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Cocaine decreases plasma insulin concentrations in non‐diabetic subjects: a randomized double‐blind study

Diabetic ketoacidosis (DKA) and the non-ketotic hyperosmolar hyperglycaemic syndrome (NKHHS) are acute complications of diabetes mellitus [1,2]. Multiple risk factors for both DKA and NKHHS have been described, but poor compliance with insulin therapy and clinical conditions known to increase counter-regulatory hormones appear to be responsible for the majority of cases [2–4]. Both DKA and NKHHS are associated with cocaine use [4–6]. Part of this association is related to omission of insulin therapy [4–7]. However, early preclinical work also suggested effects of cocaine on pancreatic function [8]. It is therefore possible that cocaine could suppress the secretion of insulin. This study investigated the effects of acute cocaine administration on plasma insulin concentrations in human subjects addicted to cocaine. Given the effects of acute cocaine on plasma cortisol [9], administration of exogenous cortisol (i.e. hydrocortisone) was employed to model cocaine-induced hypercortisolaemia, thus helping to disentangle the direct from the indirect effects of cocaine via activation of the hypothalamic–pituitary–adrenal (HPA) axis [10]. Twelve individuals [mean age ± standard error margin ( SEM ) 39.5 ± 1.0 years; three women, nine men; four White, eight Black; weight 79.9 ± 3.9 kg; body mass index (BMI) 25.8 ± 1.1 kg/m 2 ], meeting Diagnostic and Statistical Mannal of Mental Disorders (DSM-IV) criteria for cocaine dependence, were recruited by advertisement and gave written informed consent to the Massachusetts General Hospital (MGH) institutional review board (IRB)-approved protocol. The subjects’ good physical health was ascertained by physical examination, electrocardiogram, screening blood tests and urinalysis. Their fasting blood glucose concentrations were within normal limits (4.8 ± 0.26 mmol/l), and they had no past or current other Axis I psychiatric diagnosis apart from alcohol and/or marijuana abuse. All subjects were active cocaine users (confirmed by urinalysis) and were not seeking or participating in addiction treatment. They had primarily smoked cocaine for 19.9 ± 2.5 years, using it 6.5 ± 2.1 times in the month prior to study, with last use 1.4 ± 0.3 days prior to the study. At 09:00 h on the day prior to the study, subjects were admitted to the MGH General Clinical Research Centre, having refrained from cocaine for at least 10 h. They completed medical examination and structured clinical assessments. Those meeting all criteria were admitted overnight to the unit in preparation for infusions. At 08:00 h the following morning, after about 12 h of fasting, the subjects had bilateral intravenous catheters placed (left forearm for infusions, right forearm for serial venous blood sampling). Following a 60-min rest period, three infusions of cocaine (0.2 mg/kg), cortisol or saline (all three in a volume of 10 ml administered as an intravenous bolus over 30 sec) were given in a randomized, double-blind order, 2 h apart. To search for a dose of hydrocortisone that will produce similar increases in plasma cortisol concentrations to cocaine, cortisol was infused at 0.5 mg/kg ( n = 6) and 0.2 mg/kg ( n = 6). A Board-certified cardiologist was present and continuous haemodynamic monitoring was performed throughout the course of the study. Blood for insulin assays was collected into iced sodium heparin containing tubes at baseline and at 5, 10, 15, 30, 60, 90 and 120 min following the infusions. Samples were immediately placed on wet ice, centrifuged and plasma aliquots were stored at − 80 ° C. Assays were performed at the Biomarkers Core Lab, Yerkes National Primate Research Centre of the Emory University. Insulin was measured by radioimmunoassay (assay sensitivity: 3.8 mIU/ml). Comparisons between repeated serum level measurements were performed by analysis of variance (ANOVA) with time as the within-subjects factor and covaried by the baseline hormone levels. Cortisol analyses also used the dose (0.5 and 0.2 mg/kg) as the grouping factor. All analyses were two-tailed and a Pvalue < 0.05 defined statistical significance. Both cocaine ( F = 3.35; P = 0.007) and hydrocortisone ( F = 2.62; P = 0.03), but not placebo ( F = 0.92; P = 0.50), infusion resulted in a gradual and significant decline in plasma insulin levels, yielding respective mean changes from the baseline of 6.2 ± 3.76 mIU/ml, 9.9 ± 6.64 mIU/ml and 0.15 ± 5.49 mIU/ml (Fig. 1).