Reversing Mitochondrial Dysfunction is the Game Changer in Diabetes?

CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.

Mitochondrial Dysfunction and Type 2 diabetes

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic β cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction – “Mitochondrial Dysfunction and Type 2 Diabetes,” Science, 21-Jan-2005, p. 384

Let us see what is the Update in 2021

Pathogenesis of T2D can be explained by the triumvirate hypothesis

1. Decreased insulin secretion by the pancreas.
2. Increased hepatic glucose production.
3. Decreased muscle glucose uptake.

(cumulatively leads to hyperglycemia)

Expanded hypothesis

• Other tissues contributing to glucose homeostasis are adipose tissue, kidney, gut, α-cells of the pancreas and the nervous system.
• These together with the above mentioned three components are called ominous octet of diabetes.

Mitochondria play a central role in the cellular energy metabolism

• It is responsible for oxidative phosphorylation (OXPHOS) and β-oxidation of fatty acids.
• OXPHOS is essential for glucose and lipid metabolism and adenosine triphosphate (ATP) production.

Mitochondrial dysfunction has long been associated with diabetes

• Mitochondrial dysfunction is a potential cause of both IR and β-cell dysfunction. It has been implicated also more recently in the context of secondary diabetes complications.
• Stressed and decreased mitochondrial content leads to disturbances in mitochondrial biogenesis and impaired mitochondrial function.
• Further it leads to intracellular accumulation of lipid products and increased production of reactive oxygen species (ROS).

Mitochondrial disorders, caused by mutations in the mitochondrial genome, cause a specific diabetes phenotype

• MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes).
• MIDD (maternally inherited diabetes and deafness), make an interesting case for exploring the relationship between mitochondrial dysfunction and diabetes.
• Clinical features that raise suspicion for mitochondrial diabetes:
  • Multi-organ involvement.
  • Elevated serum lactate levels.
  • A more rapid progression to insulin therapy.
  • Earlier onset of diabetes-related complications compared to individuals with T2D.
  • The inability of dysfunctional mitochondria to produce sufficient ATP resulting in multi-organ defects. It affects predominantly organs with high energy requirements such as the central nervous system, muscle, retina, kidney and pancreas.

Mitochondria in diabetes are studied by many different methods

• Measuring mitochondrial content (number, volume, activity of marker enzymes or mtDNA copy number).
• Morphology or parameters related to mitochondrial biogenesis (expression of mRNA or proteins involved in these processes).
• In skeletal muscles: Mitochondrial function can be studied in vivo, using magnetic resonance spectroscopy or ex vivo, using high-resolution respirometry for measuring mitochondrial function in tissue biopsies or isolated mitochondria.
• Measuring mitochondrial function, which can also be done in many ways:
  • Protein abundance of respiratory chain complex subunits.
  • In vitro activity of different mitochondrial enzymes.
  • Ex vivo oxygen consumption (respirometry).
  • ATP synthesis.
  • In vivo measurement of ATP or phosphocreatine resynthesis rate.
• In blood cells: Membrane potential, mitochondrial mass and superoxide production in PBMCs (Peripheral blood mononuclear cells)

What we need to ponder?

• Mitochondrial dysfunction is present in different tissues and contributes to diabetes pathogenesis and complications in a plethora of ways.
• There is an undeniable correlation between T2D and IR on the one side and mitochondrial dysfunction on the other.
• It is not yet clear if this is due to a decrease in intrinsic mitochondrial function or to a decrease in mitochondrial content.
• In 2021 research is advancing to therapeutic interventions that target mitochondria.
• It could present a more integrative therapeutic approach, treating different causative and secondary defects of diabetes at once.

Role of Mitochondria in Diabetes

• Skeletal muscles:
  • When studying mitochondrial function in human muscle.
  • Disruption of normal mitochondrial dynamics is one of the most frequently proposed mechanisms behind mitochondrial dysfunction in diabetes.
  • Numerous studies show decreased expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)
  • There is also decreased expression of PGC-1α and nuclear respiratory factor-1 (NRF-1) responsive genes that encode oxidative enzyme.
  • Many studies show that when normalized to mitochondrial content (citrate synthase activity or mitochondrial DNA copy number) respiration does not differ between subjects with diabetes and healthy controls.
  • Mitochondrial dysfunction in diabetic muscle is a consequence of lower mitochondrial content and not lower intrinsic mitochondrial function.
• Liver:
  • A strong correlation has also been found between liver fat accumulation and fasting serum insulin.
  • This might be in part due to a decrease in hepatic insulin clearance.
  • Elevation of hepatocellular lipid content, also called non-alcoholic fatty liver (NAFL), precedes the manifestation of T2D.
  • NAFL along with inflammatory processes in the liver often progresses to non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
  • All of these liver pathologies have been associated with mitochondrial abnormalities.
• Blood cells
  • PBMCs have been found smaller, more spherical mitochondria and decreased total mitochondrial mass in T2D patients.
  • Platelet mitochondria from diabetic patients have been found having  lowered oxygen consumption, lower oxygen-dependent ATP synthesis, induction of mitochondrial anti-oxidant enzymes (superoxide dismutase 2 and thioredoxin-dependent peroxide reductase 3) and upregulation of oxidative stress.

So, what is happening inside with Mitochondrial Fusion, Fission and Autophagy?

• We need mitochondria remodelling to reverse type 2 diabetes. Mitochondrial remodelling involves fusion, fission and autophagy, in β‐cells.
• Through fusion, intact mitochondria can share solutes, metabolites, mtDNA and electrochemical gradients with damaged mitochondria.
• The fission event often yields mitochondria with decreased membrane potential and reduced possibility of fusion.
• Fusion and fission cycling is thought to be a process of segregating dysfunctional mitochondrial and rendering it for autophagy.
• So finally, fusion, fission and autophagy seem to be an integral part of maintaining homeostasis of β‐cell mitochondrial function in T2DM.

Interventions Targeting Mitochondria in Diabetes

• Exercise – Exercise training improves metabolic health and insulin sensitivity in T2D patients which occurs through different cellular mechanisms and mitochondria are central for many of these processes.

Pharmacological

• Many widely-used antidiabetics have been reported to affect mitochondrial function:
  • Metformin: Metformin is frequently mentioned as a respiratory complex I (CI) inhibitor and AMPK activator, especially in the context of exercise mimetics.
  • Thiazolidinediones (TZDs) or glitazones.
  • Sodium-glucose co-transporter-2 (SGLT-2) inhibitors or gliflozins, have been shown to inhibit complex I respiration in primary mouse hepatocytes and to increase expression of proteins important for mitochondrial biogenesis and function in white adipose tissue of mice with high fat diet – induced obesity and cultured adipocytes.
  • Statins used for treating hypercholesterolemia, have been shown to have an effect on mitochondrial function as well.
• Novel therapeutic approaches that target mitochondria:
  • CI inhibitors
  • AMPK activator
  • PPARs agonist
  • MPC inhibitors
  • OXPHOS modulator
  • NAD+ booster)
  • Antioxidants, sirtuin-activating compounds (STACs)
  • Mitochondrial permeability transition pore (mPTP) inhibitors
  • Mitochondrial membrane properties modulators
  • ROS scavenger
  • CoQ10 (coenzyme Q10) analogues
  • Mitochondrial-associated ER membranes (MAM) modulators)
  • Some natural products found in certain foods, such as resveratrol (which can be found in grapes and red wine) and epicatechine (found in cocoa and dark chocolate).
  • Imeglimin is a novel glucose-lowering drug that is currently being tested, with a few stage III clinical trials. It could be next BLOCK-BUSTER in diabetes market. The proposed target of imeglimin action is the mitochondrion. Imeglimin treatment has been shown to decrease glucose production and the ATP/ADP ratio and to increase mitochondrial redox potential in primary hepatocytes, without affecting mitochondrial respiration.

CME INDIA Learning Points

• Mitochondria play a key role in energy metabolism and ATP production in many tissues, including skeletal muscle, cardiac muscle, brain and liver. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis.
• Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS) and low levels of ATP.
• Inherent disorders of mitochondria such as mDNA deletions cause major disruption of metabolism and can result in severe disease phenotypes.
• Mitochondrial dysfunction characterized by reduced ATP generation and reduced mitochondrial number in skeletal muscle or reduced ATP generation and mitochondrial stimulus-secretion coupling in the pancreatic beta cell has been implicated in the pathology of chronic metabolic disease associated with type 2 diabetes mellitus and also with aging.
• Additionally, the generation of ROS from mitochondria and other cellular sources may interfere in insulin signaling in muscle, contributing to insulin resistance.
• Reduced mitochondrial oxidative capacity coupled with increased ROS generation underlies the accumulation of intramuscular fat, insulin resistance and muscle dysfunction in aging.
• Mitochondrial function is impacted in diabetic patients, but underlying tissue-specific mechanisms may differ.
• Skeletal muscle mitochondria are more affected during physical activity and are the most responsible for the health-promoting effects of exercise training.
• Mitochondrial dysfunction is also present in other tissues involved in diabetes pathogenesis and tissues affected by diabetes complications
• There is a problem of sampling human tissue for ex vivo analysis of mitochondrial function, mostly because of its invasive nature. Now  blood cells are becoming more attractive for respirometric analysis as they are easily accessible and circulate through the whole organism, thus having a potential to reflect systemic metabolic changes.
• In T2D, there is an excess of fuel (glucose and fatty acids), and often a lack of energy expenditure (sedentary lifestyle), and this disbalance becomes a chronic state. The consequential mitochondrial dysfunction further propagates IR and ectopic lipid accumulation, creating a vicious circle.
• The good thing is that respiratory capacity can be improved by changes in lifestyle, the most important being physical activity and healthy diet, as well as pharmacological agents that target mitochondria. This is the most important learning.

CME INDIA Tail Piece

References:

1. Krako Jakovljevic, N.; Pavlovic, K.; Jotic, A.; Lalic, K.; Stoiljkovic, M.; Lukic, L.; Milicic, T.; Macesic, M.; Stanarcic Gajovic, J.; Lalic, N.M. Targeting Mitochondria in Diabetes. Int. J. Mol. Sci. 2021, 22, 6642. https://doi.org/10.3390/ ijms22126642
2. Gnaiger, E.; Group, M.T. Mitochondrial physiology. Bioenerg. Commun. 2020
3. Jacobs, R.A.; Lundby, C. Contextualizing the biological relevance of standardized high-resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle. Acta Physiol. 2021, 231, e13625.
4. Liepinsh, E.; Makarova, E.; Plakane, L.; Konrade, I.; Liepins, K.; Videja, M.; Sevostjanovs, E.; Grinberga, S.; Makrecka-Kuka, M.; Dambrova, M. Low-intensity exercise stimulates bioenergetics and increases fat oxidation in mitochondria of blood mononuclear cells from sedentary adults. Physiol. Rep. 2020, 8, 1–11.
5. Singh, A.; Faccenda, D.; Campanella, M. Pharmacological advances in mitochondrial therapy. EBioMedicine 2021, 65, 103244.
6. Vial, G.; Lamarche, F.; Cottet-Rousselle, C.; Hallakou-Bozec, S.; Borel, A.; Fontaine, E. The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells. Endocrinol. Diabetes Metab. 2021, 4, 1–10.

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