Age-related onset of type 2 diabetes and impaired glucose tolerance may be due to the lowered ability of muscle mitochondria to switch from metabolizing fatty acids to metabolizing glucose in healthy elderly people compared to young people. Americans >65yo are more likely to develop type 2 diabetes or glucose intolerance. The reasons for this are largely unknown, but studies have shown that muscle insulin resistance, increased intramyocellular lipid content (IMCL, triglycerides located within muscles), and decreased metabolic rates are related to aging.
Singling out mitochondrial function in muscle cells is hard via indirect calorimetry which provide information about the body’s basal metabolic rate, not just metabolism in muscle cells. It is also reliant on blood flow, which can change due to changes in several factors. So Yale University School of Medicine developed a method for studying the flux of 2 key metabolic enzymes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 13C-labeled glucose.
During cell metabolism, pyruvate enters mitochondria >>series of reactions >> CO2, H20, acetyl-CoA. In the 1st step, pyruvate reaction is catalyzed by pyruvate dehydrogenase. Acetyl-CoA converts to citrate through the enzyme citrate synthase. This study assessed the ratio of the flux of pyruvate dehydrogenase to citrate synthase within muscle mitochondria after 24h fast and after insulin stimulation in healthy, non-smoking elderly subjects (average age was 69 years). They were matched with young subjects (average age was 27 years). Petersen et al. did an oral glucose test and checked IMCL content.
RESULTS: After fasting, elderly subjects had higher plasma glucose concentrations than the younger subjects, but other factors, eg insulin concentration, were the same for both. After ingestion of glucose, the concentration of glucose and insulin in plasma were found to be significantly higher in the elderly subjects. Proton magnetic resonance spectroscopy showed IMCL content was 73% higher in elderly subjects.
~After assessing glucose tolerance and IMCL content, they examined response to increased plasma insulin levels using hyperglycemic-euglycemic clamp studies combined with stable isotopes of glucose. Both the young and elderly groups’ insulin levels were increased while their glucose levels were kept the same by a variable infusion of glucose. But elderly subjects metabolized glucose 25% slower than the younger subjects which could be due to reduced rates of nonoxidative glucose disposal due to reduced activity of ATK2, iinsulin signaling protein.
Finally, flux of pyruvate dehydrogenase and citrate synthase in muscle cells was assessed by taking muscle biopsies before and after insulin stimulation and using LC/MS/MS. After fasting, fluxes for both enzymes were the same for the elderly subjects and the young subjects. After insulin stimulation, ratio of the flux of pyruvate dehydrogenase-to-citrate synthase increased 3X only in younger subjects.
ie after insulin stimulation, only younger group switched from lipid oxidation to G oxidation = problem in insulin signaling in the muscle associated with aging and may be a contributing factor to the higher incidence of type 2 diabetes and glucose intolerance in elderly people.
http://www.pnas.org/content/102/15/5618.full
Relative abundance of mitochondrial proteins in muscle from young and older subjects. The percentage difference (*, P < 0.05) of older relative to young is shown (n = 10/group). Negative values indicate less protein in older subjects.
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