Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice

Abstract

Islet β-cell monoamines are known to influence the insulin-releasing mechanisms. These amines are localized in the insulin-secretory granules and are inactivated by the enzyme monoamine oxidase (MAO), a hydrogen peroxide (H 2O 2)-generating enzyme. The activity of islet MAO may consequently be of importance for insulin secretion. In the present investigation, we studied the relation between islet MAO activity and plasma levels of insulin and glucose in obese ( ob ob ) hyperglycemic mice and their lean littermates. In addition, the effect of glucose on the MAO activity of in vitro-cultured islets was studied. MAO activity was assayed with serotonin, dopamine (DA), and β-phenylethylamine (PEA) as substrates. After an overnight fast in adult (age, 6 months) lean mice, islet MAO activity was increased by 35% to 70%. Plasma levels of glucose and insulin were markedly decreased as expected. However, fasting in adult obese mice either did not affect islet MAO activity (PEA and DA) or induced a slight decrease (serotonin) of approximately 25% ( P < .05). Plasma glucose levels in adult obese mice were not significantly affected by the overnight fast. However, a correlation analysis based on individual adult obese mice (fed and fasted) showed a negative correlation between plasma glucose concentration and islet MAO activity with PEA ( r = −.65, P < .02) and DA ( r = −.66, P < .02), respectively. Further, a positive correlation ( r = +.58, P < .05) was found between glucose level and islet MAO activity when using serotonin as substrate. There was no difference in islet MAO activity with PEA and DA as substrates in fed obese versus fed lean mice. However, in the fasted state, the enzyme activity was 25% to 30% lower in islets of obese mice than in those of lean mice. On the other hand, islet MAO activity with serotonin as substrate was much higher in obese versus lean mice in both fed (+300%) and fasted (+55%) animals. An overnight fast in young (age, 5 weeks) obese mice brought about a marked decrease in plasma levels of insulin and glucose, whereas islet MAO activity was unaffected. Islets from adult obese mice cultured in vitro for 3 days in high (11.1 mmol/L) glucose displayed a decreased MAO activity (12% to 25%) with DA and PEA as substrates when compared with islets cultured at low (2.8 mmol/L) glucose. No effect was observed with serotonin as substrate. The data obtained strongly suggest that glucose negatively modulates islet MAO activity. This in turn may affect insulin secretion through its effects on the monoamine content and possibly the redox state of the β cells. In the obese mouse, the regulatory influence of glucose is apparently disordered, which may be one of several factors contributing to the insulin hypersecretion associated with the obesity syndrome.