Case Report

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A 66-year-old white man had a 2.5-year history of episodic intense diaphoresis, tremulousness, and weakness without confusion or unconsciousness, relieved within 10 minutes of eating a candy bar. Episodes occurred just before or about 2 hours after meals. Because of a fasting plasma glucose level of 2.39 mmol/L (43 mg/dL), he was referred to our institution for further evaluation.

He acknowledged the daily consumption of 3 to 6 ounces of whiskey. He had chronic obstructive pulmonary disease with asthmatic bronchitis treated with Theolar (3M Pharmaceuticals, St. Paul, Minnesota), 200 mg four times daily, and a Proventil inhaler (Schering, Kenilworth, New Jersey). He had a 14-year history of leg cramps, which were treated with quinine sulfate, 325 mg four times daily.

He was 167 cm tall and weighed 84.8 kg. His blood pressure was 130/75 mm Hg, and his pulse was 88/beats per minute. An increase of the A-P diameter of the chest and scattered expiratory wheezes were noted. Results of the cardiac examination were normal. Results of the urinalysis and of tests for sodium, potassium, calcium, phosphorus, liver function, lipids, thyroid-stimulating hormone, and cortisol were also normal. His hemoglobin value was 115 g/L, and his glycated hemoglobin value was 4.7% (normal, 4% to 7%). His leukocyte count was 6.1 x 10⁹ L; his creatinine concentration was 140 µmol/L; his plasma glucose concentration was 4.39 mmol/L (nonfasting); and his insulin antibodies were negative to beef, pork, and human insulin.

Conduct of Investigation

He underwent a prolonged fast ( 72 hours) in our hospital according to standard protocol on two occasions separated by 4 weeks. During the first fast, he received treatment with quinine sulfate, 325 mg four times daily, orally, and his pulmonary medications. In the interval between the fasts, quinine sulfate and ethanol were discontinued. The second fast was conducted without quinine sulfate treatment. The patient's usual pulmonary medications were administered. At the completion of the second 72-hour fast, quinine sulfate was reinstituted at the previous dosage, and the fast was continued for another 24 hours. At the termination of each fast (at the Whipple triad in the initial fast and at 72 and 96 hours in the second fast), blood was obtained for the determination of plasma glucose, insulin, and C-peptide levels and for the detection of quinine and sulfonylurea.

View larger version (21K): [in this window] [in a new window]   Figure 1. Plasma glucose concentrations with and without quinine sulfate. Plasma concentrations during the prolonged ( 72 hours) fast during treatment with quinine sulfate, 325 mg every 6 hours, and 4 weeks later after withdrawal of quinine. At the completion of the second fast (72 hours), treatment with quinine sulfate was reinstituted. Plasma C-peptide and insulin concentrations during quinine treatment are shown, as is that at the end of the fast, when quinine was not administered.

Methods

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Results

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After 62 hours of fasting and quinine sulfate administration, symptoms of hypoglycemia developed. At that time, his plasma glucose level was 2.00 mmol/L (36 mg/dL) (Figure 1); his plasma insulin value was 36 pmol/L (normal, <36 pmol/L); and his plasma C-peptide level was 0.36 nmol/L (normal, <0.2 nmol/L). Quinine, but not sulfonylurea, was detected in the plasma. Result of ultrasound examination of the pancreas was normal. A computed tomographic scan of the abdomen showed gallstones but no pancreatic abnormality.

During the 4-week period of withdrawal from quinine sulfate, results of the C-peptide suppression test were normal [6].

A repeated prolonged fast was conducted 4 weeks after withdrawal of quinine sulfate. At 72 hours, no symptoms of hypoglycemia had developed. At that time, his plasma glucose concentration was 3.78 mmol/L (68 mg/dL) (Figure 1); his plasma insulin level was 36 pmol/L; and his plasma C-peptide value was 0.20 nmol/L. Neither quinine nor sulfonylurea was detected in the plasma. After reinstitution of quinine sulfate, his plasma glucose level decreased progressively. Twenty-four hours later, the patient's plasma glucose concentration was 2.56 mmol/L (46 mg/dL) (see Figure 1); his plasma insulin level was 36 pmol/L; and his C-peptide value was 0.23 nmol/L. Quinine, but not sulfonylurea, was detected in the plasma.

Discussion

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Few allusions have been made to quinine as the cause of hypoglycemia in persons not infected with malaria. An elderly man with severe congestive heart failure had asymptomatic hypoglycemia during treatment with quinine, 300 mg at bedtime, for muscle cramps. His hypoglycemia ameliorated after quinine was discontinued [7]. A patient with terminal carcinoma metastatic to the adrenals and renal failure had an episode of hypoglycemic coma during treatment with quinine, once daily, for severe muscle cramps [8]. The role of quinine in the genesis of the hypoglycemia in these cases is problematic because of confounding conditions that may contribute to hypoglycemia.

Quinine-induced hypoglycemia is probably mediated by insulin, given that infusion of quinine into healthy persons lowered plasma glucose and raised plasma insulin levels [1]. Also, quinine has been reported to stimulate insulin release from cultured islet cells [9]. The plasma C-peptide and insulin concentrations seen in our patient during quinine-induced hypoglycemia were in the ranges that we have observed in persons with insulinoma on both a consistent and occasional basis [10].

The normal plasma glucose responses to 72 hours of fasting without quinine sulfate and the normal C-peptide suppression test should eliminate any concern that the patient has an insulinoma. The infrequency of hypoglycemia from quinine at the usual dose of one quarter or one half that used by our patient and one sixth that used to treat malaria may reflect a dose-dependency phenomenon. We conclude that quinine sulfate in high doses may cause insulin-mediated hypoglycemia in healthy persons.