Aspects of glucose metabolism in uraemia

This thesis takes the form of a tripartite study on aspects of glucose metabolism in uraemia. The work examines certain biochemical aspects of glucose metabolism in a clinical context. Continuous ambulatory peritoneal dialysis (CAPD) is a relatively new but now established mode of renal replacement therapy, that presents an unique clinical situation in that glucose is continuously self-administered intraperitoneally to control fluid balance. The metabolic consequences are thus clinically important. The first 4 chapters review the background to the work and include the topics of glucose homeostasis, glucose metabolism in uraemia, CAPD and glycosylated haemoglobin. Chapter 5 describes the biochemical methods and chapters 6, 7 and 8 detail the three projects performed. 1. The first project "Pancreatic Beta Cell Function in Uraemia" evaluated beta cell function in renal failure. The specific objective was to determine if CAPD adversely affected the beta cell secretory capacity. Beta cell integrity was also investigated in diabetics to assess the effect of uraemia and dialysis. 2. Residual beta cell function was assessed, in 70 patients, by using intravenous glucagon stimulation and measuring in the peripheral blood the beta cell peptide response. 3. Fasting glucose and insulin concentrations were normal in uraemic patients but c-peptide was grossly elevated due to impaired renal catabolism. Following glucagon stimulation, an exaggerated blood glucose response with delayed glucose peak was observed, while the peak insulin response was normal, but the return to basal concentrations was delayed. The c-peptide response was exaggerated and peak concentrations were greatly increased. Responses were similar in all non-diabetic uraemic patients. The above features reflect glucose intolerance in uraemia which persisted despite dialysis therapy. 4. The glucagon challenge showed significant increments in the beta cell peptides reflecting adequate residual pancreatic function. The response was similar in both new and established CAPD patients compared to non-dialysed uraemics and haemodialysis subjects. Thus, it can be concluded, that despite continuous glucose administration, CAPD does not adversely affect pancreatic beta cell function. 5. Type I insulin-dependent diabetics had no beta cell response to glucagon, but type II uraemic diabetics had raised fasting c-peptide concentrations which might suggest hypersecretion of the beta cell. However, absolute concentrations can be misleading as the increase was largely due to renal impairment. This was confirmed by the lack of response to glucagon challenge, indicating no significant residual beta cell function. The effect of long-standing diabetes overshadowed any discernible effect of uraemia or dialysis. 6. The second project "Glucoregulatory Hormones and Intermediary Metabolites in CAPD" assessed the acute metabolic consequences of intraperitoneal glucose administration. Fasting hormones and metabolites were evaluated in non-dialysed uraemic and haemodialysis patients for comparison with CAPD subjects. Metabolic profiles were monitored during a CAPD cycle comparing high and low dextrose dialysate solutions. Specific groups of CAPD patients were studied including diabetics, the elderly and patients with peritonitis. 7. In the fasting state blood glucose and insulin were normal in most uraemic patients, but c-peptide was grossly elevated and glucagon moderately increased. Growth hormone was normal and cortisol, although normal in CAPD patients was increased in other uraemic subjects. The gluconeogenic precursors lactate, pyruvate and alanine were normal, but ketone bodies and glycerol tended to be elevated particularly in the elderly CAPD patient. 8. The hormone and metabolite profiles during a CAPD cycle showed greater changes with high dextrose solutions, particularly during the first two hours of dialysate dwell. Peritoneal glucose absorption induced hyperglycaemia, hyperinsulinaemia and a transient fall in glucagon, while growth hormone and cortisol were unchanged. Lactate increased, largely due to absorption from the dialysate, rather than via endogenous glycolysis, as the blood lactate increment was independent of dialysate glucose concentration. Ketone bodies and glycerol were suppressed in the early part of the cycle during the period of maximum glucose absorption. In general, the metabolic variables returned to their basal state by the end of the 6 hour cycle. Thus peritoneal glucose absorption causes hyperglycaemia which induces hyperinsulinaemia, which in turn stimulates glycolysis, inhibits gluconeogenesis and suppresses ketogenesis and lipolysis. 9. Peritonitis increased the rate of glucose and lactate absorption from the dialysate due to increased permeability of the peritoneum. Elderly patients had similar profiles to younger CAPD subjects. 10. The effect of peritoneal glucose absorption in a state of insulin deficiency was evaluated in diabetics deprived of insulin. Dialysate glucose absorption induced hyperglycaemia but no beta cell response and glucagon, growth hormone and cortisol were unchanged. Lactate increased but pyruvate and alanine were essentially unaltered. Ketone bodies and glycerol remained elevated and were not suppressed despite the ambient hyperglycaemia. Thus in a state of insulin deficiency peritoneal glucose absorption failed to stimulate glycolysis or inhibit gluconeogenesis and ketogenesis and lipolysis were maintained. 11. The third project evaluated "Glycosylated and Carbamylated Haemoglobin in Uraemia". Glycosylated haemoglobin in renal failure is a controversial subject and was reappraised in a uraemic population of over 200 patients, including non-dialysis, dialysis, transplants, diabetics with and without renal failure. 12. The study confirmed that glycosylated haemoglobin was increased in non-diabetics with uraemia, when measured by mini-column ion-exchange chromatography, but was normal when total ketoamine glycosylation of the red cell was measured by colorimetry. 13. In diabetics glycosylated haemoglobin was increased independent of methodology and both techniques showed excellent correlation. Although colorimetry is unaffected by uraemia and may be the method of choice, the chromatographic method was still useful for assessing glycaemic control in diabetics with renal failure. 14. All chromatographic HbA1 fractions increased in uraemia, but the HbA1c component was more influenced by diabetes and the HbA1a+b component by uraemia. 15. Carbamylated haemoglobin was detected in all subjects but was grossly elevated in renal failure. The increase paralleled the rise in the HbA1 fractions in non-diabetic uraemics and correlated with the severity of uraemia. 16. The concept that carbamylated haemoglobin in uraemia is analogous to glycosylated haemoglobin in diabetes warrants further investigation. From the work of this thesis further research is being done to assess the clinical usefulness and possible pathophysiological significance of carbamylated haemoglobin