All ETDs from UAB

Advisory Committee Chair

Scott W Ballinger

Advisory Committee Members

Louis J Dell'Italia

Stuart J Frank

Joseph L Messina

Douglas R Moellering

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

It has been observed that the risk of developing diabetes increases with age as well as among certain races, most notably African Americans and Hispanic Americans who are almost two times as likely to develop perturbed glucose metabolism compared to Caucasian Americans. Interestingly, there are distinct mitochondrial DNA polymorphisms that distinguish people of different races and thus may contribute to differential susceptibility to diseases of glucose metabolism. To test the hypothesis that the mitochondrial DNA (mtDNA) contributes to glucose metabolism and insulin sensitivity, two strains of mice were used with distinct mtDNA sequences namely, C57BL6/J and C3H/HeN as well as two reciprocal Mitochondrial Nuclear eXchange (MNX) strains, C57nDNA:C3HmtDNA MNX and C3HnDNA:C57mtDNA MNX. All four strains were less glucose tolerant and insulin sensitive at 18 weeks compared to 6 weeks of age, however while no differences were observed between wild-types and their nuclear matched MNX at 6 weeks of age, by 18 weeks, both MNX were more glucose tolerant and insulin sensitive than their nuclear-matched wild-type controls. Fasting blood glucose, plasma insulin, and leptin levels were consistent with the glucose and insulin tolerance results. C57nDNA:C3HmtDNA MNX also had higher insulin stimulated pAkt:total Akt ratios in muscle tissue compared to nuclear-matched wild-type controls. Although all strains had a significant oral-glucose stimulated increase in the incretin, GIP, only the C3HnDNA:C57mtDNA MNX responded with higher insulin secretion, suggesting a preservation of incretin sensitivity. Although there were no significant differences in food intake, body weight or feed efficiency between wild-types and nuclear matched MNX, C57nDNA:C3HmtDNA MNX body composition was significantly altered, with increased lean mass, decreased fat mass and lowered fat:lean ratios compared to C57nDNA:C57mtDNA wild-type control. C3HnDNA:C57mtDNA MNX had increased lean body mass percentage at 6 and 12 weeks of age compared to C3HnDNA:C3HmtDNA wild-type control, which did not persist at 18 weeks of age, but may have contributed to the improved metabolic phenotype. Thus, mitochondrial genetic background can alter glucose metabolism, improving glucose tolerance and insulin sensitivity, mediated in part by improvements in leptin secretion, GIP incretin sensitivity, improved insulin stimulated pAkt:total Akt levels in muscle, and leaner body composition.

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