To assess the effect of phosphate replacement therapy on the course of diabetic coma, 24 patients with severe diabetic ketoacidosis and 16 patients with nonketotic hyperosmolar coma were randomly assigned either to standardized conventional treatment alone or combined with phosphate infusions. Insulin and fluid therapy produced a rapid fall of plasma phosphorus; almost all patients not receiving phosphate infusions developed marked hypophosphatemia within 12 h. Hypophosphatemia was prevented by administration of 62 ± 5 mmol (range 35-140) sodium phosphate. Initial red blood cell 2,3-diphosphoglycerate (2,3-DPG) concentrations were markedly decreased in ketoacidotic patients. The recovery of 2,3-DPG upon institution of therapy was accelerated when phosphate replacement infusions were given. The increase in 2,3-DPG during the first 48 h was 56% greater (P < 0.02) when phosphate was administered, but later the difference between the two treatment groups disappeared. Nonketotic hyperosmolar coma patients revealed normal 2,3-DPG concentrations on admission, and a similar decline of plasma phosphorus occurred, as in ketoacidosis, during treatment. 2,3-DPG levels remained unaffected by phosphate therapy. While plasma calcium levels declined during the initial 48 h in both groups, transient postinfusion hyperphosphatemia was noted in 7 of 17 patients. A favorable effect of phosphate therapy on the clinical course of diabetic ketoacidosis or hyperosmolar coma could not be demonstrated. DIABETES 29: 87-95, February 1980.T he occurrence of excessive urinary phosphorus excretion in patients with uncontrolled diabetes mellitus has been recognized for more than 100 yr. 1 Severe phosphorus depletion ensued when insulin was withdrawn from diabetic subjects, 2 and marked hypo-

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Twenty-five type I diabetics (9 men, 16 women) with a mean disease duration of 19.9 years and 25 sex- and age-matched healthy control subjects were studied. Digital capillary blood flow measurements in combination with a local cooling test were assessed by nailfold videocapillaroscopy using the technique of flying spot and compared with nailfold capillary microscopy in four subgroups divided according to (A) disease duration, (B) retinopathy, (C) fasting blood glucose level, and (D) HbA1c values. Differences in morphologic capillary diameters and capillary density were found between the diabetics and the healthy control subjects. These were attributable to the patients with retinopathy. The hemodynamic findings at rest and after local cooling were unable to differentiate either between type I diabetics and healthy controls or within the different subgroups.

This study was based on the clinical observation of a higher phenprocoumon requirement in these diabetic patients simultaneously treated with phenprocoumon (Marcoumar) and dimethylbiguanide (DMB), and of a drug interaction observed in a patient. These higher requirements of phenprocoumon, suggesting an increased elimination, could have been due to an enhancement of liver microsomal enzyme activity and/or an increase in liver blood flow. Various studies were performed to test this hypothesis. The clinically suggested higher phenprocoumon requirement was proven by a drug observation study. Hence a higher tablet consumption of phenprocoumon and a diminished anticoagulatory effect was found after treatment with DMB in doses of between 1 and 3 g. An increased elimination of phenprocoumon following DMB administration was also found in a pharmacokinetic study. The activity of the liver microsomal enzyme system, investigated in animal and man, showed no changes in the liver microsomal enzymes in animal studies or the in vivo parameters of liver microsomal enzyme activity in patients. Measuring liver blood flow in dogs, utilizing the indocyanine green clearance method, an increased flow of about 33% was observed. As changes in liver blood flow can increase the metabolism of some highly lipid soluble drugs, the increased metabolism of phenprocoumon during DMB treatment could be related to the increase in liver blood flow and not to changes in liver microsomal enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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