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Precision Diabetes - Genes lead the way!

Posted by : Anusha Sunder , on Thu, Oct 07, 2021
Precision Diabetes - Genes lead the way!

Diabetes is one of the fastest growing health challenges of the 21st century, with the number of adults living with diabetes having more than tripled over the past 20 years1,2.

Diagnosis, monitoring and therapy of several diseases, including diabetes, have shifted from a ‘one size fits all’ approach to a more individualized model of care. The term ‘precision medicine’ has therefore attracted wide attention worldwide, and one of its emerging applications is in the care of individuals with diabetes mellitus3,4.

Precision diabetes medicine holds the promise of reducing uncertainty by providing therapies that are more effective, less burdensome, and with fewer adverse outcomes, which ultimately improve quality of life and reduce premature death in a diabetic5.

According to Dr.Mohan’s Diabetes Specialities Centre,precision proposes customization of health care tailored to the individual level, as diagnosis and treatment modalities are selected not only on the basis of generic symptoms and health history but also considering specific risk factor profile obtained from genetic assessment.

The following perspectives help us understand the need for precision medicine in diabetes.

Interindividual differences in response to hypoglycaemic drugs

Type 2 diabetes/T2D is a heterogeneous disease, and all patients with T2D do not respond equally to commonly used therapeutic modalities. Recent advances have helped to postulate the reasons for this differential response to treatment in various subgroups of patients with T2D. Vital biological pathways in diabetes including β-cell dysfunction, lipodystrophy, or obesity, could respond differently to drugs that act on these pathways, such as sulfonylureas, glucagon-like peptide 1 receptor agonist (GLP-1RA), Dipeptidyl peptidase-4 inhibitors (DPP4i), and thiazolidinediones5.

  • While T2D has a polygenic inheritance, the TCF7L2 gene has been shown to confer the greatest susceptibility to T2D in a wide variety of populations. TCF7L2 encodes a transcription factor that is a member of the Wntsignaling pathway and is known to be active in the beta cells.It has now been shown that this gene may also, at least partially, determine the response of patients to various oral antidiabetic agents (OADs). For instance, the rs7903146T allele of the TCF7L2 gene was more frequent in patients with T2D who failed to respond to sulphonylureas (SU)23. Similarly, carriers of the risk allele rs12255372 T/T were less likely to respond to SU than carriers of G/G6,7.

  • Genes such as pore-forming (Kir6.2, KCNJ11) and regulatory (SUR1, ABCC8) subunits of the K ATP channel influence various aspects of glucose metabolism such as β-cell K-ATP channel modulation, insulin production & pancreas development. Some studies have shown that the KCNJ11/ABCC8 E23K/S119A risk variant increases glycemic response to sulfonylureas; in contrast, the TCF7L2 diabetes risk variant reduces glycemic response to sulfonylureas5,8,9.

  • PPARγ (peroxisome proliferator-activated receptor gamma) activation induces the expression of genes involved in the insulin signaling cascade. This gene also finds importance in adipocyte and lipid metabolism.The PPARG Pro12Ala diabetes risk variant has been associated with reduced glycemic response to thiazolidinediones10,11.

Interpreting HbA1c in Diagnosis and Monitoring

  • The level of HbA1c will depend on factors that impact hemoglobin and red cell stability as well as average glucose values. Genetic testing can reveal unsuspected variants that alter HbA1c5. For instance,

  • 8% of the white population who carry two loss-of-function variants in CYP2C9 are 3.4 times more likely to achieve HbA1c target than those with normal function cytochrome P450 family 2 subfamily C member 9 (CYP2C9) due to reduced metabolism of sulfonylureas and increased serum concentrations. SLCO1B1 and CYP2C8 genotypes that alter liver uptake and metabolism of rosiglitazone can alter glycemic response (HbA1c) by as much as 0.7%5,12,13

  • Glucose transporter 2 also known as solute carrier family 2, member 2 SLC2A2 is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. In SLC2A2, the noncoding rs8192675 variant C allele is associated with greater response to metformin and is associated with reduced expression of the SLC2A2 transporter in liver, intestines, and kidneys. In individuals with obesity, those with two copies of the C allele had an absolute HbA1c reduction of ∼1.55% (compared with a reduction of ∼1.1% in those without the C allele). While this may appear to be a small difference, the SLC2A2 genotype effect is the equivalent of a difference in metformin dose of 550 mg, or about half the average effect of starting a DPP4i14,15.

Precision medicine can also help predict side-effects of medications

The CYP2C9 * 2 allele was found to increase the risk of hypoglycaemia in patients treated with SU26. The gastrointestinal side effects of metformin have been linked to the interaction between the genes encoding the organic cation transporter 1 and the serotonin reuptake transporter16,17.    

Genetic testing is crucial in Neonatal Diabetes/ND.

Sulfonylurea treatment in potassium channel-linked ND have marked impact on endogenous insulin secretion and is now considered the treatment of choice. Early treatment of sulfonylurea-responsive types of neonatal diabetes may improve neurological outcomes. It is important to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in the newborn. Other causes include infection, stress, inadequate pancreatic insulin production in the preterm infant, among others. Insulin-dependent hyperglycemia that persists longer than a week should raise suspicion for neonatal diabetes mellitus and prompt genetic testing18.

Monogenic diabetes- precision medicine provides scope to ward off misdiagnosis

Most cases of monogenic diabetes remain misdiagnosed. Perhaps the best example of precision diabetes medicine is the excellent and long-lasting glycemic response to oral sulfonylureas in insulin-dependent infants diagnosed with neonatal diabetes caused by abnormalities in the β-cell potassium channel.

  • In pancreas, Glucokinase/GCK enzyme plays a role in glucose-stimulated insulin secretion, while in liver, this enzyme is important in glucose uptake and conversion to glycogen. A variation in this gene can cause a type of Maturity Onset Diabetes of Young (MODY2). GCK mutations cause a mild non-progressive hyperglycemia since birth. Mostly characterized as asymptomatic, and stable fasting hyperglycemia usually requiring no specific oral medication or treatment.

  • Other forms of MODY diagnosed based on gene variants such as HNF1A (MODY3), HNF4A (MODY1) and ABCC8 (MODY12) are acutely sensitive to the glucose-lowering effects of sulfonylureas. Regulation of gene activity by the HNF-1A protein is critical for the growth & development of beta cells in pancreas which produce & release insulin. In pancreatic beta cells HNF4A directly activates insulin gene expression.

  • However, unless the diagnosis is precise, these therapeutic benefits are lost.

 

Diabetes is regarded as one of the most serious public health challenges of the 21st century.Response to hypoglycemic therapy may actually be related to one’s genotype. Thus, understanding relevant genes may not only help determine who is at high risk for developing the disease, but may also be useful in guiding treatment regimens. Pharmacogenetics combines genotypic and phenotypic factors to develop personalized care in various pathophysiological subgroups of persons with diabetes. Personalized medicine finds wider utility in monogenic (especially MODY and Neonatal Diabetes) than in polygenic, diabetes.

Author Bio: Anusha holds a PhD in Human Nutrition from the University of Madras, and ranks in the top 3. She has been the recipient of several esteemed awards and endowment prizes including the NSI award for consecutive years. She has also authored several research publications. Life Science, an exhaustive field where every minute innovations pile up is her consciously chosen domain of education and career. With a rich experience in nutrigenetic counselling, research data analysis, and scientific content writing, she is deeply passionate about exploring how gene-based lifestyle changes can assure good health sustenance and disease prevention in an individualistic manner. She reads extensively and draws concepts from wide ranging researches which are translated into reader-friendly documents. Such documents aim to educate people on the importance of knowing their health demands based on genetic predispositions and the need to harmonize the same with gene-specific nutritional recommendations.