1. Young Wistar rats were used as an experimental model to determine the effects of protein-energy malnutrition on glucose tolerance and insulin release. 2. Malnourished rats presented some of the features commonly found in human protein-energy malnutrition, such as failure to gain weight, hypoalbuminaemia, fatty infiltration of the liver and intolerance of oral and intravenous glucose loads. 3. The rate of disappearance of glucose from the gut lumen was greater in the malnourished rats but there was no significant difference in portal blood glucose concentration between normal and malnourished rats 5 and 10 min after an oral glucose load. 4. Insulin resistance was not thought to be the cause of the glucose intolerance in the malnourished animals since these rats had a low fasting plasma insulin concentration with a normal fasting blood glucose concentration and no impairment in their hypoglycaemic response to exogenous insulin administration. Furthermore, fasting malnourished rats were unable to correct the insulin-induced hypoglycaemia despite high concentrations of hepatic glycogen. 5. Malnourished rats had lower peak plasma insulin concentrations than normal control animals after provocation with oral and intravenous glucose, intravenous tolbutamide and intravenous glucose plus aminophyllin. This was not due to a reduction in the insulin content of the pancreas or potassium deficiency. Healthy weanling rats, like the older malnourished rats, had a diminished insulin response to intravenous glucose and intravenous tolbutamide. However, their insulin response to stimulation with intravenous glucose plus aminophyllin far exceeded that of the malnourished rats. Thus the impairment of insulin release demonstrated in the malnourished rats cannot be ascribed to a 'functional immaturity' of the pancreas.
The activity of an insulin-degrading enzyme in soluble fractions of liver homogenate (“insulinase”) was compared with clearance of immunoreactive insulin (IRI) by cyclically perfused livers from normal, protein-depleted, and starved rats. Insulin disappearance from normal liver perfusates followed first-order kinetics, and clearances remained unchanged at levels between 1 and 5 nM insulin but fell at Insulin levels above 10 nM. At saturating concentrations (0.13 μM), the maximal rate of insulin removal was 12.5 pmol/mln./gm. wet liver, whereas the maximal degrading velocity of the “insulinase” fraction was 6.0 nmol/min./gm. wet liver. Furthermore, insulin clearance by the intact liver was not influenced by many substances affecting the “insulinase” system. Proinsulin (0.83 μM) acted as a competitive inhibitor, and glucagon, somatostatin, oxytocin, casein (all 1 to 6 μM), and Trasylol (2,000 K.I.U./ml.) inhibited “insulinase” noncompetitively. N-ethylmaleimide (1 mM) inhibited “insulinase” 100 per cent and partly delayed insulin removal from perfusates either because of concomitant reductions in oxygen consumption or because of incomplete titration of either accessible groups at active sites of insulin-degrading enzymes or cofactors. When results were corrected for liver DNA, protein-depleted and starved rats, respectively, showed 80 per cent and 56 per cent of control “insulinase” activities (p < 0.005 and p < 0.005), but their intact livers cleared physiologic concentrations of insulin at similar.rates to those of controls. These differences, coupled with the lower saturability and probable higher affinity of the insulin removal process by the intact liver and the lack of inhibition of this process by “insulinase” inhibitors, suggest that the plasma membrane of the structurally preserved liver cell plays a physiologic role in the regulation of the rate of insulin catabolism either by degrading insulin itself or by limiting insulin delivery to degrading systems in the intracellular compartment.
Early insulin release after oral glucose is absent in protein-calorie malnutrition (PCM). There is an increase of the insulin-glucose ratio at 10 and 15 min induced by potassium supplementation compared to a similar group receiving an identical diet without supplementary potassium. This suggests that impaired insulin secretion in PMC is in part due to a potassium mediated disturbance of insulin release.
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