Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB206

Poster Communications

Partial inhibition of insulin secretion in prediabetes animal models improves peripheral insulin action and restores sympathetic activity

M. P. Guarino2,1, J. F. Sacramento2, R. Fonseca-Pinto1,3, S. V. Conde2

1. Health Sciences School, Polytechnic Institute of Leiria, Leiria, Portugal. 2. CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa,, Lisbon, Portugal. 3. Instituto de Telecomunicações, Leiria, Portugal.


Insulin resistance and disturbed insulin secretion are the main pathogenic events involved in prediabetes. Hyperinsulinemia has been traditionally looked at as a compensatory phenomenon, in response to defective peripheral insulin action, intimately linked to sympathetic overactivity. Considerable evidence suggest that increased insulin secretion, and not insulin resistance, is the primary abnormality in prediabetes (Juan et al. 1999; Koopmans et al. 1997). Herein, we studied the effect of pharmacological partial blockade of insulin production on insulin action and on sympathetic nervous system activity. Two groups of male Wistar rats were used: the high-fat diet group (HF, 60% lipid-rich diet for 4 weeks) and the control group. After 3 weeks of diet steptozotocin (STZ, 25mg/kg, i.p.); a drug that decreases endogenous insulin secretion; was randomly administered to half the elements of each group and, afterwards, the animals were maintained on the respective diets for another week. Insulin action was evaluated at baseline, immediately after STZ administration and one week post- STZ administration, through an insulin tolerance test (100mu/kg i.v.). Oral glucose tolerance was determined two days after insulin action (2g/kg bw, per os). After completing 4 weeks of diet, rats were anaesthetized with pentobarbital (60mg/kg) and blood pressure and heart rate were recorded to evaluate autonomic nervous system, using classical spectral analysis of heart rate variability. Blood was collected by heart puncture and fasting insulin was assessed in all the groups. Values are means ± S.E.M., compared by 2 way-ANOVA and Bonferroni post-tests. HF diet significantly decreased insulin sensitivity to 2.99±0.22% glucose/min (KITT control=4.71±0.55%glucose/min; p<0.001, n=8). STZ did not alter insulin action in control animals, but it restored the hypoglycemic response to an exogenous insulin bolus in HF rats (KITT HF post-STZ=4.90±0.15%glucose/min, n=16). STZ did not modify fasting plasma glucose, glucose tolerance or mean arterial pressure in any of the groups tested; however it significantly decreased circulating insulin levels (from 1.13±0.14ug/l in HF group to 0.60±0.12 ug/l in HF post-STZ group; p<0.05) and the sympathetic component of heart rate variability in HF rats (sympathovagal balance was 7.39 in HF group and decreased to 1.15 in HF post-STZ group). Our results indicate that indicate that hyperinsulinism plays a pathophysiological role in the development of decreased insulin action and that prevention of the early diabetes hyperinsulinemic response, through pharmacological blockade of insulin secretion, restores peripheral insulin action and decreases sympathetic nervous system activation in animal models.

Where applicable, experiments conform with Society ethical requirements