Carbohydrate and insulin metabolism in chronic kidney disease
- Biff F Palmer, MD
Biff F Palmer, MD
- Professor of Internal Medicine
- University of Texas Southwestern Medical Center
- William L Henrich, MD, MACP
William L Henrich, MD, MACP
- University of Texas Health Science Center at San Antonio
Uremia is typically associated with impaired glucose metabolism. Some patients have hyperglycemia in response to oral and intravenous glucose loads, while others are able to maintain normoglycemia by raising plasma insulin levels. Studies utilizing the euglycemic and hyperglycemic clamp techniques suggest that several disturbances in carbohydrate handling may be present. Tissue insensitivity to insulin is of primary importance, but alterations in insulin degradation and insulin secretion also may contribute [1-3]. The variable severity of these changes in individual patients explains the variable plasma levels of insulin and glucose that may be seen both fasting and following a glucose load.
This topic will review the changes in carbohydrate and insulin metabolism that occur in chronic kidney disease (CKD) and the clinical implications of these abnormalities in nondiabetics. The impact of these changes on the management of hyperglycemia in diabetic patients with end-stage renal disease (ESRD) is discussed separately. (See "Management of hyperglycemia in patients with type 2 diabetes and pre-dialysis chronic kidney disease or end-stage renal disease".)
NORMAL RENAL HANDLING OF INSULIN
The kidney plays a central role in the metabolism of insulin in normal subjects [1,2,4]. Insulin has a molecular weight of 6000 and is therefore freely filtered. Of the total renal insulin clearance, approximately 60 percent occurs by glomerular filtration and 40 percent by extraction from the peritubular vessels. Insulin in the tubular lumen enters proximal tubular cells by carrier-mediated endocytosis and is then transported into lysosomes, where it is metabolized to amino acids . The net effect is that <1 percent of filtered insulin appears in the final urine.
The renal clearance of insulin is 200 mL/min, significantly exceeding the normal glomerular filtration rate (GFR) of 120 mL/min due to the contribution of tubular secretion. From this rate of renal clearance, it can be calculated that 6 to 8 units of insulin are degraded by the kidney each day, which accounts for approximately 25 percent of the daily production of insulin by the pancreas. The contribution of renal metabolism is enhanced in diabetic subjects receiving exogenous insulin since injected insulin enters the systemic circulation directly, without first passing through the liver.
Impaired tissue sensitivity to insulin occurs in almost all uremic subjects and is largely responsible for the abnormal glucose metabolism seen in this setting [1-3]. Possible mechanisms that could account for the reduction in insulin-mediated glucose handling include: (1) increased hepatic gluconeogenesis that does not suppress normally following insulin; (2) reduced hepatic and/or skeletal muscle glucose uptake; and (3) impaired intracellular glucose metabolism due either to decreased oxidation to carbon dioxide and water or to diminished synthesis of glycogen.
- Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron 1992; 61:377.
- Adrogué HJ. Glucose homeostasis and the kidney. Kidney Int 1992; 42:1266.
- Alvestrand A. Carbohydrate and insulin metabolism in renal failure. Kidney Int Suppl 1997; 62:S48.
- Rabkin R, Rubenstein AH, Colwell JA. Glomerular filtration and proximal tubular absorption of insulin 125 I. Am J Physiol 1972; 223:1093.
- Carone FA, Peterson DR. Hydrolysis and transport of small peptides by the proximal tubule. Am J Physiol 1980; 238:F151.
- Smith D, DeFronzo RA. Insulin resistance in uremia mediated by postbinding defects. Kidney Int 1982; 22:54.
- Castellino P, Solini A, Luzi L, et al. Glucose and amino acid metabolism in chronic renal failure: effect of insulin and amino acids. Am J Physiol 1992; 262:F168.
- Alvestrand A, Wahren J, Smith D, DeFronzo RA. Insulin-mediated potassium uptake is normal in uremic and healthy subjects. Am J Physiol 1984; 246:E174.
- Goecke IA, Bonilla S, Marusic ET, Alvo M. Enhanced insulin sensitivity in extrarenal potassium handling in uremic rats. Kidney Int 1991; 39:39.
- McCaleb ML, Izzo MS, Lockwood DH. Characterization and partial purification of a factor from uremic human serum that induces insulin resistance. J Clin Invest 1985; 75:391.
- Mak RH. Intravenous 1,25 dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int 1992; 41:1049.
- Kautzky-Willer A, Pacini G, Barnas U, et al. Intravenous calcitriol normalizes insulin sensitivity in uremic patients. Kidney Int 1995; 47:200.
- Lin SH, Lin YF, Lu KC, et al. Effects of intravenous calcitriol on lipid profiles and glucose tolerance in uraemic patients with secondary hyperparathyroidism. Clin Sci (Lond) 1994; 87:533.
- Eidemak I, Feldt-Rasmussen B, Kanstrup IL, et al. Insulin resistance and hyperinsulinaemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity. Diabetologia 1995; 38:565.
- Fliser D, Pacini G, Engelleiter R, et al. Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int 1998; 53:1343.
- Goldberg AP, Geltman EM, Gavin JR 3rd, et al. Exercise training reduces coronary risk and effectively rehabilitates hemodialysis patients. Nephron 1986; 42:311.
- Borissova AM, Djambazova A, Todorov K, et al. Effect of erythropoietin on the metabolic state and peripheral insulin sensitivity in diabetic patients on haemodialysis. Nephrol Dial Transplant 1993; 8:93.
- Mak RH. Effect of recombinant human erythropoietin on insulin, amino acid, and lipid metabolism in uremia. J Pediatr 1996; 129:97.
- Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 1970; 282:182.
- DeFronzo RA, Tobin JD, Rowe JW, Andres R. Glucose intolerance in uremia. Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin. J Clin Invest 1978; 62:425.
- Fadda GZ, Hajjar SM, Perna AF, et al. On the mechanism of impaired insulin secretion in chronic renal failure. J Clin Invest 1991; 87:255.
- Perna AF, Fadda GZ, Zhou XJ, Massry SG. Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone. Am J Physiol 1990; 259:F210.
- Oh HY, Fadda GZ, Smogorzewski M, et al. Abnormal leucine-induced insulin secretion in chronic renal failure. Am J Physiol 1994; 267:F853.
- Hajjar SM, Fadda GZ, Thanakitcharu P, et al. Reduced activity of Na(+)-K+ ATPase of pancreatic islets in chronic renal failure: role of secondary hyperparathyroidism. J Am Soc Nephrol 1992; 2:1355.
- Nadkarni M, Berns JS, Rudnick MR, Cohen RM. Hypoglycemia with hyperinsulinemia in a chronic hemodialysis patient following parathyroidectomy. Nephron 1992; 60:100.
- Kokot F, Wiecek A, Grzeszczak W, et al. Influence of erythropoietin treatment on glucose tolerance, insulin, glucagon, gastrin and pancreatic polypeptide secretion in haemodialyzed patients with end-stage renal failure. Contrib Nephrol 1990; 87:42.
- Chagnac A, Weinstein T, Zevin D, et al. Effects of erythropoietin on glucose tolerance in hemodialysis patients. Clin Nephrol 1994; 42:398.
- Hong SY, Yang DH. Insulin levels and fibrinolytic activity in patients with end-stage renal disease. Nephron 1994; 68:329.
- RUNYAN JW Jr, HURWITZ D, ROBBINS SL. Effect of Kimmelstiel-Wilson syndrome on insulin requirements in diabetes. N Engl J Med 1955; 252:388.
- Weinrauch LA, Healy RW, Leland OS Jr, et al. Decreased insulin requirement in acute renal failure in diabetic nephropathy. Arch Intern Med 1978; 138:399.
- Peitzman SJ, Agarwal BN. Spontaneous hypoglycemia in end-stage renal failure. Nephron 1977; 19:131.
- Arem R. Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am 1989; 18:103.
- Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol 2009; 4:1121.