Effects of Uraemic Serum, Urea, Creatinine and Methylguanidine on Glucose Metabolism

Abstract

S U M M A R Y1. Uptake of glucose by the rat diaphragm in vitro and utilization of glucose by human erythrocytes were inhibited by urea, creatinine and, to an even greater extent, by urea plus creatinine. Guanidine, methylguanidine and guanidinoacetic acid individually had a small enhancing effect on glucose uptake and utilization but collectively there may be an additive effect. Urate, p-cresol and p-cresylsulphate had no appreciable effects.2. Dialysis of uraemic patients greatly decreased, or abolished, the inhibitory effect of their sera on glucose uptake by hemidiaphragms.3. Administration of urea or creatinine lowered the oral glucose tolerance of patients with moderately impaired renal function.4. In ten normal dogs intravenous glucose tolerance curves were unchanged during methylguanidine administration, whereas in five dogs oral glucose tolerance curves became flattened. 5. Fasting blood glucose of five alloxan-diabetic dogs was decreased during administration of methylguanidine and increased again when administration was discontinued.

Characterization and partial purification of a factor from uremic human serum that induces insulin resistance.

“…These observations have led to the suggestion that a circulatory factor(s) is responsible for inducing insulin resistance (2, 6). The incubation of a variety of tissues obtained from normal animals with whole (4,7,8) or partially purified (9) sera, obtained from chronically uremic patients, inhibits basal uptake of glucose. The insulin stimulation of glucose uptake and metabolism by rat adipocytes is also reduced following preincubation with uremic human serum (4,10).…”

Hyperglucagonemia of Renal Failure

“…Additional factors considered by many investigators to be important in the pathogenesis of carbohydrate intolerance in uremia include interference with glucose phosphorylation (13,15), potassium deficiency (16), accumulation of urea, creatinine, ammonia, and guanidine derivatives (17), systemic acidosis (18) and peripheral insulin resistance (13).…”

Uremic Intoxication

“…Such a toxic effect was attributed to the cyanate deriving from the spontaneous conversion of U [20]. Administration of U to chronic uremic patients on maintenance hemodialysis induced a clearly evident carbohydrate intolerance [21], and the same effect was induced in normal volunteers [22] and patients with mild renal failure to whom U had been given in such doses as to increase their plasma U levels to the values found in severe uremia [9]. Finally, carbohydrate intolerance was also induced in normal dogs intoxicated with U [7].…”

“…Normal dogs, injected with high doses of MG, died within 15 days from anemia due to hemolysis and reduced red cell production, from gastric ulcers with bleeding, and from peripheral neuro pathy [6]. When lower doses were given to maintain the plasma MG levels of dogs as high as those of severe uremic patients, the same symptoms appeared though less severe [2], Administration of MG to dogs induced cer tain metabolic abnormalities, which are also typical of the uremic state: hypertrygliceridemia [7], inhibited intestinal absorption of calcium [7], increase in the plasma fibrinogen levels, and depressed fibrinolytic activity [8], and im provement of the carbohydrate intolerance in dogs with alloxan diabetes [9],…”

“…This opinion is based on the observation that no appreci able disturbances were induced in normal subjects injected intravenously with such amounts of CR as to raise its plasma level to more than 100 mg/100 ml for short periods of time [15]. However, further experimental work has shown that when added in vitro to normal blood at concentrations similar to those found in the plasma of severe uremic patients, CR increased spontaneous autohemolysis [16], and when injected in normal dogs it shortened their red cell survival [17], Given by mouth to renal patients with a moderate impair ment of the renal excretory function and, therefore, unable to eliminate it rapidly, CR induced an unmistakeablc intolerance to carbohydrates [9], Finally, CR induce a tranquilizing effect in normal rats [18]. All this suggests that CR cannot be regarded as an inert substance, and it may contribute to cause certain uremic symptoms such as hemolysis, carbohydrate intolerance, and drowsiness.…”