Mitochondrial Mutations and Diabetes

Mitochondrial function is crucial for maintaining cellular metabolism and growth and plays a role in some forms of diabetes.

Diabetes mellitus causes much morbidity and mortality for Americans and people worldwide. In addition, it significantly reduces the quality of life and life span of patients that have diabetes. Mitochondrial dysfunction is a factor that plays into diabetes development. There have been two types of mitochondrial diabetes discovered:  maternally inherited diabetes and deafness (MIDD) and diabetes and deafness (DAD). Hereditary mitochondrial disorders are caused by mutations in the mitochondrial DNA (mtDNA) which encodes for part of mitochondrial proteins and mitochondrial tRNA. This study will show the mutations associated with diabetes and related disorders. 

The body ages, the body goes gradual decline, and many of the functions of the body change and deteriorate over time. Some studies showed the range of pro-inflammatory markers that aging can change. Mitochondrial function is crucial for maintaining cellular metabolism and growth. A range of diseases and age-related disorders are prone to mitochondrial issues, including cancer, diabetes, CV diseases, and atherosclerosis. Mitophagy is a form of macroautophagy that degrades the damaged mitochondria. Mitophagy is considered the primary mechanism for many mitochondria processes, but a deficiency can play a severe role in various diseases. Two major mitophagy pathways are PINK1-Parkin-dependent and PINK1- Parkin-independent. The dysfunction of any of these functions can manifest into increased production of reactive oxygen species (ROS), biomarkers that can cause cancer. In addition, ROS can cause low-grade and chronic inflammation and other diseases.  

Diabetes is characterized by long-term elevated blood glucose, which, if it is not managed correctly, can affect the cardiovascular system, kidney, eyes, and nervous system. About 8.8% of the world population have diabetes; 89% of diagnosed cases are type 2 diabetes, but 9% are type 1 diabetes. Type 1 diabetes is the destruction of pancreatic b-cells. Type 2 diabetes is a chronic disease that may cause obesity-induced insulin resistance.  

Diabetes is easy to detect by checking the patient’s blood sugar, but the problem is distinguishing the types of diabetes based on mitochondrial changes. Since there is a change in metabolism, there is a logical assumption that mitochondria play a vital role because the mitochondria are a significant function regarding metabolism. However, it is not easy to make a defined correlation. Even if there is no definition, it is still studied that mitochondrial dysfunction is associated with diabetes. There was an association between the number of mutations likely to contribute to diabetes development and mechanisms.  

mtDNA described in older studies showed that they were considered “mtDNA diseases” such as heart and cardiovascular system diseases. A total of 54 mtDNA mutations, many different forms of diabetes, have been identified and are likely to grow. Furthermore, many of the identified mutations are associated with type 2 diabetes and MIDD diabetes.  

The place is defined as the most diverse within the mtDNA molecule, and mtDNA alterations have been related to a range of human diseases, including cancer. The specific processes that relate D-loop mutations to the development of the diabetes phenotype are still being investigated. These alterations will impact overall mitochondrial function through altered mtDNA replication and mtDNA depletion. The ATP generation deficit affects the most sensitive cells and tissues, leading to disease progression. Some human malignancies and other illnesses have been shown to have mtDNA depletion. Age-dependent mtDNA loss was found in pancreatic cells, implying a connection. 

There is currently no pharmacological treatment for diabetes-related mitochondrial mutations. Even though metformin is the most commonly used agent for type 2 diabetes, it is not recommended in mitochondrial diabetes because of the side effect of lactic acidosis. The best options would be using the SGLT-2 and GLP-1 RA and their derivatives. SGLT-2, as shown in many studies, improves mitochondrial functions, such as the two agents Dapagliflozin and Empaglizolin. GLP-1 RA’s are known to provide action on the mitochondria, promoting the production of anti-inflammatory molecules. The role of chronic inflammation and age-related decline is partially responsible for the accumulation of mtDNA mutations.  

Practice Pearls: 

• Mutations in the mitochondrial DNA (mtDNA) are frequent in individuals with diabetes. 
• While most mtDNA mutations are one-of-a-kind and found exclusively in a single group, some are more common than others.  
• Researchers and physicians face the most significant difficulty in detecting and modeling heteroplasmic mtDNA mutations in vitro. So far, the mutations linked to mitochondrial diabetes have been found in mtDNA regions involved in chromosomal replication, mitochondrial translational machinery, or mitochondrial genes producing essential proteins, such as NADH–ubiquinone oxidoreductase components. 

2021. Dabravolski, V.Orekhova. The role of mitochondrial mutations and chronic inflammation in diabetes. US national library of medicine July 2021. 

Idris Aderoju, Pharm.D. Candidate, Florida A&M University