Mitochondria and Diabetes

The role of intracellular organelles in polygenic and complex pathologies such as diabetes mellitus has become of increasing interest, yet the relevance of mitochondrial function, or factors related to mitochondrial function such as reactive oxygen species to diabetes remains controversial. This section summarises recent clinical findings which suggest that loss of mitochondrial plasticity may contribute to the development of diabetes by promoting insulin resistance, and that oxidative stress induced by mitochondria may trigger apoptosis in a number of organs, thus contributing to diabetes-associated complications.

Mitochondria- Functional and Pathological significance

Mitochondria are complex cellular organelles that play a pivotal role in adenosine triphosphate (ATP) synthesis, generation of reactive oxygen species (ROS), nutrient sensing and programmed cell death. Recent years have witnessed increasing interest in the role of mitochondria, as mediated by their contribution to oxidative stress, in a number of pathologies ranging from neurodegenerative to metabolic diseases.

This has prompted the development of new methods to investigate mitochondrial function in vivo, through assessment of ATP generation and ATP synthase flux, and ex vivo biopsy samples. Although in vivo assessment of mitochondrial function involves cutting edge magnetic resonance spectroscopy, the final readout cannot elucidate specific abnormalities at the individual respiratory complex level, nor can it provide information regarding potential compensatory changes in mitochondrial content and efficiency.

Highly sensitive methods such as high resolution respirometry and specialized fluorophores for real-time detection of mitochondrial membrane potential and reactive oxygen species allow detailed investigation of mitochondrial efficiency and, through use of multiple substrate and inhibitors, can provide more information about the influence of individual complexes. Although several epidemiological studies, genome wide association studies and investigations based on animal models suggest that the mitochondria might contribute to the development of diabetes and associated co-morbidities, the functional link between mitochondrial function and diabetes remains unclear.

Mitochondria and Insulin resistance

Insulin resistance, a combination of lower insulin response and sensitivity, is a central feature in the development and progression of type 2 diabetes (T2D), and might also be important in type 1 diabetes (T1D). A reduced maximal effect of insulin reflects decreased insulin responsiveness, whereas lower insulin sensitivity is defined by the need for a higher insulin concentration to elicit the maximal response to insulin, i.e. a right shift of the dose response curve [1].

Under physiological conditions, insulin activates the tyrosine kinase of the insulin receptor, which stimulates insulin receptor substrate (IRS) phosphorylation followed by activation of phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B (PI3K-AKT). Several mechanisms can induce insulin resistance by interfering with the insulin signaling cascade, such as elevated blood glucose, lipids or amino acids levels, oxidative and endoplasmic reticulum stress, systemic and cellular inflammation and genetic polymorphisms in the signalling molecules.

By virtue of their ability to make transient functional responses to changing nutritional availability, endocrine signals or changes in the cellular environment, mitochondria display a flexibility known as mitochondrial plasticity. In clinical terms, loss of mitochondrial plasticity in T2D is reflected in a lower maximal oxidative phosphorylation capacity and reduced ATP flux, despite higher nutrient availability in the circulation.

Whilst this apparent loss of mitochondrial plasticity in patients with overt and long term diabetes is attributed to lower mitochondrial content, the role of this phenomenon on the development of diabetes is still debatable. Insulin resistant high risk, first degree relatives (FDR) of individuals with polygenic T2D appear to have approximately 30% lower maximal oxidative phosphorylation capacity and ATP flux in skeletal muscles as compared to insulin sensitive individuals [2]. Interestingly, insulin sensitive FDR have been observed to have an ATP flux comparable to healthy individuals [3].

Impairment of myocellular mitochondrial activity has been associated with decreased mitochondrial substrate oxidation and tricarboxylic acid cycle (TCA) activity, and an increased accumulation of lipid intermediates such as diacylglycerols and ceramides. This increase in intramyocellular lipids is known to blunt the insulin signaling response through the activation of protein kinase C (PKC) isoforms, and subsequent inhibitory phosphorylation of insulin receptor substrate (IRS).

A similar phenomenon has been observed in liver cells, in that insulin resistant individuals with higher hepatic lipid content have lower maximal oxidative phosphorylation capacity and higher oxidative stress [4]. An inter-organ crosstalk between muscles and liver tissue is also indicated by the association between myocellular ATP flux and hepatic lipid content, independent of age, body mass index and glucose tolerance [5].

Another hypothesis linking abnormal mitochondrial function and insulin resistance is based on the pathological effect of chronically generated ROS. Both T1D and T2D are closely associated with higher ROS generation coupled with lower antioxidant capacity. Oxidative stress is thought to damage cellular proteins, lipids and nucleic acids, subsequently resulting in endoplasmic reticulum stress, and activation of the unfolded protein response. Unfolded protein response-mediated activation of pattern recognition receptors such as toll like receptor (TLR) has been shown to trigger the autoimmune response, thus possibly linking abnormal mitochondrial function with predominantly autoimmune T1D [6]. Moreover, ROS are also known to contribute to higher generation and accumulation of advanced glycation end products (AGE) which are known to influence the inflammatory response.

Mitochondria and Diabetic Co-morbidities

Brownlee is credited with developing the “Common Soil hypothesis” in his renowned Banting lecture. Mitochondrial ROS have since then been thought to play an important unifying role in the development and progression of diabetes-associated complications such as diabetic retinopathy, neuropathy, nephropathy as well as macrovascular complications such as diabetic cardiomyopathy [7]. Although epidemiological studies have not substantiated a direct causal contribution of mitochondria to diabetic complications, apoptosis and fibrosis mediated by mitochondrial ROS are well documented in various in vitro models.

Furthermore, intervention studies with anti-oxidants such as pentoxyfilline, alloxan and mitochondrial targeted antioxidants such as MitoQ® have provided promising preliminary indications of renoprotection, improved retinal blood flow etc [8][9][10]. These interventions unfortunately do not appear to resolve the complications entirely, thus suggesting that the pathophysiological nature of oxidative stress may be secondary to abnormal mitochondrial function, and highlighting the need for therapy specifically targeting mitochondrial function .

Alternatively, exercise interventions, although heterogeneous in design and implementation, appear to have a positive impact on measures of insulin sensitivity, as well as outcomes of diabetes associated complications. While these improvements were previously attributed to an improvement in glycemic control, some studies have shown that mitochondrial function, content and whole body energy-metabolism improve, independent of blood glucose and lipids [11][12]. Exercise training has also been linked with lower systemic oxidative stress, and improved anti-oxidant response in the chronic setting.

In conclusion, clinical and experimental evidence of the role of mitochondria in the development of diabetes is accumulating, but future studies must aim to approach mitochondrial function and health more holistically, assessing multiple factors simultaneously in order to address the significance of impaired mitochondrial function in people with a well characterised diabetes phenotype.

References

  1. ^ Brehm A, Roden M. Glucose clamp techniques. In: Roden M, editor. Clinical Diabetes Research, West Sussex:Wiley; 2007,p.43-76.

  2. ^ Petersen KF, Dufour S, Befroy D, Garcia R, and Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350: 664–671.

  3. ^ Kacerovsky-Bielesz G, Chmelik M, Ling C, Pokan R, Szendroedi J, Farukuoye M, Kacerovsky M, Schmid AI, Gruber S, Wolzt M, Moser E, Pacini G, Smekal G, Groop L, and Roden M. Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes. Diabetes 2009; 58: 1333–1341.

  4. ^ Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, Herder C, Carstensen M, Krausch M, Knoefel WM, Schlensak M, Roden, M. Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis. Cell Metab 2015; 21: 739-746.

  5. ^ Szendroedi J, Kaul K, Kloock L, Straßburger K, Schmid AI, Chmelik M, Kacerovscky M, Kacerovsky-Bielesz G, Prikoszovich T, Brehm A, Krssak M, Gruber S, Krebs M, Kautzky-Willer Am Moser E, Pacini G, Roden, M. Lower fasting muscle mitochondrial activity relates to hepatic steatosis in humans. Diabetes care 2014; 37: 468-474.

  6. ^ Pozzilli P, Buzzetti R. A new expression of diabetes: double diabetes. Trends Endocrinol Metab 2007; 18: 52-57.

  7. ^ Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 2011; 7: 176-184.

  8. ^ Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, Laffel L, King GL. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 1999; 22:1245-1251.

  9. ^ He T, Cooper MA. Diabetic nephropathy: renoprotective effects of pentoxifylline in the PREDIAN trial. Nat Rev Nephrol 2014; 10:547-548.

  10. ^ Green K, Brand MD, Murphy MP. Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 2004; 53: S110-S118.

  11. ^ Petersen KF, Price TB, Bergeron R. Regulation of net hepatic glycogenolysis and gluconeogenesis during exercise: impact of type 1 diabetes. J Clin Endocr Metab 2004; 89:4656-4664.

  12. ^ Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. PNAS 2011; 108:13705–13709.

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.