Toxicological Effects during and following Persistent Insulin‐Induced Hypoglycaemia in Healthy Euglycaemic Rats

Abstract

New insulin analogues with a longer duration of action and a 'peakless' pharmacokinetic profile have been developed to improve efficacy, safety and convenience for patients with diabetes. During non-clinical development, according to regulatory guidelines, these analogues are tested in healthy euglycaemic rats rendering them persistently hypoglycaemic. Little is known about the effect of persistent (24 hr/day) insulin-induced hypoglycaemia (IIH) in rats, complicating interpretation of results in pre-clinical studies with new longer-acting insulin analogues. In this study, we investigated the effects of persistent IIH and their reversibility in euglycaemic rats. Histopathological changes in insulin-infused animals included partly reversible axonal and reversible myofibre degeneration in peripheral nerve and skeletal muscle tissue, respectively, as well as reversible pancreatic islet atrophy and partly reversible increase in unilocular adipocytes in brown adipose tissue. Additionally, results suggested increased gluconeogenesis. The observed hyperphagia, the pancreatic, peripheral nerve and skeletal muscle changes were considered related to the hypoglycaemia. Cessation of insulin infusion resulted in transient hyperglycaemia, decreased food consumption and body-weight loss before returning to control levels. The implications for the interpretation of non-clinical studies with long-acting insulin analogues are discussed.

The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue

“…In cynomolgus monkeys, the normal serum/ plasma glucose level is about 3-4 mmol/L, 6,8,9,12 as compared to about 3.5-5 mmol/L in Göttingen minipigs, 4-6 mmol/L in Beagle dogs, 8-10 mmol/L in rats and 3.9-5.6 mmol/L in humans. [13][14][15][16][17][18] Therefore, relatively small absolute decrements in blood glucose level will correspond to a high percentage decrease; here, for instance, the fall in blood glucose level by 1.4 mM seen in the female after the first dose corresponded to a 36% decrease. In addition, the NHP was shown to have a higher basal insulin secretion, measured by C-peptide, compared to humans.…”

“…Whereas rats are known to increase food intake in response to hypoglycaemia, this has to our knowledge not been documented in monkeys and it has been suggested that food intake in NHPs is not particularly responsive to excursions in blood glucose levels because they tend to eat small and variable amounts during the day and not large quantities at once. 17,20 Unfortunately, food consumption could not be assessed in the present study, as the insulin-dosed monkeys were housed with naïve animals that share food. The group housing with naïve animals as well as the group hierarchy could also have influenced food intake of the dosed animals.…”