Modulation of hunger by plasma glucose and metformin

The plasma glucose concentration is a major short-term regulator of hunger and food intake. In patients with diabetes, therapies lowering plasma glucose are frequently associated with body weight gain, suggesting that lowered plasma glucose leads to increased feelings of hunger and food intake. However, as many physiological and symptomatic responses to low plasma glucose are attenuated after repeated episodes of hypoglycemia, this may also pertain to feelings of hunger. Here we tested whether the stimulatory effect of low plasma glucose on feelings of hunger is likewise reduced by repeated episodes of hypoglycemia. As metformin has been shown to reduce plasma glucose levels without increasing body weight and also to decrease food intake, we tested for possible interacting effects of this substance with hypoglycemia-induced hunger. Feelings of hunger were assessed by rating scales during 3 consecutive hypoglycemic clamps performed on 2 consecutive d in 15 normal weight men. Subjects were tested once while being treated with 850 mg metformin twice daily and once while receiving placebo. Treatment was started 14 d before the clamp experiments and was performed in a random order and double-blind fashion. Hypoglycemia markedly enhanced feelings of hunger (P < 0.001). However, rated feelings of hunger on the first and last hypoglycemic clamps were comparable (P = 0.304). Compared with placebo, metformin decreased feelings of hunger during hypoglycemia (P = 0.015). This reduction was not associated with a decrease in posthypoglycemic food intake as measured by the number of cookies consumed after the last clamp (P = 0.676). Data indicate that the stimulatory effect of low plasma glucose on hunger is not attenuated after repeated episodes of hypoglycemia, which implies that, in contrast to other symptoms, hunger is not subject to adaptive attenuation upon repeated hypoglycemia. Metformin attenuates hypoglycemia-induced hunger, but does not appear to influence posthypoglycemic food intake.