Diabetics Genetics

Abstract: Diabetes is a metabolic disorder which is manifested when insulin secretion by pancreas is not sufficient or when the peripheral tissues show resistance towards secreted insulin. The onset of diabetes is usually in childhood in type 1 diabetes whereas onset of diabetes is seen in elderly age in type 2 diabetes. In diabetes mellitus elevated blood glucose levels are seen which needs to be kept in control. In longer run hyperglycemia leads to many serious multiple organ damage such as damage to kidneys (diabetic nephropathy), eyes (diabetic retinopathy), nerves, arteries and heart. The common symptoms of diabetes mellitus include poly urea (frequent urination), frequent thirst (poly dipsia), skin infections, weight loss etc. There are other types of diabetes such as gestational diabetes (onset is seen in early pregnancy stages), neonatal diabetes and maturity onset of the diabetes (MODY). Neonatal and MODY are due to mutations in one gene which are classified under mongenic type of diabetes. The underlying reasons for type 1 and type 2 diabetes are our genes. Type 1 diabetes is a autoimmune disease and genes responsible are HLA genes, IDDM2 and CTLA4. Whereas ABCC8, KCNJ11 genes are involved in susceptibility of type 2 diabetes. Diagnosis includes fasting blood glucose test, random blood glucose test, oral glucose tolerance test and A1C test. Regular therapy includes use of insulin injections in type 1 diabetes and use of oral hypoglycemic agents or insulin injections in type 2 diabetes. Recent therapy includes gene therapy such as improving differentiation and regeneration of beta cells in type 2 diabetes whereas preventing autoimmunity of beta cells is specific in treatment of type 1 diabetes.

1. 1.      Introduction:

The current review includes overview of diabetes mellitus. It includes various types of diabetes based on epidemiology followed by diagnosis of diabetes mellitus for different types of diabetes mellitus, causes of diabetes type 1 and type 2, signs and symptoms. The review also includes genetic information and genetic factors for diabetes type 1 and 2 i.e. the genes responsible for susceptibility of diabetes are discussed. Gene mutation process is also discussed in the review. The review also discusses about gene therapy role in treatment and prevention of diabetes type 1 and 2, which is followed by future role of genetics in treatment of diabetes mellitus.

The goal of the review is providing an insight of diabetes mellitus mainly the genetic information and genetic factors involved in type 1 and type 2 diabetes. It is then followed by gene therapy for diabetes mellitus. The therapy for type 1diabetes and type 2 diabetes are discussed separately. The review also provides an understanding of types of diabetes mellitus their diagnosis, signs and symptoms. Though the review discusses briefly about diabetes mellitus, the main focus is on genetic factors underlying the cause of diabetes mellitus.

Diabetes Review:

1. 2.      Diabetes:

2.1.      What is Diabetes? :

The report by American Diabetes Association (January 2012) indicates diabetes mellitus is a disorder in which hyperglycemia- an elevated blood glucose level is seen.  The reason behind this is dysfunction of pancreas in insulin secretion or if secreted properly dysfunction in insulin action or both can be underlying reasons.  Beta cells of pancreas secrete insulin which is required for utilization of glucose by body cells. Many pathogenic processes are the reasons for causing Diabetes mellitus. It may be by developing autoimmune destruction of beta cells of pancreas thereby person becomes insulin deficient. The reason for carbohydrate, protein and fat metabolism is due to defective action of insulin on targeted cells. In diabetes insulin deficiency may be a result of diminished insulin secretion or tissue response for insulin is reduced. Decreased insulin secretion or reduced tissue response may exist together in a person.

2.2.      Types of Diabetes:

As proposed by Emily loghmani (2005) reported the classification of diabetes mellitus is based on etiology. There are two types of Diabetes mellitus, type I (juvenile or insulin dependent) and type II. In type I insulin is not secreted from pancreas and requires intake of insulin injection daily. Type I diabetes is generally detected in childhood or in adolescent age. In type II insulin secretion is reduced and resistance to insulin by cells is seen by which blood glucose level increases (hyperglycemia). To manage hyperglycemia food intake is to be reduced, physical activity should be increased along with use of medication orally. The onsent of type II diabetes is generally seen in elderly age. The report by American Diabetes Association (January 2012) indicates Gestational diabetes is another type in which intolerance of glucose is seen with onset of pregnancy. The last type of diabetes are of specific types which include diabetes due to genetic defects in insulin action, defect of gene responsible for beta cell function, exocrine pancreas disease, drug or chemical induced, endocrinopathies and may be due to infections.

2.3.      Diagnosis tests:

The report by WHO consultaion indicates that in an asymptomatic person diagnosis of diabetes should not be concluded on basis of single abnormal glucose level in blood. For asymptomatic person additional blood testing i.e. either fasting or random blood glucose level or oral glucose tolerance test (OGTT) must be checked. If the test is failed the person should undergo retesting after certain period until the diagnosis becomes clear. Diabetes in children is usually diagnosed by elevated blood glucose levels. However in asymptomatic children fating blood glucose is to be estimated.

As stated by NDIC (2014) for diagnosis of Diabetes any one of the following tests are done

• Glycohemoglobin test or A1C test or hemoglobin A1c (HbA1c)
•  Oral glucose tolerance test (OGTT)
• Fasting plasma glucose (FPG) test
• Random plasma glucose (RPG) test

If in A1C, OGTT, FPG and RPG tests values are 6.5% or above, 200mg/dL or above, 126mg/dL or above and 200mg/mL respectively for a subject then it is diagnosed as diabetes.

To diagnose type II diabetes A1C test is recommended. But it is not use to detect type I and gestational diabetes. In A1C test the values reflect the average blood glucose levels of three months, the values do not reflect daily blood glucose level fluctuations.  The advantage of this test is that it can be done at any time of day i.e. it does not require fasting samples making the subject convenient.

FPG is usually performed to detect both type I, type II and pre diabetes. To perform this test person should be on fast for 8h before withdrawing blood sample. It is less expensive test and for better results it is recommended to take blood sample in morning hours.

OGTT is usually performed to diagnose gestational, diabetes and pre diabetes. OGTT is not a convenient test but it is more sensitive test. It is done after subject is on fast for 8h and then 75g of glucose dissolved in water is administered to subject. After 2h of having glucose water blood sample is taken. If the values result from 144-199 mg/dL then it is diagnosed as pre diabetes. If the values lie above 200 mg/dL then it is diagnosed as diabetes.

2.4.      Causes of Diabetes:

2.4.1.      Causes for Type 1 Diabetes: As stated by Web MD, type I diabetes is caused due to destruction of beta cells which produce insulin by body’s own antibodies i.e. autoimmune disease, there by insulin secretion is diminished. Type I is usually a genetic predisposition disease.

2.4.2.      Causes for Type 2 Diabetes: Type II diabetes is due to insulin resistance and to a less extent of insulin deficiency. The report of Johns Hopkins state that the signs and symptoms of diabetes include frequent urination (poly urea), frequent thirst, weight loss, infections. In type I diabetes the symptoms include sweating, seizures, dizziness, loss of consciousness, hunger, trembling and confusion. After long run higher blood glucose levels damages kidneys, eyes and arteries thereby causing risk of heart attacks, chest pain and heart pain. Nerve damage may occur leading to pain and tingling in arms and legs.

1. 3.      The influence of gene:

3.1.      Genetic information and genetic factors:

F Pociot and M F McDermott (2002) suggests that type I diabetes (T1D) is not only a autoimmune genetic disorder but environment factors also influence the occurrence of T1D. There are two chromosomal regions which contribute to the occurrence of T1D. They are HLA region (human leukocyte antigen) on chromosome 6p21.3 and insulin gene region on chromosome 11p15.

As reported by NCBI (2004) there are 18 genome regions which contain HLA genes. These genome regions may several genes, which have been labeled from IDDM1 to IDDM18. HLA genes encode glycoproteins which are found on most of the cell surfaces. They help immune system in identifying the body’s own cells (self) and foreign invaders (non-self) such as bacteria, viruses etc. Alleles of HLA genes are responsible for developing T1D-autoimmune disorder. MHC (major histocompatibility complex) are the glycoproteins encoded by HLA genes. Two types of MHC are MHC class I and MHC class II which display aminoacid chains (antigens) and T cells (immune cells) recognizes the antigens. MHC I displays antigens from inside the cell and MHC II displays from outside the cell. When T cell recognizes these antigens immune response is generated. In normal subjects T cell binds to only antigens generated by foreign bodies. But in T1D T cells binds to self/body’s own healthy cells. The genes which encode MHC class II are associated with T1D. The genes are HLA-DQ, HLA-DP, and HLA-DR.

DR3 or Dr4 are causative gene for T1D and DR2 is protective. The subject who inherit either DR3 or DR4 or both are susceptible for T1D. As DR genes there are some genes of DQ which are protective and causative of T1D. Subject who has DR causative gene tend to inherit DQ causative gene simultaneously and those subjects have tendency of developing T1D.

IDDM2 locus contains INS (insulin gene). Mutations this gene result in a rare of diabetes which is comparable to Maturity onset diabetes in young (MODY). Different variations of INS (SNPs and variable number tandem repeats) are involved in susceptibility of T1D and T2D. On chromosome 11 INS gene is located. On INS gene many single nucleotide polymorphisms (SNPs) which are also responsible for susceptibility of diabetes mellitus. The contribution of IDDM2 locus for T1D is about 10%. When the DNA sequence is repeated several times (varies in different individuals) and sequence is followed one after the other, these repeat sequences are called as VNTRs (Variable number tandem repeats).

The three different classes of VNTR in INS (insulin gene) are given below:

• Class I- It has alleles which are in the range from 26 to 63 repeated units.
• Class II-It has alleles which has an average of around 80 repeated units.
• Class III-It has alleles which range from 141 to 209 repeated units.

Class I VNTRs are present in most of Caucasians and out of them 70% have alleles ranging from 30-44 repeats. Class III VNTRs are present in remaining with 110 repeats and class II VNTRs are seen very rare. Class I VNTRs (short class alleles) are responsible for type 1 diabetes. Class III VNTRs are protective and helps in three fold reduction of type 1diabetes.

The onset of type 2 diabetes (T2D) is usually in older age. Along with inheritance, food intake and physical exercise also plays an important role in onset of T2D. Many genes are responsible for occurrence of T2D. Hepatocyte nuclear factor 4 alpha (HNF4A), calpain 10 (CAPN10) and sulphonylurea receptor (ABCC8) are associated with T2D. Sulphonylurea receptor located in pancreas contains ATP-sensitive potassium channel. This channel plays a crucial role in secretion of insulin induced by glucose ions. This action is linked by signals derived from rise in ATP by glucose metabolism and subsequent membrane depolarization (as KATP channels are closed) and ultimately causing insulin secretion. So KATP channels activity plays important role in insulin release. Oral antidiabetics (sulphonylureas class) act by modulating KATP channels and are used to lower blood glucose levels in T2D. They bind to KATP channels making them closed and help in releasing the insulin. KATP channel activity is modulated by subtype of SUR i.e. SUR1 or SUR2A and SUR2B. SUR1 is encoded by ABCC8 and remaining two subtypes are encoded by ABCC9. Mutuations in ABCC8 causes impaired insulin secretion . As reported by Sunita singh (2011) the genes responsible for T2D are peroxisome proliferator-activated receptor gamma (PPARG), potassium inwardly rectifying channel-subfamily J (KCNJ11), glucokinase (GCK), insulin receptor substrate-1 (IRS-1), protein tyrosine phosphatase 1B (PTPN), the nuclear lamina gene (LMNA).

3.2.      Gene mutation process:

As reported by NIDDK (NationalInstitute ofDiabetes andDigestive and KidneyDiseases) some kinds of diabetes are caused by mutations in single genome and are known as monogenic. It accounts for about 1-5% of diabetes cases. They are inherited in most of the cases and are developed spontaneously in very few cases. NDM (neonatal diabetes mellitus) and MODY (maturity onset diabetes of the young) are two different forms of monogenic diabetes. The onset of NDM is in first 6 months of life. Due to NDM the growth of fetus is hindered. The onset of MODY is usually in early adulthood. Monogenic diabetes is mostly caused by dominant gene. If mutation is recessive then gene must be inherited from both the parents.

1. The influence of treatment:

4.1.      Role of genetics in treatment and prevention of diabetes:

 As stated by T. Yamaoka for gene therapy of diabetes there are different ways involved. Preventing autoimmunity of beta cells is most specific type of gene therapy for hindrance of type 1 diabetes mellitus which is in preclinical stage. In the same way improving the insulin sensitivity of body cells is specific for treating type 2diabetes by gene therapy. Reducing apoptosis of beta cells, improving insulin secretion and relieving the complications associated with diabetes are required commonly for therapy of both type 1 and type 2 diabetes. Various approaches which are employed currently in gene therapy for insulin replacement include beta cell growth stimulation, inducing regeneration and differentiation of beta cells,  producing insulin by genetic engineering of other cells i.e. non insulin producing cells and genetic engineering of beta cells followed by their transplantation. For treating type 1 diabetes proliferation and regeneration of beta cells is of limited use as it is autoimmune disease and antibodies continues to destruct the beta cells. So it is recommended to utilize non beta cells which are genetically engineered and are not prone to auto immunity along with transplantation of islet cells are prospective therapies in treating type 1 diabetes. It is suggested to use subjects own beta cells for proliferation and differentiation in gene therapy of diabetes type 2 as those cells would be free from auto immunicity. However it should be noted that these techniques are highly difficult.

University of Wisconsin-Maidson (22 July 2013) indicated that DNA based insulin gene therapy is another technique for treating type 1 diabetes. In this therapy a small sequence of DNA when injected works after sensing hyperglycemia i.e. increased blood glucose concentrations (usually occurs after having meal). Glucose inducible response element (GIRE) helps in prompting the injected DNA there by producing insulin. In this therapy instead of pancreatic cells targeting the liver cells are targeted.

Park KS (Dec 2006) indicated that the influence of genes and environmental factors on development of T2D is very complex. Once the genetic information, i.e. the gene responsible for T2D is detected preventing T2D becomes easier. So prevention of diabetes through genetic means is possible only after knowing complete genetic information.

4.2.      Future role of genetics in Diabetes:

As reported by WHO for treating diabetes the main barrier is that lack of consistent results across population determining the genetic variations. Lack of consistent results may be due to environment factors interacting with genetic factors. To overcome this problem epidomology of diabetes is required which is not easier as human genome is not completely established. Also issues like health risks and outcomes, quality assurance, economics, ethical, social, confidentiality and legal need to be considered. Considering all the issues will serve as development of treatment guidelines for diabetes

1. Conclusion:

Diabetes mellitus is a metabolic disorder in which elevated blood glucose levels are seen. Diabetes mellitus is of mainly two types, also there are other types such as gestational diabetes, pre diabetes etc. Type 1 diabetes is usually seen in childhood (juvenile diabetes) which requires intake of insulin injections. Whereas type 2 diabetes is seen in old age/elderly age. Type 1 diabetes is generally due to genetic predisposition. People with type 2 diabetes are usually overweight or obese, although genetic factors are also involved. In rare form of diabetes such as neonatal or maturity onset of the diabetes (MODY) mutations in one gene can cause diabetes which is called as monogenic form of diabetes. Type 1 diabetes is a autoimmune disease in which body’s own cells are destroyed by antibodies. The genetic factors involved are HLA genes, IDDM2 and CTLA4. There are many genes involved for occurrence of type 2 diabetes. Diabetes susceptibility genes can be found out by studying whole genome linkage studies of 2 generations people belonging to one family. The genes involved in type 2 diabetes are ABCC8, KCNJ11 etc. Many persons experience symptoms like frequent urination, feeling thirstier, loss of weight etc. For diagnosis of diabetes tests such as fasting blood glucose level, random blood glucose level, oral glucose tolerance test, A1C tests are used. Common therapy or medication for diabetes depends on type of diabetes. In type 1 diabetes there is no cure and lifelong intake of insulin injections is required. In type 2 diabetes either intake oral hypoglycemic agents or insulin injections is required along with life style changes like doing physical activity and consuming less calorie food. Recent therapies include gene therapy by which insulin intake is circumvented. This includes prevention of autoimmunity of beta cells, transplantation etc are suggested for treating type 1 diabetes. Whereas inducing regeneration and differentiation of beta cells is encouraged in treatment of type 2 diabetes.

1. 6.      References:
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4. Report of a WHO consultation. 1999. Part1: Diagonosis and classification of diabetes mellitus. https://www.staff.ncl.ac.uk/philip.home/who_dmg.pdf. Accessed on 18/09/14.
5. WebMD. Diabetes health centre.  http://www.webmd.com/diabetes/types-of-diabetes-mellitus. Accessed on 18/09/14.
6. Johns Hopkins medicine. http://www.hopkinsmedicine.org/gim/core_resources/Patient%20Handouts/Handouts_May_2012/Diabetes%20Mellitus%20Type%201.pdf. Accessed on 18/09/14.
7. F Pociot and M F McDermott. 2002. Genes and Immunity 3, 235–249.
8. National diabetes information clearing house NDIC. 2014. Diagnosis of diabetes and pre diabetes.   http://diabetes.niddk.nih.gov/dm/pubs/diagnosis/#3. Accessed on 18/09/14.
9. NCBI. 2004. Genetic factors in type 2 diabetes. The landscape of diabetes. http://www.ncbi.nlm.nih.gov/books/NBK1665/. Accessed on 18/09/14.
10. Sunita Singh. 2011. The genetics of type 2 diabetes Mellitus: a review, Journal of Scientific Research. 55,  35-48
11. NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases.
12. Monogenic Forms of Diabetes:Neonatal Diabetes Mellitus andMaturity-onset Diabetes of the Young. http://diabetes.niddk.nih.gov/dm/pubs/mody/Monogenic_Diabetes_508.pdf. Accessed on 18/09/14.

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