Divergence in exercise-induced adaptive change in glucose tolerance between low and high responders to training

In a previous study, we found moderate heritability (25%) of a training-induced adaptive change in glucose tolerance and divergence between low and high responders of rats in the 1 generation from founding parents. PURPOSE: The purpose of this study was to test the hypotheses that 1) divergence in a training-induced change in glucose tolerance between the low and high responders would be maintained in a 2 generation and 2) changes in insulin secretion and action would differ between the two lines of the responders after training. SUBJECTS: Seventy-one 2 generation offspring of N/NIH strain of rats (40 in the low responding line and 31 in the high responding line) were used for the study. METHODS: All rats underwent an intraperitoneal glucose tolerance test before and after an 8-day intense intermittent swim training (8-10 bouts of 20-sec swim and 20-sec rest between bouts), carrying weight on the tail (14% body weight). Blood glucose was measured using a standard glucometer and the levels of plasma insulin and C-peptide were determined using radioimmunoassay kits from samples obtained before, and 30 and 60 minutes after a glucose injection (2g/kg body weight). ANALYSIS: The area under glucose curve (AUC) was calculated using a trapezoid rule. Improvement in glucose tolerance (= posttraining AUC pretraining AUC) and changes in insulin secretion and sensitivity were analyzed using 2 x 2 ANOVA or MANOVA followed by t-test at a significant α-level of P≤ 0.05. RESULTS: Improvement in glucose tolerance in the high line was significantly higher (12%, P<0.05) than that in the low line, showing the maintenance of divergence between the two lines. A significant improvement in insulin sensitivity of peripheral tissues after the training was found in the high line (42%, p<0.05) not in the low line. No difference in insulin secretion capacity between the two lines existed whereas a significant increase in hepatic insulin extraction occurred only in the low line (15%, P<0.05) after the training. CONCLUSION: These results demonstrate that a genetic animal model with a selective breeding for training-induced adaptive change in glucose tolerance is feasible and insulin action to peripheral tissue and insulin clearance by hepatic tissue may be responsible for a various extent of improvement in glucose tolerance after training. The finding of the maintained divergence in a training-induced change in glucose tolerance between the two lines in this study also confirms that the extent of change in glucose tolerance after training is a heritable trait. Introduction Diabetes, especially type 2 diabetes, is a significant public health problem resulting in substantial morbidity and mortality creating enormous economic consequences of medical expenditures for many countries. The number of adults with diabetes in the world will rise from 135 million in 1995 to 300 million in the year 2025 with the majority from developing countries (12). The polygenic metabolic syndrome is characterized by insulin resistance, hyperinsulinemia, glucose intolerance, obesity, dyslipidemia, and hypertension. Insulin plays an important role in maintaining the homeostasis of blood glucose by facilitating glucose entry into insulin-sensitive tissues such as skeletal muscles. In the presence of insulin resistance, the pancreas secretes insulin more than usual to compensate for the loss of insulin action and to maintain blood glucose within a normal limit, resulting in hyperinsulinemia. However, over time the pancreas fails in secreting insulin at a higher rate than usual, resulting in an impaired insulin secretion. Insulin resistance, impaired insulin secretion and compensatory hyperinsulinemia have been proposed as a causal link to the development of the diabetes. One important factor in the management of Type 2 Diabetes is exercise. Several benefits of exercise training include: decreased blood glucose (14,4,21), improved glucose tolerance (14,4,21), increased insulin sensitivity (14,4,21,23,31), change in body composition (4), decreased hypertension (4), improved hepatic insulin sensitivity (36), decreased HbA1C (8), decreased blood triglycerides (4,22), increased HDL-cholesterol (4), decreased psychological stress and self-esteem (4). Many biochemical changes contributing to these benefits after exercise include: increased GLUT-4 expression, an insulin-induced glucose transporter (4,9), increased glycogen stores (4,20), increased muscle oxidative capacity (20), increased hepatic insulin signaling (36), increased enzyme activity of metabolic pathways such as AMP-activated protein kinase (AMPK) and calcineurin (4,9), citrate synthase and beta-hydroxyacyl-CoA dehydrogenase (11), decreased phosphofructokinase activity (11), increased PI3-kinase associated with IRS-1 and IRS-2 and increased Akt-1/PKB (15). In addition to enzyme function, specific genes related to glucose metabolism have been identified. Genes such as IPF1, NEUROD1, PAX6, and MafA have been linked to individuals with diabetic phenotypes (18,30,19,27). Exercise-induced changes in insulin level and insulin action have also been linked to individual genotypes including PPARγ (32), β3AR (33,34), ACE (5,24,6) and uncoupling proteins (33). With the identification of genetic markers of diabetic individuals, scientists