Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.

Skeletal muscle atrophy was a characteristic of type 1 diabetes (T1DM) prior to insulin discovery and replacement. Indirect calorimetry during the post-absorptive state demonstrated that increased fuel oxidation during transient insulin deprivation in T1DM caused depletion of energy stores. Further, insulin has a critical role in preserving muscle mitochondrial content and function by enhancing mitochondrial biogenesis and proteostasis. Insulin deficiency not only inhibits mitochondrial biogenesis but also accelerates the degradation of mitochondrial proteins, causing a decline in mitochondrial content and efficiency. Inefficient mitochondrial respiration, reflected by the uncoupling of oxidative phosphorylation and consequent decline in ATP production, adversely affects many cellular functions and causes high oxidative stress. Oxidative stress adversely affects cardiovascular functions and damages many skeletal muscle proteins, accelerating their degradation and explaining muscle atrophy. Increased degradation of muscle proteins increases amino acid efflux that stimulates the liver to synthesize many non-insulin-dependent proteins, potentially contributing to macrovascular complications. This phenomenon explains a paradoxical increase in whole-body protein synthesis during insulin deficiency. Further, the mitochondrial biology of brain regions rich in insulin receptors concurrent with accelerated transport of ketones and lactate across the blood-brain barrier during insulin deficiency seems to protect the brain from oxidative stress. In contrast, insulin resistance associated with less ketone and lactate production renders the brain susceptible to protein oxidative damage. Oxidative damage and reduced ATP production potentially explain the higher prevalence of dementia in insulin-resistant people. Enhancement of insulin sensitivity by aerobic exercise and metformin in pre-clinical studies prevents mitochondrial dysfunction and oxidative damage to the brain.