**1. Introduction**

122 Biomedical Science, Engineering and Technology

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### *A few words about mitochondria ….*

Mitochondria are active intracellular structures that collide, divide, and fuse with other mitochondria. Mitochondria exist as branched-chain reticulum networks, but can also exist as punctuated structures. Their distribution within the cells is quite diverse, is regulated by the interactions with the cytoskeleton and maintained by the balance between mitochondrial fusion and fission.

Mitochondria play crucial physiological functions that underlie the distortions of fragile balance between health and disease. In recent years, the role of mitochondria has gained much interest in the field of diabetic pathology since mitochondrial abnormalities were found in insulin resistance and in both types of diabetes.

### *A few words about hyperglycaemia and diabetes….*

Hyperglycaemia, resulting from uncontrolled regulation of glucose metabolism, is widely recognized as the causal link between diabetes and diabetic complications. Diabetes mellitus has been classified into two forms. Type 1 diabetes, which accounts for about 10% of all cases of diabetes, is caused by autoimmune destruction of pancreatic β-cells that implies insulin deficiency. Type 2 diabetes, the more prevalent form of diabetes, is considered a heterogeneous disease due to the multiplicity of factors that cause the observed phenotype. It results from the combination of insulin resistance and/or a β-cell secretory defects. The explosive increase in the prevalence of type 2 diabetes is predicted in the nearest future. It is considered that about 220 millions people all over the world may suffer from the condition, and an equal number is thought to be "prediabetic", having early symptoms and not yet full manifestation of the disease.

### *A few words about impact of hyperglycaemia on mitochondria …..*

Hyperglycaemia has been indicated as one of the main causes of altered mitochondrial function in diabetic individuals (animals and humans). Rather huge variation in the extent of damage has been observed and attributed to both the type and duration of diabetes studied. General consensus points out to the formation of glycation products as a crucial mechanism, by which hyperglycaemia affects mitochondrial and cellular function in diabetes.

Hyperglycaemia elicits an increased ROS production, presumably to the major extent originating from mitochondrial respiratory chain. ROS play a central role in mediating various metabolic defects associated with a diabetic state. Therefore, the inhibition of ROS production and/or enhancement of ROS scavenging might prove to be beneficial therapies. Alterations in metabolic regulators and glucose-stimulated insulin secretion are also associated with mitochondrial dysfunction in diabetes.

Impairments in mitochondrial function are intrinsically related to diabetes. The prevailing hypothesis is that hyperglycaemia-induced increase in electron transfer donors (NADH and FADH2) may increase electron flux through the mitochondrial electron transport chain. Consequently, the ATP/ADP ratio and hyperpolarisation of the mitochondrial membrane (electrochemical potential difference) also become increased. This high electrochemical potential difference generated by the proton gradient leads to partial inhibition of the electron transport in the complex III, resulting in the augmented electron flow towards coenzyme Q. In turn, this drives partial reduction of O2 to generate the free radical anion superoxide. It is accelerated reduction of coenzyme Q and generation of ROS that are believed to constitute the fundamental source for mitochondrial dysfunction that plays a critical role in diabetes-related metabolic disorders and tissue histopathology.

### *A few words about oxidative stress…..*

Oxidative stress has been implicated as a major contributor to both the onset and the progression of diabetes and its associated complications. Some of the consequences of an oxidative environment may be the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction, which can ultimately lead to the diabetic disease state. Experimental and clinical data suggest an inverse association between insulin sensitivity and ROS levels. Oxidative stress can arise from a number of different sources, like the disease state or lifestyle, including episodes of ketosis, sleep restriction, and excessive nutrient intake. Oxidative stress can be reduced by controlling calorie intake, hyperglycaemia and mitochondrial metabolism.

It is now established that 90% of intracellular ROS are generated by mitochondria. The mitochondrial respiratory chain is the principal source of cellular oxygen radicals (ROS), such as superoxide anion radicals and hydroxyl radicals. The primary factor governing mitochondrial ROS generation is the redox state of the respiratory chain. If the membrane potential across the inner mitochondrial membrane rises above a certain threshold value, a massive stimulation of ROS generation occurs. Electrons leak mainly from the complexes I and III of the electron transport chain (ETC) and thereby generate incompletely reduced forms of oxygen. The rise in a membrane potential may occur as a consequence of augmented delivery of electrons to the respiratory chain, which results from either increased glucose or fatty acid oxidation or as a result of altered ETC stoichiometry. Consequently, an increased reverse electron flow occurs. Also, there is an evidence that increased cytosolic generation of ROS might precipitate increased mitochondrial ROS. The balance between the genesis of physiological mitochondrial ROS and antioxidant defenses may thus become disturbed, causing numerous pathological events, and finally leading to cell death.

*A few words about an interesting association between mitochondrial ATP production and ATP deficiency in pathology….* 

Mitochondria are the primary source of ATP production in every cell. Therefore, disruption of mitochondrial respiratory function is regarded as a key event in the development of pathologic complications due to ATP depletion in different tissues, like for instance in heart tissue in diabetic patients. However, no general consensus has been raised about the occurrence of mitochondrial defects under diabetic conditions. Evidence associating diabetes with impaired mitochondrial respiratory function in the liver, heart and kidney of diabetic animals dates back more than 45 years. Despite this long history of research, we have still no comprehensive knowledge on the nature and extent of mitochondrial dysfunction in diabetics, as well as about the mechanisms linking this secondary metabolic abnormality with the primary metabolic defect in insulin and hyperglycaemia. The relationship between mitochondrial dysfunction and diabetic pathology has also not yet been defined and elucidated.

### *In summary…..*

124 Biomedical Science, Engineering and Technology

Hyperglycaemia elicits an increased ROS production, presumably to the major extent originating from mitochondrial respiratory chain. ROS play a central role in mediating various metabolic defects associated with a diabetic state. Therefore, the inhibition of ROS production and/or enhancement of ROS scavenging might prove to be beneficial therapies. Alterations in metabolic regulators and glucose-stimulated insulin secretion are also

Impairments in mitochondrial function are intrinsically related to diabetes. The prevailing hypothesis is that hyperglycaemia-induced increase in electron transfer donors (NADH and FADH2) may increase electron flux through the mitochondrial electron transport chain. Consequently, the ATP/ADP ratio and hyperpolarisation of the mitochondrial membrane (electrochemical potential difference) also become increased. This high electrochemical potential difference generated by the proton gradient leads to partial inhibition of the electron transport in the complex III, resulting in the augmented electron flow towards coenzyme Q. In turn, this drives partial reduction of O2 to generate the free radical anion superoxide. It is accelerated reduction of coenzyme Q and generation of ROS that are believed to constitute the fundamental source for mitochondrial dysfunction that plays a

Oxidative stress has been implicated as a major contributor to both the onset and the progression of diabetes and its associated complications. Some of the consequences of an oxidative environment may be the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction, which can ultimately lead to the diabetic disease state. Experimental and clinical data suggest an inverse association between insulin sensitivity and ROS levels. Oxidative stress can arise from a number of different sources, like the disease state or lifestyle, including episodes of ketosis, sleep restriction, and excessive nutrient intake. Oxidative stress can be reduced by controlling calorie intake,

It is now established that 90% of intracellular ROS are generated by mitochondria. The mitochondrial respiratory chain is the principal source of cellular oxygen radicals (ROS), such as superoxide anion radicals and hydroxyl radicals. The primary factor governing mitochondrial ROS generation is the redox state of the respiratory chain. If the membrane potential across the inner mitochondrial membrane rises above a certain threshold value, a massive stimulation of ROS generation occurs. Electrons leak mainly from the complexes I and III of the electron transport chain (ETC) and thereby generate incompletely reduced forms of oxygen. The rise in a membrane potential may occur as a consequence of augmented delivery of electrons to the respiratory chain, which results from either increased glucose or fatty acid oxidation or as a result of altered ETC stoichiometry. Consequently, an increased reverse electron flow occurs. Also, there is an evidence that increased cytosolic generation of ROS might precipitate increased mitochondrial ROS. The balance between the genesis of physiological mitochondrial ROS and antioxidant defenses may thus become

disturbed, causing numerous pathological events, and finally leading to cell death. *A few words about an interesting association between mitochondrial ATP production and ATP* 

Mitochondria are the primary source of ATP production in every cell. Therefore, disruption of mitochondrial respiratory function is regarded as a key event in the development of pathologic complications due to ATP depletion in different tissues, like for instance in heart tissue in diabetic patients. However, no general consensus has been raised about the occurrence of mitochondrial defects under diabetic conditions. Evidence associating

critical role in diabetes-related metabolic disorders and tissue histopathology.

associated with mitochondrial dysfunction in diabetes.

*A few words about oxidative stress…..* 

*deficiency in pathology….* 

hyperglycaemia and mitochondrial metabolism.

In this chapter we discuss how to possibly modulate the "vicious circle" established between mitochondria, oxidative stress and hyperglycaemia. The potential application of some existing and some new agents possessing promising anti-glycation properties to reduce glycation phenomenon and to increase the antioxidant defense system by targeting mitochondria is discussed. Moreover, this chapter outlines various mechanisms present in mitochondria that may lead to the development of diabetes. Intervention and therapy that alter or disrupt these mechanisms may serve to reduce the risk of development of this pathology.
