormalities in glucose metabolism depend on the quantity of infused ammonium.Key words: Rat, ammonium infusion, blood ammonia, glucose metabolism, plasma immunoreactive insulin.In 1955 Bessman et al [4] suggested that the neurotoxicity of hyperammonemia in porto-systemic encephalopathy results from a disturbance in cerebral glucose utilization. The observation, in hepatic coma, of a decrease in cerebral oxygen consumption [12,22] and an increase in some intermediates of glucose metabolism [11,35] supports this hypothesis. However the influence of variations in ammonium metabolism on the regulation of carbohydrate metabolism is still debated [10,34]. Recently, we noted that I. V. glucose tolerance was worse in cirrhotic patients with hepatic coma than in those without porto-systemic encephalopathy [30]. One factor which could explain this observation, was the increase in arterial blood ammonia which was consistently observed during hepatic coma. Thus we noted in both normal and cirrhotic subjects, infused with ammonium chloride or acetate, that a transitory elevation in arterial blood ammonia invariably brought about a very significant diminution in I. V. glucose tolerance [31] and an inhibition of the insulin secretion induced by the glucose load [32]. However, in these studies, we were unable to show any correlation between these anomalies and the blood ammonia levels. The aim of * Presented at the 9th Meeting of the European Association for the Study of the Liver. Hemsedal, Norway, september [6][7] 1974 the present study was to compare in normal rats the action of a moderate or gross hyperammonemia on glucose tolerance and insulin secretion. Material and MethodsThree groups of 15 male Wistar rats, weighing 250-300 g and fasted for 20 hours, were used. Afte...

The stimulus-secretion coupling of glucose-induced insulin release. Metabolic and functional effects of NH4+ in rat islets.

“…The latter phenomenon was '45Ca UPTAKE (percent) DISCUSSION The present findings confirm that NH4+ is a potent inhibitor of insulin release. Previous reports have indicated that 0.1-1.0 mM NH4+ inhibits glucose-stimulated insulin release both in vitro using pieces of pancreas removed from the golden hamster (11) and in vivo in rats (13) and men (12) infused with NH4+. A role for NH4+ in the abnormality of islet function seen in cirrhotic patients (12,31) was also documented.…”

“…For this purpose, we have used NH4+, which is known to lower the concentration of reduced pyridine nucleotides in liver cells, by regulating the activity of glutamate dehydrogenase (8)(9)(10). Previous reports have already indicated that NH4+ is an inhibitor of insulin release (11)(12)(13). However, to our knowledge, the mode of action of NH4+ upon islet function had not as yet been explored in any great detail.…”

Possible Role of Hyperammonaemia and/or of Portosystemic Shunts on the Variability of the TSH Response to TRH in Cirrhotic Patients

“…Hyperammonaemia itself cannot be considered as playing a role in the increase of TSH release. Effectively the action of the ammonium ion has to be assimilated to that of catecholamines (Schlienger et al 1975) which are antagonists of the TRH action (Burrow et al 1977). Thus, portosystemic shunts, the resulting hyper¬ ammonaemia and the hepatic encephalopathy which often follows them, are factors which can affect TRH-induced TSH release in cirrhotics.…”

PCO2 and [K+]p in Metabolic Acidosis

“…Greater degrees of acute acidemia might have lent significance to the trend toward increases in plasma potassium levels despite the complicating hyperinsulinemia. Second, infusion of ammonium salts inhibits insulin release independent of the associated acidosis (11)(12)(13). Thus interpretation of the effects of the acute NH 4 Cl load on the plasma insulin levels of the normal volunteers studied becomes even more difficult.…”