Antimalarial drugs and glucose metabolism.

the diastereoisomer of quinine, can also cause this compliAn accurate and promptly-available blood or plasma glucose cation [2]. The 4-aminoquinoline chloroquine is known to concentration may, on its own, be very useful clinically but influence glucose metabolism in ways which could lead to is a limited measure of glucose tolerance in a patient with a low blood glucose concentrations [3, 4], although reports of disease such as malaria. The measurement of serum insulin chloroquine-treated patients with acute malaria who have in addition to glucose gives improved but still relatively developed hypoglycaemia are rare [5]. Recently, the crude information regarding complex, non-linear feedback quinoline methanol mefloquine has been shown to reduce between the pancreas and tissues which produce or utilise plasma glucose concentrations during a conventional prophyglucose. Because of this situation, a number of physiological lactic course in healthy young adults [6]. In all these tests and associated mathematical models have been develsituations, raised serum or plasma insulin concentrations oped which allow a better characterisation of factors which have been observed. regulate plasma glucose in humans. The maintenance of appropriate plasma glucose concenAmongst the most technically demanding and labour trations in both basal and fed states is largely a function of intensive are ‘clamp’ studies in which the plasma glucose the action of insulin. Counter-regulatory hormones, especoncentration, and also the serum insulin if necessary, can cially glucagon, become important only when the plasma be maintained or ‘clamped’ at predetermined levels through glucose starts to fall below normal. However, increased the simultaneous intravenous infusion of dextrose and insulin catecholamine and cortisol secretion in the absence of at rates which are calculated from the results of frequent hypoglycaemia occurs in stress situations including infections. bedside plasma glucose sampling. Conventional clamp studies Other factors such as increased plasma free fatty acid are, however, concerned primarily with the direct estimation concentrations and ketonaemia may also contribute to a of insulin sensitivity (for which they are regarded as the raised basal plasma glucose. However, continued host and reference method) rather than insulin secretory capacity [7], parasite glucose demand, impaired hepatic glycogenolysis though hyperglycaemic clamps have been recently highand gluconeogenesis, cytokine effects and the inability of lighted as an underutilised tool for assessment of beta cell the patient to take sufficient carbohydrate by mouth because responsiveness [8]. of nausea and vomiting increase the propensity to hypoglyIn an attempt to simplify the testing process but still caemia in malaria [1]. The added influence of hyperinsulinaeprovide robust estimates of pancreatic beta cell secretory mia due to antimalarial treatment can result in severe, capacity and its effect on tissue glucose uptake, two other refractory hypoglycaemia with serious neurological and approaches have been developed which provide results other sequelae if it remains undetected or inadequately consistent with those of clamp studies. The first is based on treated. the ‘minimal model’, which is a compartmental analysis Several questions arise concerning the effect of antimalarial of plasma glucose and insulin concentrations during a drugs on plasma glucose and insulin concentrations. Which frequently-sampled intravenous glucose tolerance test drugs have the greatest effect on insulin secretion and why? (FSIVGTT) [9]. Estimates of insulin sensitivity (SI), glucose Is this effect related to the total or free (unbound) plasma effectiveness (SG) and pancreatic responsiveness (w1 and w2) concentration of the drug? Is there synergism between are generated [10]. The minimal model has been used antimalarial drugs of the same or different classes? Do the effectively to assess aspects of glucose tolerance in a variety drugs have other effects on glucose metabolism which could of different physiological situations and disease states [11]. contribute to hypoglycaemia? Are there special situations, The second approach is that which underlies Homoeostasis during either prophylactic or treatment courses, in which Model Assessment (HOMA) and Continuous Infusion of drug effects on glucose metabolism are exaggerated or, Glucose with Model Assessment (CIGMA). HOMA is conversely, attenuated? Do specific effects suggest novel applied in the fasting or post-absorptive state [12] and ways of preventing or treating hypoglycaemia? The published CIGMA involves standardised dextrose administration over data relating to these questions will be assessed in the present an hour to achieve a suprabasal but still physiological plasma review including, where possible, their reanalysis or reinglucose concentration [13]. These analyses are based on a