Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM
Abstract
:1. Introduction
2. Definition of Uncontrolled T2DM
3. Insight into the Monogenic and Polygenic Causes of Uncontrolled T2DM
3.1. The Complex Relationship Between MODY, T2DM, and Genomic Instability
3.2. Genetic Contributions to Diabetes: MODY and Uncontrolled T2DM
3.3. The Candidate Genes Associated with the Development of MODY
3.3.1. Genes Harboring Rare Variants That Cause GCA-MODY
3.3.2. An Update on HNF1A
3.3.3. HNF4A-MODY Overview
3.3.4. KCNJ11 Variants That Are Associated with an Increased Risk of T2DM in Adults
3.4. The Candidate Genes Associated with the Development of Late-Onset T2DM
3.4.1. The Transcription Factor 7-like 2 (TCF7L2) and Its Association with Beta-Cell Dysfunction in T2DM
3.4.2. GLIS3 Is Considered a Contributing Factor to Polygenic Nature of T2DM
3.4.3. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Diabetes, Obesity, and Atherosclerosis
3.4.4. The LEP Variant and Its Potential Contribution to Insulin Resistance and Metabolic Syndrome
3.4.5. The UCP1 rs45539933 Gene Variant Is Associated with Obesity and Diabetes
3.4.6. The OPG Variant and Its Potential Contribution to Hypertension, and Diabetes
4. Diabetes Inheritance and Personalized Treatment Approaches
4.1. Current Treatment Guidelines for Diabetes
4.2. Genetic Variability and Ethnic Differences in Drug Response
5. Obesity and Its Association with Insulin Resistance
5.1. Gene-Environment Interactions in Obesity
5.2. Implications for Personalized Medicine and Obesity Management
5.3. Treatment Options for MODY and Prediabetic Patients
6. Future Perspectives
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADA | American Diabetes Association |
BMI | Body mass index |
CV | Cardiovascular |
CNS | Central nervous system |
DPP-4 | dipeptidyl peptidase-4 |
FTO | Fat mass and obesity-associated |
FDA | Food and Drug Administration |
GLIS3 | Gli-similar 3 |
GLP-1 | Glucagon-like peptide-1 |
GIP | Glucose-dependent insulinotropic polypeptide |
GWAS | Genome-wide association studies |
HNF4α | hepatocyte nuclear factor 4-alpha |
HbA1C | Plasma glycosylated hemoglobin A1C |
MC4R | Melanortin-4 receptor |
MeSH | Medical subject headings |
MODY | Maturity-onset diabetes of the young |
NF-κB | Nuclear factor-κB |
OPG | Osteoprotegerin |
PPARγ | Peroxisome proliferator-activated receptor Gamma |
SNPs | Single nucleotide polymorphisms |
SGLT2 | Sodium-glucose co-transporter-2 |
T2DM | Type 2 diabetes mellitus |
TGFβ | Transforming growth factor beta |
WHO | World Health Organization |
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Genes | Role of Gene Product | Rare Variants | Phenotypic Abnormalities | References |
---|---|---|---|---|
The most potential pathogenic genes in MODY | ||||
Gck | Glucokinase catalyzes the rate-limiting step of the glycolysis pathway, functions as the glucose sensor in pancreatic beta cells | c.1015del, p.(glu339Argfs*14) p.G72R, C220Y, p.L58P, p.F123S | Mild hyperglycemia, overweight Glycemic | [32,33,34] |
Hnf1a | Hepatic nuclear factor 1-alpha is critical for the growth and development of beta cells in the pancreas, controls genes involved in liver development, regulates cell growth and survival, and acts as a tumor suppressor. | R200C T196A P291fsinsC H126D | Decreased insulin secretion Increased hepatogenic secretion of atherogenic lipoproteins Liver steatosis Decreased glucose transporter GLUT2 expression, reduced ATP production | [35,36,37,38] |
Hnf4a | Hepatic nuclear factor 4-alpha controls genes that are important for the development and function of beta cells in the pancreas. | rs4735692 V393I c.110T>c, c.1097C>G p.R114W | Associated with obesity Reduced transcriptional activity and insulin secretion Increases risk of diabetes | [39,40,41,42] |
Kcnj11 | Encodes pore-forming inwardly-rectifying potassium channel subunits (Kir6.2) | rs5215, rs5218, and rs5219 | MODY, T2DM, elevated FBS, high BMI | [43,44,45,46] |
The most significant genes that might play an essential role in late-onset T2DM | ||||
tcf7l2 | A key regulator of insulin secretion in pancreatic beta-cells | rs7903146 | T2DM, less obesity, lower insulin secretion and higher insulin action at diabetes onset | [47,48,49] |
glis3 | A transcription factor: Regulator of islet development, insulin gene transcription, and obesity-induced compensatory β-cell proliferation | P/LP GLIS3, rs10758593 rs 7034200 | Neonatal diabetes mellitus, T2DM congenital hypothyroidism and polycystic kidney | [50,51,52] |
pparγ | A transcription factor: master regulator of adipogenesis, energy balance, lipid biosynthesis, and insulin sensitivity; cellular target of TZDs | rs4684847 rs1801282 | T2DM, impaired insulin sensitivity, partial lipodystrophy | [53,54,55] |
lep | A regulator of appetite and energy balance | rs147287548 G2548A | T2DM, severe obesity, hyperglycemia | [42,56] |
ucp1 | A regulator of energy balance and mitochondrial-induced oxidative stress | rs45539933 | T2DM, increased body fat accumulation, risk of insulin resistance | [57,58,59] |
opg | A decoy receptor for receptor-activator for NF-κB ligand (RANKL) | rs2073618 | T2DM, inflammation, hypertension | [60] |
Conditions | Medicines | MAO | Outcomes | Side Effects | Comments |
---|---|---|---|---|---|
Adjunctive medications for MODY | |||||
GCK-MODY | Dorzagliatin | A glucokinase activator | Improves glycemic control | Potential gastrointestinal issues, hypoglycemia, and headaches | |
Heterozygous loss of function in Hnf1a | Low-dose sulfonylurea | Stimulate insulin secretion from the pancreas | Improves glycemic control | Hypoglycemia | |
Homomozygous Hnf1a mutations | There are currently no approved treatments. | ||||
HNF1B-MODY | SGLT2 inhibitors Semaglutide Insulin | Increase glycosuria A GLP-1 receptor agonist A hormone | Lowers blood glucose levels Helps manage blood sugar levels Regulates blood sugar levels | Increased urination frequency and urinary tract infection Diarrhea hypoglycemia | |
HNF4A-MODY | Empagliflozin | SGLT2 inhibitor | Improves glycemic control | ||
The FDA approved new treatments for adults with pre-diabetes and obesity or overweight | |||||
T2DM | Brenzavvy (bexagliflozin) | A dual agonist for the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors | Improves hyperglycemia and promotes weight loss | It may cause ketoacidosis, a serious, potentially life-threatening complication that occurs when the body produces high levels of acids in the blood | It works similarly in Asian, Black or African American, and White adults |
T2DM | Mounjaro (tirzepatide) | Selectively binds to and activates both the GIP and GLP-1 receptors to target GIP and GLP-1, the native incretin hormones | Improves blood sugar control, promotes weight loss | It may cause serious side effects including inflammation of the pancreas (pancreatitis), low blood sugar, allergic reactions, kidney problems (kidney failure), severe stomach problems, and complications of diabetes-related eye disease (diabetic retinopathy) | It works similarly in Asian, Black or African American, and White adults |
CKD associated T2DM | Kerendia (finerenone) | Blocks the mineralocorticoid receptor | It reduced the risk of kidney failure associated with T2DM, having a heart attack or stroke, being hospitalized for heart failure, and dying from cardiovascular disease | The most common side effects included high potassium levels in the blood (hyperkalemia), low blood pressure (hypotension), and low sodium levels in the blood (hyponatremia). | No notable difference in side effects was observed by racial subgroups. |
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Bazzazzadehgan, S.; Shariat-Madar, Z.; Mahdi, F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules 2025, 15, 414. https://doi.org/10.3390/biom15030414
Bazzazzadehgan S, Shariat-Madar Z, Mahdi F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules. 2025; 15(3):414. https://doi.org/10.3390/biom15030414
Chicago/Turabian StyleBazzazzadehgan, Shadi, Zia Shariat-Madar, and Fakhri Mahdi. 2025. "Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM" Biomolecules 15, no. 3: 414. https://doi.org/10.3390/biom15030414
APA StyleBazzazzadehgan, S., Shariat-Madar, Z., & Mahdi, F. (2025). Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules, 15(3), 414. https://doi.org/10.3390/biom15030414