The role of mitochondria in the pathogenesis of type 2 diabetes

Abstract

The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.

Figure 1

Basic structural and functional features of the mitochondrial reticulum (illustrated from left to right). The mitochondrial reticulum is composed of an inner and outer membrane, between which lies the intermembrane space, and a matrix contained within the inner membrane. The surface of the inner membrane is folded into cristae. The organization and distribution of the mitochondrial reticulum is controlled by interactions with cytoskeletal elements such as microtubules. The matrix contains the enzymatic machinery for fatty acid β oxidation, which generates acetyl-CoA from acyl chains, and reducing equivalents in the form of NADH and FADH₂ in the process. Acetyl-CoA fuels the TCA cycle, which also produces NADH and FADH₂. These donate electrons to the ETC, leading to the generation of a proton gradient across the inner mitochondrial membrane. Dissipation of this gradient through the mitochondrial ATPase generates ATP. Delay of electron transport by the ETC results in the production of ROS, which can activate UCPs that dissipate the proton gradient without producing ATP. The electrochemical gradient also causes cytoplasmic Ca⁺⁺ to enter the matrix, buffering cytoplasmic Ca⁺⁺ levels and promoting TCA cycle flux. Mitochondria are also crucial in the generation of iron-sulfur clusters that form the prosthetic group of numerous proteins involved in multiple cellular pathways. The mitochondrial reticulum undergoes continuous fusion and fission reactions that involve both the inner and outer mitochondrial membranes, allowing redistribution of matrix content, such as mtDNA, within the reticulum. The proteins that compose all mitochondrial machineries are encoded both by mtDNA and by nuclear DNA. The master transcription factor operating on mtDNA is TFAM, which is encoded in the nuclear genome. The expression of mitochondrial genes in the nucleus is driven by numerous transcription factors, which are in turn controlled by specific coactivators and corepressors that respond to cellular energy demands.

Figure 2

Visualization of the dynamic nature of the mitochondrial reticulum in a cultured muscle cell. C2C12 mouse myoblasts were stained with MitoTracker green and imaged in culture at 37 C. Images of a segment of the cell captured at 30-sec intervals are shown on the left. The comparison between successive frames reveals scission events (arrowheads), branching events (V), and fusion events (brackets) occurring at 30-sec intervals.

Figure 3

Coupled and uncoupled respiration. Electrons derived from reduced donors NADH and FADH₂ are transported within the ETC to molecular oxygen, producing water. The flow of electrons within the ETC is coupled to translocation of protons due to the large amount of free energy released during electron transport. The remainder of this free energy is released as heat. The proton gradient thus produced is dissipated through the mitochondrial ATPase, and the consequent decrease in free energy drives ATP synthesis. This process is known as OXPHOS, or coupled respiration. Under circumstances where NADH and FADH₂ are available, but movement of electrons down the respiratory chain is slow, some of those electrons will be released from the respiratory chain and reduce molecular oxygen, forming the superoxide anion O₂⁻, hydrogen peroxide, and the hydroxyl radical OH⁻. These are the main ROS formed at steady state. Accumulation of ROS activates UCPs, which dissipate the proton gradient without producing ATP, resulting in uncoupled respiration.

Figure 4

Hypothesized mechanism by which free fatty acid (FFA) excess impairs insulin secretion. A, As described above, the activity of the ETC leads to the synthesis of ATP and the generation of a small amount of ROS. In the β-cell, both ATP and ROS are signals that trigger insulin secretion. Excessive accumulation of ROS is mitigated normally by the activation of UCP2, which dissipates the proton gradient, decreasing both ATP and ROS production. The presence of this normal negative feedback loop suggests that the control of excessive ROS generation is imperative in the β-cell, even if it occurs at the expense of decreasing ATP synthesis. B, In the presence of excess FFA, this normal feedback loop is compromised by a direct activation of UCP2 by FFA, as well as an effect of FFA to increase the amount of UCP2. Thus, uncoupling occurs to an excessive degree, compromising ATP synthesis enough to impair insulin secretion and β-cell fitness.

Figure 5

Dynamic relationship between oxidative activity and fuel load leading to development of disease. In this diagram, oxidative capacity refers to the ability to generate energy in response to varying energy requirements, and balance is indicated by oxidative capacity equaling or exceeding fuel loads. A, High oxidative activity can ensue from high-energy requirements (chronic exercise, high metabolic rate). Individuals with a high oxidative capacity will have high tolerance to large fuel loads. B, Low oxidative activity can ensue from a lack of energy requirement (sedentary lifestyle) or inability to generate energy (mitochondrial myopathies, intrauterine exposures, genetics) as seen in the failure of ATP synthesis in DM patients in response to exercise. Individuals with low oxidative capacity are intolerant to moderate-high fuel loads that lead to ROS generation, lipid accumulation, incomplete oxidation, and acute insulin resistance. C, Insufficient oxidative capacity can be resolved by compensatory mechanisms that increase oxidative activity (e.g., exercise, top right) decrease fuel load (weight loss, middle right), or resolve maladaptive patterns of oxidative stress. Insufficient compensation results in chronic insulin resistance (bottom right).

Figure 6

Vicious cycle leading to progressively increased risk of DM. An individual’s intrinsic mitochondrial oxidative capacity is determined by numerous factors including genetic and ethnic background, intrauterine exposures, and age. Chronic fuel excess, in the setting of suboptimal oxidative activity, results in fatty acid accumulation, incomplete oxidation, increased oxidative stress, and ROS generation leading to impairment in oxidative capacity, compounding the deleterious effects of fuel excess. With time, mitochondrial damage ensues, further exacerbating the process. Together, these factors contribute to progressively impaired insulin sensitivity, insulin secretion, and heightened risk of DM.