Insulin dosing affects plasma levels of biochemical parameters in a time-dependent manner in Sprague-Dawley rats

Changes in levels of various biochemical blood parameters are used as indicators of metabolic effects or potential toxicity when performing non-clinical safety studies of new drug candidates in rats. Additionally, since biochemical blood parameters are often affected during safety testing of new insulin analogues the effect of insulin dosing on these parameters was investigated. Non-diabetic rats were dosed with either vehicle or insulin once daily for 28 days. On Day 28, biochemical blood parameters as well as insulin exposure were measured, at two hour intervals during a 24 h period, to investigate time-dependent as well as time-independent changes. Insulin dosing lowered plasma glucose level for 4 h, corresponding to the peak plasma insulin level. Chronic insulin dosing increased food consumption and bodyweights. Additionally, plasma urea as well as CK and LDH levels increased. Hyperphagia was most likely driven by hypoglycaemia thereby also increasing body weight through insulin-stimulated fatty acid uptake into adipose tissue. Increased urea, CK and LDH levels, suggests that the return to normoglycaemia was driven mainly by increased hepatic gluconeogenesis, as reflected by increased ureagenesis and skeletal muscle proteolysis (increased CK and LDH). A better understanding of insulin-induced changes to biochemical blood parameters may aid the interpretation of changes in these parameters in non-clinical safety studies with new drug

Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30–50% (4–6 mM versus 7–9 mM in controls). The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain neuronal glucose transporter were decreased, whereas levels of lipid peroxidation products were unchanged. Discontinued infusion was followed by transient systemic hyperglycaemia and decreased food consumption and body weight. After 4 weeks, plasma levels of lipid peroxidation products were increased, possibly as a consequence of hyperglycaemia-induced oxidative stress. The present data suggests that chronic moderate hyperinsulinaemic hypoglycaemia causes increased body weight and hyperleptinaemia. This is accompanied by decreased neuronal glucose transporter levels, which may be leptin-induced

Effect of maternal hypoglycaemia during gestation on materno-foetal nutrient transfer and embryo-foetal development:Evidence from experimental studies focused primarily on the rat

Glucose is the major energy substrate during embryogenesis and the embryo is dependent on glucose from the maternal circulation to ensure normal metabolism and growth. The placenta plays a key role in this nutrient transfer in mammals, both during embryogenesis and after the development of the chorio-allantoic placental circulation. Maternal hypoglycaemia is accompanied by foetal hypoglycaemia and maternal counter-regulatory measures including a priority to keep nutrients in the maternal circulation by restricting their transfer to the foetus. Concomitantly, the foetus initiates its own counter-regulatory attempt to secure nutrients for its development and survival. Despite these measures, there is a general decrease in nutrient transfer to the foetus, which may have severe consequences for foetal development such as malformations and delayed skeletal development

Changes in bone mass associated with obesity and weight loss in humans : Applicability of animal models

The implications of obesity and weight loss for human bone health are not well understood. Although the bone changes associated with weight loss are similar in humans and rodents, that is not the case for obesity. In humans, obesity is generally associated with increased bone mass, an outcome which is exacerbated by advanced age and menopause. In rodents, by contrast, bone mass decreases in proportion to severity and duration of obesity, and is influenced by sex, age and mechanical load. Despite these discrepancies, rodents are frequently used to model the situation in humans. In this review, we summarise the existing knowledge of the effects of obesity and weight loss on bone mass in humans and rodents, focusing on the translatability of findings from animal models. We then describe how animal models should be used to broaden the understanding of the relationship between obesity, weight loss, and skeletal health in humans. Specifically, we highlight the aspects of study design that should be considered to optimise translatability of the rodent models of obesity and weight loss. Notably, the sex, age, and nutritional status of the animals should ideally match those of interest in humans. With these caveats in mind, and depending on the research question asked, our review underscores that animal models can provide valuable information for obesity and weight-management research