Mechanism of compensatory hyperinsulinemia in normoglycemic insulin-resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in beta-cells.

The cause of compensatory hyperinsulinemia in normoglycemic insulin-resistant states is unknown. Using spontaneously hypertensive rats (SHR), we tested the hypothesis that a lowered beta-cell set-point for glucose causes a hypersecretion of insulin at a normal glucose level. Islets isolated from normoglycemic hyperinsulinemic SHR were compared to age-matched (12 wk old) Wistar-Kyoto (WK) rats. The ED50 for glucose-induced insulin secretion was 6.6 +/- 1.0 mM glucose in SHR versus 9.6 +/- 0.5 mM glucose in WK (P < 0.02). Glucokinase enzymatic activity was increased 40% in SHR islets (P < 0.02) without any change in the glucokinase protein level by Western blot. The level of the beta-cell glucose transporter (GLUT-2) was increased 75% in SHR islets (P < 0.036). In summary, the beta-cell sensitivity for glucose was increased in these normoglycemic insulin resistant rats by an enhanced catalytic activity of glucokinase. We have identified a regulatory system for glucokinase in the beta-cell which entails variable catalytic activity of the enzyme, is modulated in response to variations in whole-body insulin sensitivity, and is not dependent on sustained changes in the plasma glucose level.

[1]  J. Leahy,et al.  Increased Catalytic Activity of Glucokinase in Isolated Islets From Hyperinsulinemic Rats , 1994, Diabetes.

[2]  R. Bergman,et al.  Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function , 1993, Diabetes.

[3]  D. Romsos,et al.  Threshold for glucose-stimulated insulin secretion in pancreatic islets of genetically obese (ob/ob) mice is abnormally low. , 1993, The Journal of nutrition.

[4]  C. Jung,et al.  Interaction of facilitative glucose transporter with glucokinase and its modulation by ADP and glucose‐6‐phosphate , 1993, Journal of cellular physiology.

[5]  L. Recant,et al.  Genetically obese rats with (SHR/N-cp) and without diabetes (LA/N-cp) share abnormal islet responses to glucose. , 1992, Metabolism: clinical and experimental.

[6]  T. Buchanan,et al.  Enhanced Glucose Tolerance in Spontaneously Hypertensive Rats: Pancreatic β-Cell Hyperfunction With Normal Insulin Sensitivity , 1992, Diabetes.

[7]  J. Parsons,et al.  Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. , 1992, Endocrinology.

[8]  E. Schaftingen,et al.  The regulatory protein of liver glucokinase. , 1992, Advances in enzyme regulation.

[9]  S. Bhathena,et al.  Multiple Alterations in Insulin Responses to Glucose in Islets From 48-h Glucose-Infused Nondiabetic Rats , 1990, Diabetes.

[10]  E. Van Schaftingen,et al.  Regulation of glucokinase by a fructose-1-phosphate-sensitive protein in pancreatic islets. , 1990, European journal of biochemistry.

[11]  J. Leahy,et al.  Islet Mass and Function in Diabetes and Transplantation , 1990, Diabetes.

[12]  W. Malaisse,et al.  Perturbation of pancreatic islet function in glucose-infused rats. , 1990, Metabolism: clinical and experimental.

[13]  C. Ucla,et al.  Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Sorenson,et al.  Nutrient and hormonal regulation of the threshold of glucose-stimulated insulin secretion in isolated rat pancreases. , 1988, Endocrinology.

[15]  B H Frank,et al.  Quantitative study of insulin secretion and clearance in normal and obese subjects. , 1988, The Journal of clinical investigation.

[16]  C. Wollheim,et al.  Tissue-specific expression of glucokinase: identification of the gene product in liver and pancreatic islets. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[17]  F. Matschinsky,et al.  Adaptation of Glycolytic Enzymes: Glucose Use and Insulin Release in Rat Pancreatic Islets During Fasting and Refeeding , 1981, Diabetes.

[18]  S. Genuth.  Plasma insulin and glucose profiles in normal, obese, and diabetic persons. , 1973, Annals of internal medicine.

[19]  R. Turner,et al.  A sensitive, precise radioimmunoassay of serum insulin relying on charcoal separation of bound and free hormone moieties. , 1972, Acta endocrinologica.

[20]  P. J. Randle,et al.  The pentose cycle and insulin release in mouse pancreatic islets. , 1972, The Biochemical journal.

[21]  G. Spears,et al.  A method for deriving kinetic constants for two enzymes acting on the same substrate. , 1971, The Biochemical journal.

[22]  G. Grodsky,et al.  Excessive Insulin Response to Glucose in Obese Subjects as Measured by Immunochemical Assay , 1963, Diabetes.