Metabolic Effects of Low-Dose Insulin Therapy on Glucose Metabolism in Diabetic Ketoacidosis

The effect of low-dose insulin treatment (5–10 U/h) on hepatic glucose production (HGP) and peripheral glucose disposal was determined in 5 insulindependent diabetes mellitus (IDDM) subjects who were admitted with diabetic ketoacidosis (DKA; plasma glucose 598 ± 50 mg/dl, blood pH 7.20 ± 0.06, plasma bicarbonate 12 ± 2 meq/L). Basal hepatic glucose production (4.3 ± 0.5 mg · kg¹ min¹) in the DKA patients was 1.5- to 2-fold greater (P < .01) than in controls (2.1 ± 0.1 mg · kg⁻¹ · min⁻¹) and nonketotic IDDM subjects (2.9 ± 0.3 mg · kg⁻¹ · min⁻¹), whereas tissue glucose disposal was significantly reduced (1.7 ± 0.1 vs. 2.1 ± 0.1 mg kg⁻¹ min⁻¹ P < .05). After the institution of insulin therapy (1 mU · kg⁻¹ · min⁻¹), the plasma glucose concentration fell at the rate of 60 ± 5 mg· dl⁻¹ h⁻¹ to reach a value of 220 ± 10 mg/dl, which was maintained constant for 2 h (insulinclamp technique). Blood pH (7.21 ± 0.06 to 7.35 ± 0.05) and plasma bicarbonate (12 ± 3 to 18 ± 2 meq\L) both increased during insulin therapy (P < .01). The decline in plasma glucose concentration during insulin therapy primarily resulted from a suppression of HGP (from 4.3 ± 0.5 to 1.7 ± 0.2 mg · kg⁻¹ min⁻¹ P < .01) and to a lesser extent from the stimulation of tissue glucose disposal (1.7 ± 0.2 to 2.6 ± 0.3 mg kg⁻¹ min⁻¹ P < .01). At this time, urine glucose excretion decreased from 2.6 ± 0.2 to 0.6 ± 0.1 mg kg⁻¹ min⁻¹. During the 2-h period of the insulin clamp (steady-state plasma glucose 220 ± 1 0 mg/dl, plasma free insulin 85 ± 5 (ill/ml), HGP in the DKA patients was further suppressed (1.70 ± 0.20 to 1.00 ± 0.20 mg · kg⁻¹ min⁻¹1) but remained well above (P < .01) rates observed in control subjects (0.1 ± 0.02 mg · kg⁻¹ · min⁻¹) and nonketotic diabetic subjects (0.2 ± 0.1 mg · kg⁻¹ · min⁻¹). At the end of the 2-h insulin-clamp period, the rate of tissue glucose uptake (3.2 ± 0.3 mg kg⁻¹ · min⁻¹) had not increased significantly above the rate observed at the start of the clamp (2.6 ± 0.2 mg/kg). Urinary glucose losses during the insulin-clamp period averaged 0.10 ± 0.01 mg · kg⁻¹ · min⁻¹. In summary, in DKA, 1) hyperglycemia results from both a markedly increased rate of HGP and a modest decrease in tissue glucose uptake, 2) the ability of insulin to suppress HGP and to stimulate tissue glucose uptake is severely impaired, and 3) during the initial 6-h period of insulin therapy, urinary glucose losses (0.4 mg kg⁻¹ min⁻¹), stimulation of tissue glucose uptake (increment 1.5 mg kg⁻¹ min⁻¹), and suppression of HGP (decrement 3.3 mg · kg⁻¹ · min⁻¹) all contributed to the decline in plasma glucose. However, from the quantitative standpoint, inhibition of HGP is the most important determinant in the decline in plasma glucose concentration after institution of insulin therapy.