Effect of Pancreas Transplantation on Free Fatty Acid Metabolism in Uremic IDDM Patients

To assess the effect of pancreas transplantation on free fatty acid (FFA) and glucose metabolism, we studied seven uremic IDDM patients (HbA1c 9.1%), nine IDDM patients after combined kidney-pancreas transplantation (HbA1c 5.8%), seven patients with chronic uveitis (HbA1c 5.6%), and nine normal control subjects (HbA1c 5.5%) by means of the [3-3H]glucose and [1-14C]palmitate infusion techniques combined with indirect calorimetry and euglycemic insulin clamp. In the postabsorptive state, pancreas-transplant patients had similar plasma glucose and FFA concentrations and non-statistically different rates of hepatic glucose production (HGP) and FFA turnover, while demonstrating a reduced rate of FFA oxidation (42 ± 5 vs. 73 ± 10 μmicromol · m−2 · min−1; P < 0.05) compared with control subjects. After 180 min of tracer equilibration, all subjects underwent a low-dose (100 min, 8 mU · m−2 · min−1) followed by a high-dose (100 min, 40 mU · m−2 · min−1) euglycemic insulin infusion. During insulin infusion, pancreas-transplant patients showed a greater inhibition of FFA concentration (609 ± 76 to 58 ± 15 micromol/l) compared with healthy subjects (681 ± 90 to 187 ± 25 micromol/l; P < 0.01 vs. pancreas-transplant patients). FFA turnover and oxidation rates during both low-dose and high-dose insulin infusions were lower in pancreas-transplant patients compared with healthy subjects (P < 0.03 and P < 0.01, for turnover and oxidation, respectively). Uremic IDDM patients demonstration altered basal and insulin-mediated glucose metabolism. Pancreas transplantation normalized only insulin-mediated glucose oxidation, leaving the stimulation of non-oxidative glucose disposal still markedly defective. In conclusion, patients after pancreas transplantation have normal basal FFA turnover and reduced basal FFA oxidation rates. During hyperinsulinemia, pancreas-transplant patients show a normal inhibition of FFA turnover and FFA oxidation. Insulin-mediated glucose metabolism remained abnormal after pancreas transplantation. Our findings may be related to the effect of chronic immunosuppressive therapy on glucose and FFA metabolism.

[1]  G. Boden,et al.  Insulin receptor down-regulation and impaired antilipolytic action of insulin in diabetic patients after pancreas/kidney transplantation. , 1994, The Journal of clinical endocrinology and metabolism.

[2]  J. Bagdade,et al.  Effects of Insulin Treatment on Lipoprotein Composition and Function in Patients With IDDM , 1992, Diabetes.

[3]  J. Sturis,et al.  Insulin Secretory Profiles and C-Peptide Clearance Kinetics at 6 Months and 2 Years After Kidney-Pancreas Transplantation , 1992, Diabetes.

[4]  S. Haffner,et al.  Prospective analysis of the insulin-resistance syndrome (syndrome X). , 1992, Diabetes.

[5]  P. Björntorp,et al.  Effect of Free Fatty Acids on Insulin Receptor Binding and Tyrosine Kinase Activity in Hepatocytes Isolated From Lean and Obese Rats , 1992, Diabetes.

[6]  W. Duckworth,et al.  Lipid Status After Pancreas-Kidney Transplantation , 1992, Diabetes Care.

[7]  K. Minaker,et al.  Islet cell responses to glucose in human transplanted pancreas. , 1991, The American journal of physiology.

[8]  J. Velosa,et al.  Effects of pancreas transplantation on postprandial glucose metabolism. , 1991, The New England journal of medicine.

[9]  P. Diem,et al.  Systemic Venous Drainage of Pancreas Allografts as Independent Cause of Hyperinsulinemia in Type I Diabetic Recipients , 1990, Diabetes.

[10]  L. Groop,et al.  Mechanisms of insulin resistance after kidney transplantation. , 1989, Transplantation.

[11]  L. Groop,et al.  Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. , 1989, The Journal of clinical investigation.

[12]  M. Davidson,et al.  Possible role for the glucose-fatty acid cycle in dexamethasone-induced insulin antagonism in rats. , 1987, Metabolism: clinical and experimental.

[13]  W. Mitch,et al.  Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis. , 1987, The Journal of clinical investigation.

[14]  M. Taskinen.  Lipoprotein lipase in diabetes. , 1987, Diabetes/metabolism reviews.

[15]  G. Schonfeld.  Diabetes, lipoproteins, and atherosclerosis. , 1985, Metabolism: clinical and experimental.

[16]  R. DeFronzo,et al.  Is glucose intolerance harmful for the uremic patient? , 1985, Kidney international. Supplement.

[17]  M. Walters.  Steroid hormone receptors and the nucleus. , 1985, Endocrine reviews.

[18]  W. Mitch,et al.  Specific defects in insulin-mediated muscle metabolism in acute uremia. , 1985, Kidney international.

[19]  A. Gelet,et al.  Metabolic control of type I (insulin dependent) diabetes after pancreas transplantation. , 1985, British medical journal.

[20]  P D Klein,et al.  Rapid determination of whole-body bicarbonate kinetics by use of a digital infusion. , 1984, The American journal of physiology.

[21]  A. Chait,et al.  In Vivo Stimulation of Low-Density Lipoprotein Degradation by Insulin , 1984, Diabetes.

[22]  R. DeFronzo,et al.  Effect of fatty acids on glucose production and utilization in man. , 1983, The Journal of clinical investigation.

[23]  M. Trovati,et al.  Insulin binding to isolated monocytes and adipocytes in the study of hypoglycemic subjects and in the follow-up of patients with insulinoma. , 1983, Diabete & metabolisme.

[24]  C. Groth,et al.  SUCCESSFUL OUTCOME OF SEGMENTAL HUMAN PANCREATIC TRANSPLANTATION WITH ENTERIC EXOCRINE DIVERSION AFTER MODIFICATIONS IN TECHNIQUE , 1982, The Lancet.

[25]  R. Eckel,et al.  Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique. , 1982, The Journal of clinical investigation.

[26]  R. Stout.  The Role of Insulin in Atherosclerosis in Diabetics and Nondiabetics: A Review , 1981, Diabetes.

[27]  N. Abumrad,et al.  Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. , 1981, Metabolism: clinical and experimental.

[28]  C. Kahn,et al.  Alterations in insulin binding induced by changes in vivo in the levels of glucocorticoids and growth hormone. , 1978, Endocrinology.

[29]  J. Roth,et al.  Insulin receptors in patients with insulinomas: changes in receptor affinity and concentration. , 1977, The Journal of clinical endocrinology and metabolism.

[30]  J. Olefsky.  Effect of dexamethasone on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes. , 1975, The Journal of clinical investigation.

[31]  G. Reaven,et al.  Reappraisal of the role of insulin in hypertriglyceridemia. , 1974, The American journal of medicine.

[32]  J. Wahren,et al.  Uptake of individual free fatty acids by skeletal muscle and liver in man. , 1972, The Journal of clinical investigation.

[33]  N. Baker,et al.  Effect of glucose ingestion on the metabolism of free fatty acids in human subjects. , 1969, Journal of lipid research.

[34]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.

[35]  R. S. Gordon,et al.  The metabolism of albumin-bound C14-labeled unesterified fatty acids in normal human subjects. , 1958, The Journal of clinical investigation.

[36]  J. Mazza.  Pancreatic and islet transplantation for diabetes. , 1993, The New England journal of medicine.

[37]  L. Groop,et al.  Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. , 1991, The Journal of clinical investigation.

[38]  S. Glantz,et al.  Primer of Applied Regression & Analysis of Variance , 1990 .

[39]  B. Issekutz,et al.  Oxidation of plasma FFA in lean and obese humans. , 1968, Metabolism: clinical and experimental.