Understanding comprehensive link between diabetes, heredity and genes

Genes from 240 mammal species explain human disease risks in 1st-ever study
Type 2 diabetes, which accounts for the majority of diabetes cases, has a complex interplay between genetic predisposition and environmental factors. Photo: IANS

Projected to affect over 700 million adults worldwide by 2045, diabetes is one of the fastest-growing non-communicable disease and it poses a significant public health challenge. It is a chronic metabolic disorder characterized by high blood sugar levels over a prolonged period giving rise to systemic complications of various organs resulting in significant morbidity and mortality in the long run. While lifestyle factors such as diet, lifestyle pattern and exercise play a crucial role in risk predisposition and development of diabetes, genetics also plays a vital role in determining an individual's predisposition to developing the condition. On World Diabetes Day, let’s understand what the different types of diabetes are, their effects and the role of genetics.

Classically Diabetes has been broadly categorized into two main types: Type 1 and Type 2
Type 1 Diabetes: It is an autoimmune condition in which the body's immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. This form of diabetes is primarily genetic and often manifests in early childhood or adolescence. A slow progressive variant is seen in adults commonly known as latent autoimmune diabetes in adults (LADA).

Type 2 Diabetes: This is more common and accounts for almost 90% of cases globally. It has a complex interplay between genetic predisposition and environmental factors. It occurs when the body becomes resistant to insulin, or the pancreas fails to produce enough insulin to maintain normal blood sugar levels. Type 2 diabetes has a strong genetic component but is also influenced by lifestyle factors such as poor diet, lack of exercise, and obesity.

Other types
Gestational DM (GDM): Gestational diabetes occurs in women during pregnancy and is likely to affect about 7% of pregnancy cases. Such females have over 10 times the risk of developing postpartum Type 2 diabetes mellitus (T2DM).

Maturity-onset diabetes of young (MODY): This is a monogenic variant of type 2 diabetes, characterized by abnormalities of insulin secretion but with normal insulin function. MODY occurs during childhood or adulthood, before the age of 25 years. Roughly 2%-5% of T2DM patients have MODY. MODY are classified based on the underlying molecular genetic defect: MODY1 (HNF4A); MODY2 (GCK); MODY3 (HNF1A); MODY4 (PDX1); MODY5 (HNF1B); MODY6 (NEUROD1); MODY12 (ABCC8), and MODY13 (KCNJ11).

Factors that contribute to an individual's risk of developing diabetes
» Family History: People with a family history of diabetes are at a higher risk of developing the condition. If a parent or sibling has diabetes, it significantly increases the likelihood of other family members being diagnosed.

» Genetic Variants (polymorphisms): Certain genetic variants have been linked to an increased risk of diabetes. These variants cumulatively can affect insulin production, insulin resistance, and other factors related to glucose metabolism.

» Monogenic Diabetes: Some rare forms of diabetes, known as monogenic diabetes, are caused by mutations in a single gene. These mutations disrupt normal insulin production and function leading to diabetes from a young age.

» Epigenetic Changes: Environmental factors, such as diet and lifestyle, can cause epigenetic changes that influence how genes are expressed. These changes can affect insulin sensitivity and contribute to diabetes risk.

Heredity and Type 2 Diabetes
Type 2 diabetes, which accounts for the majority of diabetes cases, has a complex interplay between genetic predisposition and environmental factors. Individuals with a family history of Type 2 diabetes are more likely to develop the condition, highlighting the significant hereditary component. However, lifestyle choices, such as maintaining a healthy weight, regular physical activity, and a balanced diet, can mitigate the risk even in genetically predisposed individuals.

Some of the Key Genes that are Associated with the Risk of Diabetes
TCF7L2 (Transcription Factor 7-Like 2) - TCF7L2 is one of the most significant genes associated with Type 2 diabetes. Variants in this gene have been found to increase the risk of developing Type 2 diabetes significantly. TCF7L2 is involved in regulating insulin secretion and glucose metabolism.

PPARG (Peroxisome Proliferator-Activated Receptor Gamma) - PPARG plays a crucial role in insulin sensitivity and adipocyte (fat cell) differentiation. Variants in this gene are linked to an increased risk of Type 2 diabetes. Certain diabetes medications, such as thiazolidinediones, target the PPARG pathway to improve insulin sensitivity.

INS (Insulin) - The INS gene provides instructions for producing insulin, a hormone that regulates blood sugar levels. Mutations or variations in this gene can lead to impaired insulin production, contributing to both Type 1 and Type 2 diabetes.

IRS1 (Insulin Receptor Substrate 1) - IRS1 is involved in insulin signal transduction. Genetic variations in IRS1 have been associated with insulin resistance and an elevated risk of Type 2 diabetes. Insulin resistance is a key factor in the development of Type 2 diabetes.

KCNJ11 (Potassium Voltage-Gated Channel Subfamily J Member 11) - KCNJ11 encodes a protein that forms a part of the pancreatic beta-cell membrane and is involved in insulin secretion. Variants in this gene are associated with an increased risk of Type 2 diabetes due to impaired insulin secretion.

HNF1A (Hepatocyte Nuclear Factor 1 Alpha) - HNF1A is a transcription factor that plays a crucial role in pancreatic development and insulin production. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), a rare form of diabetes characterized by early onset and a strong genetic basis.

Specific genetic testing for diabetes can be informative in understanding the risk profile, drug response, optimisation of drug therapy, long-term prognosis, and any familial risk.

Diabetes and genetics share a complex relationship, with multiple genetic factors influencing an individual's risk of developing the condition. While genetic predisposition plays a significant role, lifestyle choices remain crucial in diabetes prevention and management. By understanding the interplay between genetics and diabetes, individuals can make informed decisions about their health, empowering them to take proactive measures to reduce their risk and lead healthier lives. Genetic research continues to advance our understanding of diabetes, offering hope for more personalized and targeted approaches to prevention and treatment in the future.
(Dr Anup Rawool is Associate Director, Medical Genetics and Head, Scientific and Medical Affairs, MedGenome)

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