Diabetes Inheritance: Mother vs Father - Health blog from Hyderabad Diabetes Centre

India is facing a significant health challenge with over 77 million adults affected by diabetes. This condition arises from difficulties in regulating blood sugar levels due to problems with insulin production or utilization. While genetics are a contributing factor to diabetes, lifestyle choices also play a crucial role. This article delves into the genetic aspects of diabetes.

In addition to familial history, certain genetic factors play a role in the development of type 1 diabetes. Studies have identified specific genes, such as HLA genes, that are associated with an increased risk of developing the disease. These genes play a key role in regulating the immune response, and variations in these genes can make individuals more susceptible to autoimmune attacks on the beta cells.

It is important to note that genetics alone do not determine who will develop type 1 diabetes. Environmental factors, such as viral infections or exposure to certain toxins, are also believed to trigger the autoimmune response in genetically susceptible individuals. Researchers continue to study the complex interplay between genetics and environment in the development of type 1 diabetes in the hopes of developing better prevention and treatment strategies.

Genetic Influence on Type 2 Diabetes

Type 2 diabetes demonstrates a more pronounced genetic link, with specific gene variations affecting insulin release and glucose control. A family history of type 2 diabetes heightens the risk, with genes like ABCC8, GCGR, and TCF7L2 being influential.

The genetic risk for type 2 diabetes includes:

A 40% lifetime risk if one parent has type 2 diabetes.
A 70% lifetime risk with both parents affected by type 2 diabetes.
A tripled risk if a close relative has type 2 diabetes.

In addition to genetic factors, lifestyle choices and environmental aspects also impact the risk of developing type 2 diabetes.

Genetics and Gestational Diabetes

Gestational diabetes, occurring during pregnancy due to insulin regulation issues, has unclear genetic ties but can be influenced by a family history of different diabetes types.

Research suggests that genetics may play a role in the development of gestational diabetes. Certain genes involved in insulin production and processing may contribute to an increased risk of developing the condition during pregnancy.

While the exact genetic factors are still being studied, having a family history of type 2 diabetes or other forms of diabetes can increase the likelihood of developing gestational diabetes. It is important for pregnant women with a family history of diabetes to monitor their blood sugar levels closely and work with healthcare providers to manage and prevent gestational diabetes.

Factors Affecting Diabetes Risk

Age, genetic predisposition, and family medical history all contribute to diabetes risk. Making lifestyle changes such as weight loss, regular exercise, reduced alcohol intake, and a healthy diet can mitigate the risk of developing diabetes.

Common Questions about Diabetes and Genetics

Is diabetes inherited from the mother or father?

Having a diabetic mother slightly raises the risk, while having both parents with diabetes further increases it.

Can diabetes occur without a family history?

Although genetics influence diabetes, other factors can lead to its development in individuals without a family history.

Is diabetes solely hereditary?

No, as lifestyle choices and weight also impact the development of diabetes.

What is the likelihood of a child developing diabetes?

Risk factors vary based on parental history, emphasizing the significance of lifestyle practices like healthy eating and exercise in managing diabetes risk.

Genetic Mutations in Type 2 Diabetes Risk

Mutations in genes related to glucose control can elevate the risk of type 2 diabetes, affecting insulin production and glucose monitoring. Lifestyle choices such as physical activity and nutritious eating also contribute to the risk.

Strategies for Diabetes Prevention

To prevent diabetes, maintaining a healthy lifestyle, including proper nutrition, exercise, and regular monitoring, is essential. Avoiding unhealthy habits like smoking and excessive alcohol consumption further reduces the risk.

SLIDESHOW

American Diabetes Association. Explore the Genetics of Diabetes. https://www.diabetes.org/diabetes/genetics-diabetes

Lyssenko V, Groop L, Prasad RB. Genes linked to Type 2 Diabetes: The Role of Inherited Risk from Parents. Rev Diabet Stud. 2015;12(3-4):233-242. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5275752/

Further Insights into Diabetes Genetics

Bitter melon, known for its health benefits, is traditionally used for conditions like diabetes. Learning how celebrities manage diabetes can offer inspiration and raise awareness about the condition.

An understanding of the types and risk factors of diabetes is crucial for effective management and prevention through lifestyle modifications.

Recent studies have shown that abnormal methylation of the maternal allele of KCNQ1 can impact nearby genes and disrupt pancreas development, which may contribute to the risk of type 2 diabetes (T2D). Additionally, research in mice has indicated a connection between the paternal allele of KCNQ1 and decreased beta-cell mass due to histone modifications on the adjacent CDKN1C gene.
Imprinted genes such as KCNQ1 and KLF14 play crucial roles in regulating the growth of embryos and placentas, suggesting that epigenetic effects can be inherited. Maternal factors, particularly KLF14, influence gene expression, leading to changes in T2D risk and various metabolic traits. Modifications in gene and protein expression in embryos and placentas caused by maternal influences underscore the importance of the intrauterine environment. Maternal conditions like obesity and diabetes can alter the epigenetic patterns of imprinted genes, potentially impacting the susceptibility to T2D.
A genetic variant near KLF14 on chromosome 7q32.3 has been associated with T2D and high-density lipoprotein (HDL) cholesterol levels. Evolutionary studies suggest that KLF14 has undergone accelerated evolution specific to humans. Maternally expressed KLF14 affects metabolic pathways and gene expression in adipose tissue, influencing insulin sensitivity.
Imprinted genes have significant roles in the development of metabolic organs and postnatal metabolic control, which are influenced by changes in the maternal environment. Shifts in gene expression, glucose transporters, and placental development due to maternal factors emphasize the impact of the intrauterine environment on offspring health.
Growing evidence suggests that the parent-of-origin effects on T2D susceptibility loci like MOB2, TCF7L2, and THADA are crucial. Limited data on fetal tissues and allele-specific gene expression underline the importance of these effects.
Identifying markers for parent-of-origin effects can enhance our understanding of fetal programming mechanisms and aid in developing intervention strategies for metabolic disorders. Early diagnosis and identifying new drug targets can improve disease prevention and prognosis.
Ongoing research is revealing the genetic landscape of T2D, emphasizing the need to consider various cell types in genetic studies to comprehensively understand disease mechanisms. Exploring the genetic regulation of circadian rhythms may clarify the link between different dietary habits, disruptions in sleep patterns, and the risk of T2D, as demonstrated in epidemiological studies. Understanding parent-of-origin effects is essential for genetic risk assessment in predicting diabetes and providing family counseling. Furthermore, including parents in studies investigating new environmental exposures among individuals with and without diabetes can be beneficial. Enhancing our molecular knowledge of the genetic basis of T2D will enable the more precise categorization of diabetes subtypes for personalized medical therapies based on the underlying pathophysiology.
**Legend:** R/O = risk allele / other allele. EAF = risk allele frequency. OR Paternal = odds ratio for paternal effect, OR Maternal = odds ratio for maternal effect.
The transmission of risk alleles in KCNQ1 and KLF14 from mothers and in MOB2 from fathers has been associated with an increased risk of T2D. Abbreviations: OR – odds ratio, KCNQ1 – potassium channel, voltage-gated, KQT-like subfamily, member 1, KLF14 – Krüppel-like factor 14, MOB2 – MOB kinase activator 2.
The authors declare no conflicts of interest.

20. The impact of common genetic variants related to type 2 diabetes on alpha- and beta-cell function, as well as insulin action in humans, was studied by Jonsson and colleagues in 2013.
21. Lyssenko and co-authors discovered a common variant in MTNR1B that is linked to an increased risk of type 2 diabetes and early insulin secretion impairment in 2009.
22. The study by Florez et al. in 2012 explored the effects of genetic variants previously associated with fasting glucose and insulin on the Diabetes Prevention Program.
23. Prokopenko and colleagues identified a central role for GRB10 in regulating islet function in humans in 2014.
24. Taneera et al. used a systems genetics approach to identify genes and pathways related to type 2 diabetes in human islets in 2012.
25. Prokopenko et al. demonstrated the influence of variants in MTNR1B on fasting glucose levels in Nature Genetics in 2009.
26. The study by Sparso and collaborators in 2009 showed that the G-allele of rs10830963 in MTNR1B increases the risk of impaired fasting glycemia and type 2 diabetes in Europeans.
27. Walford et al. investigated how common genetic variants affect the transition between fasting glucose metabolic states in Diabetologia in 2012.
28. Vangipurapu et al. associated liver and adipocyte insulin resistance indices with susceptibility loci for type 2 diabetes in non-diabetic Finnish men in 2011.
29. The study by Simonis-Bik and colleagues in 2010 revealed that gene variants in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B impact different aspects of pancreatic beta-cell function in relation to type 2 diabetes.
30. Lentivirus shRNA Grb10 targeting the pancreas was used by Doiron et al. in 2012 to induce apoptosis and improve glucose tolerance by reducing plasma glucagon levels.
31. Nitert et al. showed in 2012 the effect of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of individuals with type 2 diabetes.
32. Nilsson et al. found epigenetic alterations in the human liver from subjects with type 2 diabetes and reduced folate levels in 2015.
33. Liu and colleagues in 2014 discovered that Grb10 promotes lipolysis and thermogenesis through phosphorylation-dependent feedback inhibition of mTORC1.
34. The concept of genomic imprinting in mammalian development and the parental tug-of-war was discussed by Moore and Haig in 1991.
35. Haig and Graham in 1991 investigated genomic imprinting and the insulin-like growth factor II receptor in Cell.
36. Coadaptation in mother and infant regulated by a paternally expressed imprinted gene was studied by Curley et al. in 2004.
37. The relationship between epigenetics, brain evolution, and behavior was explored by Keverne and Curley in 2008.
38. Haig in 2014 discussed coadaptation and conflict in the evolution of genomic imprinting in Heredity.
39. Frost and colleagues in 2010 evaluated allelic expression of imprinted genes in adult human blood in PLOS ONE.
40. Temporal changes in imprinting status at the KCNQ1 locus in human islets were analyzed by Travers et al. in 2013 to understand the molecular mechanism for type 2 diabetes susceptibility.
41. Latham reviewed stage-specific and cell type-specific aspects of genomic imprinting effects in mammals in Differentiation in 1995.
42. Wang et al. in 1996 performed positional cloning of the KVLQT1 gene associated with cardiac arrhythmias.
43. Neyroud et al. identified genomic organization of the KCNQ1 K+ channel gene and C-terminal mutations in the long-QT syndrome in 1999.
44. KCNQ1 gain-of-function mutation in familial atrial fibrillation was reported by Chen and colleagues in 2003.
45. Lee et al. in 1999 found loss of imprinting of a paternally expressed transcript in Beckwith-Wiedemann syndrome independent of insulin-like growth factor II imprinting.
46. Smilinich et al. in 1999 associated a maternally methylated CpG island in KvLQT1 with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.
47. Yasuda et al. in 2008 linked variants in KCNQ1 with susceptibility to type 2 diabetes mellitus in Nature Genetics.
48. Kong et al. in 2009 discussed the parental origin of sequence variants associated with complex diseases in Nature.
49. Hanson et al. in 2013 highlighted strong parent-of-origin effects in the association of KCNQ1 variants with type 2 diabetes in American Indians.

50. Studies conducted by Asahara S et al. in 2015 revealed that a paternal allelic mutation at the Kcnq1 locus can lead to a reduction in pancreatic beta-cell mass through epigenetic modification of Cdkn1c. This research was published in the Proceedings of the National Academy of Sciences of the United States of America. The doi number for this study is 10.1073/pnas.1422104112.

51. Research by Court F et al. in 2014 focused on genome-wide parent-of-origin DNA methylation analysis to explore human imprinting complexities and propose a germline methylation-independent mechanism of establishment. The findings were published in Genome Research with a doi of 10.1101/gr.164913.113.

52. In a study published in Nature Genetics by Umlauf D et al. in 2004, imprinting along the Kcnq1 domain on mouse chromosome 7 was analyzed. The research highlighted repressive histone methylation and recruitment of Polycomb group complexes. The doi number for this study is 10.1038/ng1467.

53. Teslovich TM et al. conducted research in 2010 on the biological, clinical, and population relevance of 95 loci for blood lipids. This study was published in Nature with a doi of 10.1038/nature09270.

Voight BF, Scott LJ, et al. (2010) identified twelve type 2 diabetes susceptibility loci through large-scale association analysis. The findings were published in Nature Genetics with a doi of 10.1038/ng.609.
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Li L, Keverne EB, et al. (1999) focused on the regulation of maternal behavior and offspring growth by paternally expressed Peg3. The study was published in Science with a doi of 10.1126/science.284.5412.330.
Ge ZJ, Liang QX, et al. (2014) studied how maternal obesity and diabetes may cause DNA methylation alteration in the spermatozoa of offspring in mice. The research was published in Reproductive Biology and Endocrinology with a doi of 10.1186/1477-7827-12-29.
Fadista J, Vikman P, et al. (2014) conducted a global genomic and transcriptomic analysis of human pancreatic islets to reveal novel genes influencing glucose metabolism. The study was published in Proceedings of the National Academy of Sciences of the United States of America with a doi of 10.1073/pnas.1402665111.
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Adkins RM, Somes G, et al. (2010) studied the association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes. The research was published in Pediatric Research with a doi of 10.1203/PDR.0b013e3181f1ca99.

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