Hepatic extraction of insulin was examined in anesthetized dogs before and after constant infusion of insulin (20 and 50 mU/min) with use of samples from the portal vein, mesenteric vein, left common hepatic vein, and the femoral artery. In 19 dogs, measurement of portal vein insulin concentration indicated an overall recovery of 110% of the insulin infused. The range varied from 9 to 303%, indicating the potential for serious error in sampling the portal vein. Equilibrium arterial insulin concentrations were achieved 20 min after starting the infusion. Prior to insulin infusion, hepatic extraction of insulin averaged 4.56 plus or minus 0.43 mUmin, representing an extraction coefficient of 0.42 of the insulin presented to the liver. The proportion of insulin extracted by the liver did not change significantly during insulin infusion despite a 10-fold increase in portal vein insulin concentrations. During the infusion of insulin, a significant proportion of the extraheptic clearance of insulin occurred in the mesenteric circulation. Infusion of insulin was associated with a significant increase in insulin extraction by tissues other than the liver and splanchnic beds. Initially, hepatic glucose output average 36 plus or minus 3 mg/min; by 20 min after insulin infusion, it was 16 plus or minus 5 mg/min. Despite continuation of insulin infusion, hepatic glucose output returned to control values even though arterial glucose concentration continued to fall. Hepatic glucose output increased with termination of insulin infusion.

Spontaneous, prolonged hypoglycemia was observed in one nondiabetic and one mildly diabetic patient, both with chronic renal insufficiency. Although both patients had abnormal oral glucose tolerance tests, half-time disappearance of glucose was usually normal during intravenous glucose tolerance tests. Both patients developed persistent hypoglycemia during the tolbutamide tolerance test, but the insulin responses were not consistent with an islet cell adenoma. The hypoglycemia did not seem to reflect increased insulin secretion, increased insulin sensitivity or impaired glycogenolysis as assessed by the blood glucose response to glucagon. Although some factor associated with chronic renal disease was probably responsible for the hypoglycemia, the underlying mechanism was not defined. DIABETES 22:493-98, July, 1973.It is well recognized that patients in chronic renal failure develop some degree of abnormal carbohydrate tolerance. 1 " 5 The disturbance in glucose homeostasis most commonly manifests itself as glucose intolerance, referred to as renal diabetes. 1 " 3 -5 ' 6 On rare occasions prolonged and refractory hypoglycemia has been observed independent of a known hypoglycemic stimulus and without adequate explanation. 7 ' 8 Diabetic patients occasionally develop improved carbohydrate tolerance and decreased insulin needs as renal insufficiency develops. 9 " 11 Episodes of severe and prolonged hypoglycemia in diabetic, uremic patients on insulin or oral hypoglycemic agents have also been reported. 12 Recently, spontaneous hypoglycemia was documented in three diabetic patients in renal failure who were being managed by diet alone 7 and in one nondiabetic with a comparable level of renal insufficiency. 8 The latter case is, to our knowledge, the first report of hypoglycemia occurring with renal insufficiency in the absence of diabetes. Recently, we observed hypoglycemia in two patients in

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Two juvenile diabetics (previously reported 2 ) age 13 and 15, were studied on the metabolic ward simultaneously. The degree of severity of their diabetes was similar and their programs were identical in a quantitative chemical sense. Insulin was gradually withdrawn until both were spilling approximately 100 gm. of urinary sugar per day. Carbutamide was then added in doses ultimately reaching 16 gm. per day. Figure 6 shows the results in both boys. The first was responsive to the large dosage used. The second showed increased glycosuria without a concomitant increase in blood sugar, suggesting a renal effect. During this study it was noted that the responsive youngster was excreting the carbutamide mostly in the acetylated form, in contrast to the nonresponsive boy in whom the major portion of the drug was present in the free form. Further studies which we hope will throw light on this variation are in progress. SUMMARYWe have reported some of our experiences with two oral sulfonylurea compounds in sixty ambulatory diabetics. The drugs were effective in approximately 75 to 80 per cent of the cases and side effects were not a serious problem. Initial experiences with an intravenous sodium tolbutamide response test suggest that it is of little value in predicting which patients will be responsive.The diabetic glucose tolerance test of one nine-yearold boy was changed to normal by small doses of carbutamide. In another juvenile there was no change in the curve while on the drug. Balance studies in two hospitalized diabetics were paradoxical in that, while on identical programs one youth was responsive, the other, unresponsive. REFERENCES 1 Splitter, Thomas Stanford; Brown, Frederic L., Jr.; Friskey, Roger; Grindel, Lois; Kinsell, L. W.: Observations on diabetics treated with carbutamide and tolbutamide. California Medicine, in press.