About 30 million people in the United States have diabetes. Over 90% of them have type 2 diabetes. Type 2 diabetes is caused by defects in insulin secretion by pancreatic beta-cells and insulin action in the peripheral tissues such as liver, muscle, and fat cells. One of the primary risk factors contributing to type 2 diabetes is obesity. However, it is not well understood how obesity leads to type 2 diabetes. We hypothesized that obesity alters various metabolic rate constants that maintain glucose homeostasis. When alterations in the metabolic rate constants reach certain levels (threshold), onset of type 2 diabetes would ensue and progress as obesity increases. If this hypothesis were correct, a time period when onset of type 2 diabetes occurs could be identified by studying alterations of the metabolic rate constants over time. Furthermore, such knowledge can be used as a diagnostic tool to assess how advanced a patient is in the progression of type 2 diabetes. Accordingly, appropriate and effective treatment strategies can be designed.
The objective of this study was to monitor alterations in key metabolic rate constants as obesity increases and determine the time period when the threshold occurs. We elected to monitor the rate constants in the differential equations by Lombart et al., which describes a simple model of glucose homeostasis involving several organs including insulin-dependent and insulin-independent tissues. Key metabolic rate constants were monitored every 2 weeks over a period of 7 months in B6D2F1 mice fed a high fat diet (HFD) by performing intraperitoneal glucose tolerance tests and estimating the rate constants through simulation and optimization using Arena ™ and OptQuest™, respectively. Mice fed the HFD gained weight significantly over time (23.96 g vs. 53.56 g). Fasting blood glucose levels were overall elevated with vast fluctuations (143 mg/dl at week 0 vs. 203 mg/dl at week 16) and basal insulin levels obtained from simulations were also elevated ~5 fold at week 16 (1186.75 pmole/L) from week 0 (218.33 pmole/L). Two rate constants Ipi (indicator of blood insulin concentration when the liver switches from glucose uptake to release) and K6 (insulin clearance from the blood) were significantly altered when the metabolic changes occurred. Mice fed the HFD for 7 months had not reached a full blown diabetes state and glucose homeostasis unexpectedly fluctuated between normal and impaired, rather than reaching a threshold and progressing gradually to overt diabetes. A new hypothesis that natural defense mechanisms against impaired glucose homeostasis may exist is postulated and understanding of the specific defense mechanisms may provide new strategies to treat or prevent obesity-associated type 2 diabetes.
|Advisor:||Ko, Hoo Sang, Kwon, Guim|
|School:||Southern Illinois University at Edwardsville|
|Department:||Mechanical and Industrial Engineering|
|School Location:||United States -- Illinois|
|Source:||MAI 55/02M(E), Masters Abstracts International|
|Subjects:||Biomedical engineering, Industrial engineering|
|Keywords:||Obesity, Optimization, Simulation, Type 2 diabetes|
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