Type 2 diabetes can be assessed from the perspective of mitochondrial dysfunction as not just a side effect, but a factor in its progression. Symptoms like fatigue and difficulty concentrating can be a sign that mitochondria aren’t functioning properly, and that same underlying dysfunction may be feeding the disease process itself. When mitochondria are impaired, they tend to produce excess reactive oxygen species, which can damage cells and tissues throughout the body.
The original trigger for that mitochondrial impairment may have been nutrient deficiency, toxin exposure, infection, chronic stress, or even inherited genetic factors. But once dysfunction sets in, several downstream processes start compounding each other: impaired oxidative phosphorylation, oxidative stress, lipid peroxidation, hyperglycemia and insulin resistance all feed into one another, creating an ongoing cycle of damage. The studies below give insight into this interaction, and point toward two interventions, diet and exercise, that appear able to interrupt it.
Oxidative Stress and Mitochondrial DNA
Memon et al. (2021) followed 2,387 Swedish women, ages 50–59, over a mean of 17 years. At baseline, 125 already had type 2 diabetes; another 179 developed it by follow-up. Those with low mitochondrial DNA copy number at baseline were more likely to be diagnosed with diabetes over the following years, and this association was even stronger among those without pre-diabetes at baseline.
Unsurprisingly, low mitochondrial DNA copy number tracked with several known risk factors: glucose intolerance, high systolic blood pressure, high triglycerides, smoking, aging, and lower education. But the association with type 2 diabetes held up even after adjusting for these confounders. There was a notable association with smoking status: smokers with low mitochondrial DNA copy number were more likely to develop diabetes, while smokers with high mitochondrial DNA copy number were less likely to. The authors describe the underlying mechanism as a feedback loop: reactive oxygen species generated by the electron transport chain can damage mitochondrial DNA, and this damage further impairs respiration, with reduced mitochondrial DNA copy number serving as a marker of that ongoing dysfunction.
Increased Oxidative Damage with Obesity and Diabetes Together
Chattopadhyay et al. (2015) examined mitochondria isolated from white adipose tissue collected during unrelated abdominal surgeries, comparing four groups: obese type 2 diabetics, obese non-diabetics, non-obese type 2 diabetics, and non-obese non-diabetic controls. Across markers of lipid peroxidation (malondialdehyde and fluorescent lipid peroxidation products), hydrogen peroxide production, and the antioxidant enzymes superoxide dismutase and glutathione peroxidase, the same consistent pattern emerged: controls had the healthiest values, obese type 2 diabetics had the worst, and the other two groups fell in between — with the differences reaching statistical significance between groups.
The authors’ proposed explanation: non-obese type 2 diabetics appear to have elevated reactive oxygen species primarily due to reduced antioxidant enzyme activity, while obese individuals face a double hit — both impaired antioxidant defenses and damage to the electron transport chain, which is consistent with these researchers’ earlier finding of impaired oxidative phosphorylation in obese participants but not in non-obese type 2 diabetics. They note that hyperglycemia, hyperinsulinemia, and elevated free fatty acids all add further oxidative stress— and that the resulting excess reactive oxygen species can directly interfere with insulin signaling, feeding into insulin resistance. Other studies have shown that oxidative stress contributes to cardiovascular, retinal, and kidney diabetic complications. A certain level of oxidative stress is present in health; it’s even produced during normal cellular metabolism. But when the electron transport chain is damaged, it produces excessive reactive oxygen species because NADH builds up when cellular respiration is not able to keep up with oxidizing it.
Methylmalonic Acid as a Mitochondrial Stress Marker
Wang et al. (2020) evaluated methylmalonic acid (MMA) as a marker of mitochondrial dysfunction and oxidative stress, using data from 23,437 NHANES participants (mean age 46.2). Plasma or serum MMA above 120 nmol/L was associated with greater all-cause mortality risk. Notably, even among people with normal B12 status (≥400 pmol/L), MMA levels above 250 nmol/L — a threshold sometimes used to flag B12 deficiency — were associated even more strongly with mortality.
High MMA correlated with age, lack of exercise, and cardiac risk factors, but not with HbA1c or insulin resistance. Mechanistically, MMA rises when mitochondria can’t keep up with metabolizing it — B12 deficiency is one cause, but not the only one — and elevated MMA can itself worsen oxidative stress and damage the electron transport chain further. The authors found homocysteine (which would be expected to track with MMA if B12 deficiency were the main driver) wasn’t strongly associated with elevated MMA in their data. They also cite research linking elevated MMA to worse diabetic peripheral neuropathy. Given these findings, I’d want to check serum MMA as part of a mitochondrial workup, and follow up with B12 testing if it comes back above 120 nmol/L.
Acylcarnitines and Incomplete Beta-Oxidation
Mihalik et al. (2010) measured plasma acylcarnitines in obese individuals with and without type 2 diabetes, compared to healthy, non-overweight (but sedentary) controls, both after fasting and after four hours of insulin-maintained euglycemia. Certain acylcarnitines were found to be elevated in proportion to participants’ HbA1c levels. Insulin brought acylcarnitine levels down from their fasting peak in everyone, but was less effective at doing so — and at lowering free fatty acids — in the diabetic participants.
Long-chain acylcarnitines were elevated in both obese groups regardless of diabetes status, but short- and medium-chain acylcarnitines were significantly higher specifically in the diabetic group — pointing to incomplete beta-oxidation rather than a problem with fatty acids entering the mitochondria. The researchers checked whether malonyl-CoA might be inhibiting carnitine acyltransferase-1 (the enzyme that helps fatty acids enter the mitochondria as acylcarnitines) by comparing 16-carbon acylcarnitines to free carnitine — if carnitine acyltransferase-1 were inhibited, 16-carbon acylcarnitines would be low relative to free carnitine. This was not the case: free carnitine was low relative to 16-carbon acylcarnitines, indicating fatty acids were successfully entering the mitochondria and beginning beta-oxidation. Instead, the ratio of 8-carbon to 16-carbon acylcarnitines was significantly elevated in diabetics, suggesting impaired beta-oxidation, or perhaps the products of beta-oxidation were not getting into the electron transport chain, causing a backup. Four-carbon acylcarnitines — likely succinylcarnitine — were nearly twice as high in diabetics compared to non-diabetics, pointing to a problem getting succinyl-CoA into the citric acid cycle.
Diet as an Intervention: Olive Oil, Nuts, and Antioxidant Enzymes
Sureda et al. (2016) looked at 75 participants from the PREDIMED trial who had spent five years on a Mediterranean diet — about half already diagnosed with diabetes, the rest with metabolic syndrome involving multiple cardiovascular risk factors like smoking, high blood pressure, and high cholesterol. Participants provided with plentiful olive oil or nuts showed better overall compliance with the Mediterranean diet, and at the five-year mark had higher extracellular superoxide dismutase and catalase along with lower xanthine oxidase — despite actually consuming more calories than the group not given olive oil or nuts.
The authors discuss several contributors to the reactive oxygen species load implicated in insulin resistance — the electron transport chain, nitric oxide synthase, NADPH oxidase, and xanthine oxidase — with superoxide anions in particular capable of damaging mitochondria if not adequately cleared by superoxide dismutase. Their proposed explanation is that the vitamin C and polyphenol content of the Mediterranean diet may be what’s driving the increase in extracellular superoxide dismutase, which in turn helps counter insulin resistance.
Exercise Restores Mitochondrial Quality Control
Fealy et al. (2019) had 10 obese, prediabetic, sedentary volunteers exercise for 12 weeks and found measurable improvement in the mitochondrial fragmentation typically seen with diabetes. Insulin sensitivity improved, along with aerobic capacity and fat oxidation, while fat mass and fasting glucose decreased.
The study highlights the mitochondrial fusion-and-fission cycle that normally maintains mitochondrial quality — producing new healthy mitochondria while clearing out dysfunctional ones through mitophagy. Excessive caloric intake, hyperglycemia, and high saturated fatty acids have all been found to push this system toward more fragmentation and more reactive oxygen species, contributing to insulin resistance. Exercise moved things the other direction: it increased mitochondrial number and size and improved their function, giving them greater capacity for fatty acid oxidation — which helps preserve insulin sensitivity. The researchers also found that FIS1 and Parkin — proteins involved in fission and mitophagy — were both reduced after 12 weeks of exercise, which they interpret as a sign that exercise made the existing mitochondria healthier overall, making them better candidates for fusion rather than targets for fission and mitophagy. They note this is a different pattern than what’s seen with a single bout of acute exercise, which tends to increase mitochondrial turnover instead — favoring clearance of damaged mitochondria and production of new ones.
The Takeaway
Mitochondrial dysfunction and type 2 diabetes appear to reinforce each other — damaged mitochondria generate more oxidative stress, and that oxidative stress further impairs mitochondrial function and insulin signaling. But the research on diet and exercise suggests this cycle isn’t fixed: both diet and exercise were shown to measurably improve mitochondrial quality and function, offering a potential path to interrupting the cycle rather than just monitoring its progression.
The content of this blog is for educational purposes and is not intended as medical advice. Please work with a qualified healthcare provider for personalized guidance.
References
Chattopadhyay, M., Khemka, V. K., Chatterjee, G., Ganguly, A., Mukhopadhyay, S., & Chakrabarti, S. (2015). Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Molecular and Cellular Biochemistry, 399(1–2), 95–103.
Fealy, C. E., Mulya, A., Axelrod, C. L., & Kirwan, J. P. (2019). Exercise training remodels human skeletal muscle mitochondrial fission and fusion machinery towards a pro-elongation phenotype. Acta Physiologica, 225(4).
Memon, A. A., Sundquist, J., Hedelius, A., Palmér, K., Wang, X., & Sundquist, K. (2021). Association of mitochondrial DNA copy number with prevalent and incident type 2 diabetes in women: A population-based follow-up study. Scientific Reports, 11(1).
Mihalik, S. J., Goodpaster, B. H., Kelley, D. E., Chace, D. H., Vockley, J., Toledo, F. G. S., & DeLany, J. P. (2010). Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity, 18(9), 1695–1700.
Sureda, A., Bibiloni, M. del M., Martorell, M., Buil, C. P., Marti, A., Pons, A., Tur, J. A., & Martinez, G. M. Á. (2016). Mediterranean diets supplemented with virgin olive oil and nuts enhance plasmatic antioxidant capabilities and decrease xanthine oxidase activity in people with metabolic syndrome: The PREDIMED study. Molecular Nutrition & Food Research, 60(12), 2654–2664.
Wang, S., Liu, Y., Liu, J., Tian, W., Zhang, X., Cai, H., Fang, S., & Yu, B. (2020). Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population. Redox Biology, 37.
Northern Nutritionals 
Leave a comment