Dexamethasone
induced diabetes; a model to screen insulin sensitisers?
Subhabrata K, Sangha R B, and Nayak N
Objective: To evaluate the effect of
oral antidiabetic drugs on glucocorticoid induced diabetes mellitus in albino
rats.
Introduction: Glucocorticoids induce
diabetes mellitus mainly by increasing peripheral insulin resistance. There are
different factors, which lead to excess of glucocorticoids, stress being one of
them 1. Obesity is the main feature of the epidemic of type 2 diabetes
mellitus. Beta hydroxysteroid dehydrogenase 1 enzyme is expressed in increased
quantity in the visceral fat of these patients. Transgenic mice expressing
around 20% excess of this enzyme develop the typical
features of metabolic syndrome, viz. Obesity, hyperinsulinemia, impaired
glucose tolerance, dyslipidemia, hypertension etc., This enzyme converts
inactive cortisone to active cortisol 2. Diabetes induced by large
dose of diabetes poses a challenging situation in clinical practice 3. All these factors led us
to conduct this study.
Material &
Methods:
Male albino rats weighing 200-300g were selected.
They were divided into groups of six. Diabetes was induced by giving 12mg/kg of
dexamethasone intraperitoneally for six days. Glibenclamide, Metformin,
&Rosiglitazone were given orally one week before and during dexamethasone
administration. The control group received 2% gum acacia suspension in lieu of
the vehicle used for the above drugs. Fasting glucose and IPGTT glucose levels
were recorded on the sixth day.
Results: Glibenclamide was not
effective in reducing blood sugar level in doses of 5mg/kg as well as 15mg/kg
per day. Metformin 500mg/kg & Rosiglitazone 8mg/kg reduced fasting glucose
as well as GTT glucose levels. Intraperitoneal
glucose test was conducted by injecting 2.5 g/kg of glucose & blood glucose
level was measured 1 hour later using one touch glucometer & strips.
Statistical analysis for significance was made using
paired‘t’ test. P values <0.05 are considered significant. Results are
expressed as means ± SEM. Results are shown in
charts.
Conclusion: In vitro studies have
shown that dexamethasone dose dependently inhibits insulin release mediated by
glucose as well as other insulin releasers including Tolbutamide 4. Therefore insulin
releasers are not effective in high dose dexamethasone induced diabetes
mellitus. When glucose is given intraperitoneally, only a drug with systemic
effect other than insulin releasers are effective. The results in our study agree
with the invitro study. Thus it is inferred that high dose dexamethasone
induced diabetes combined with intraperitoneal glucose tolerance test may be a
suitable model to screen insulin sensitisers.
References:
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D.J Weatherall, J.G.G Ledingham, D.A Warrell, et al, editors.
2.
Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS.
A transgenic model of visceral obesity and the metabolic syndrome.
: Science.2001; 294(5549): 2166-70.
3. Braithwaite SS, Barr WG,
Rahman A, Quddusi S. Managing diabetes during glucocorticoid therapy. Postgrad
Med. 1998; 104:163-166, 171, 175-176.
4. Cécile Lambillotte, Patrick Gilon, and Jean-Claude
Henquin. Direct Glucocorticoid Inhibition of Insulin
Secretion. J. Clin. Invest. 1997. 99:414-423