Shifts in metabolic parameters surrounding glucose homoeostasis resulting from tricyclic antidepressant therapy: implications of insulin resistance?

Abstract

This study displayed the physiological effects the tricyclic antidepressants amitriptyline or trimipramine have on glucose homoeostasis in male Wistar rats. An insulin secreting cell line (INS-1) was also used to determine effects tricyclic antidepressants have on insulin secretion and insulin displacement. Thirty rats each received a 1 mg kg-1 dose of amitriptyline or trimipramine for a period of 14 weeks; another 14 rats served as the control group. Blood glucose, serum insulin and muscle and liver glycogen levels were determined. Kidney, liver and muscle insulin degradation was measured and compared with insulin degrading enzyme concentrations in the latter two tissues. INS-1 cells were used to determine the effect 1 microM amitriptyline has on insulin secretion. Displacement studies for [3H]glibenclamide by amitriptyline or trimipramine were undertaken on INS-1 cells. A significant increase in blood glucose (P<0.01) was found for both test groups after 6 and 14 weeks of receiving the medication, which may be related to a significant decrease in liver and muscle glycogen levels (P<0.001). Serum insulin levels remained unchanged, although a significant increase in insulin degradation was observed in the muscle, liver and kidney, which may be related to a significant increase in insulin degrading enzyme (P<0.001) that was found. A significant increase in insulin secretion was observed for the INS-1 cells treated with amitriptyline, although no significant displacement for the [3H]glibenclamide was evident for amitriptyline or trimipramine. The significant alterations in glucose homoeostasis observed, as well as the significant changes associated with insulin secretion and degradation associated with amitriptyline or trimipramine treatment, imply that prolonged use of these medicines may lead to insulin resistance and full blown diabetes.

Psychiatric disorders and general medical conditions: implications for the clinician

“…51 The recent literature has however mostly focused on the effects of psychotropic medications on metabolic and cardiovascular health. Some evidence is emerging for the potential effects of antidepressants on the parameters of weight and metabolic health [52][53][54] , although it is somewhat surprising to see the relative lack of information and studies with antidepressants when compared to the anti-psychotics. From the information currently available, it seems that there is a highly variable effect, with certain SSRI's such as paroxetine seemingly more likely to have adverse metabolic effects than other SSRI's.…”

Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary

“…This hypothesis (Henneberg and Hoyer, 1995;Frölich et al, 1998) became one of the most debated topics with regard to the possible origin of sporadic AD (for recent considerations see De la Monte and Wands, 2005;Cole et al, 2007;Kim et al, 2007). Furthermore, some recent findings give reason to assume that brain IDE might be also involved in other neurological and neuropsychiatric diseases (Morelli et al, 2004;Zhao et al, 2006;Chadwick et al, 2007).…”

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays

“…There were three chemotypes identified as actives: tricyclic antidepressants (metitepine, amitriptyline, butriptyline), phenylpropanone anti-arrhythmics, and the muscarinic antagonist mebeverine. The effects of tricyclics on insulin levels have been studied in rats [ 17 ] and humans [ 18 ]. Moreover, it is well described that various monoaminergic GPCRs regulate beta cell function, including muscarinic, dopaminergic, and adrenergic receptors and these effects can be observed in INS-1 cells [ 19 – 21 ].…”