Diabetes MODY

Diabetes MODY

Only one type of diabetes may be able to develop without obesity and that is Diabetes MODY. Nothing effects the pancreas like stress, life style, raising cholesterol levels, hypertension and other thing else who be able the cause of insulin deficiency. Diabetes MODY depends on DNA base.

Diabetes is a silent killer disease. Diabetic person must control his sugar level in the body, after diagnosis the diabetes and must start treatment as well under the advises of physician and principals of medical science and must not ignore, otherwise it is very harmful for human body and life as well.

Diabetes MODY: Causes, Symptoms, Diagnosis and Treatment

MODY is an acronym for Maturity Onset Diabetes of the Young.

Diabetes MODY

Diabetes type 2 and diabetes type 1 are two basic diabetes types. The causes of these two types about same with some difference.
Look at the cause’s these two types.

  • Being obese or overweight (having a waist size of 31.5 inches or more (women) or more than 37 inches (men)
  • Physical inactivity
  • Having high blood pressure or raised cholesterol levels
  • Being of South Asian and African-Caribbean descent
    Eating an unhealthy diet
  • Imbalance diet
  • Smoking
  • Having a first-degree relative with type 2 diabetes
  • Heredity
  • Luxurious lifestyle (Less walk & Exercise)
  • Insulin Defiance or less production
  • Stress

Condition of Diabetes

When we look at the causes of diabetes, we notice that main cause of all types of diabetes is obesity and being overweight in the men and women. But only one type of diabetes may be able to develop without obesity and that is Diabetes MODY.

MODY does not have link to obesity, and typical MODY patients are young and not necessarily being overweight. Nothing effects the pancreas like stress, life style, raising cholesterol levels, hypertension and other thing else who be able the cause of insulin deficiency. In this situation, the physicians diagnose some sub types of diabetes like diabetes 1 and 1.5 and named these Diabetes LADA and MODY.

What is Diabetes MODY ?

MODY is a genetic disease and transfers from parent to children by the changing a single gene. There are 50% chances of diabetes in children of parent having diabetes inheriting this gene and consequently developing MODY diabetes themselves. This type of diabetes is different from other types and due to heredity it transfers from parents to their children and goes from one generation to next.

Diabetes MODY does not has any external cause, it is directly caused by the change in a single gene. If the parents are having with MODY, the children are 50% in risk of MODY. In whole world; it is very few numbers of persons suffering from MODY. Only 2% of total diabetic persons are with MODY. It is noticeable that usually this form of diabetes may often go without diagnose in early stage.

TYPES OF MODY

There are twelve types of MODY have been identified still.We keep these types in three rows.

  • The rarest forms of diabetes of MODY
  • The most common rare forms of diabetes of MODY
  • The most common types of MODY

1- The rarest forms of diabetes of MODY

This form of diabetes is the rarest and we can diagnose in one or two families. So we do not have further details about this type.

2-The most common rare forms of diabetes of MODY

There are three types of this Form: –

MODY Form 1

MODY Form 2

MODY Form 3

Above 3 types are divided by depending on rising conditions of blood glucose. Effects and features point of view, the MODY type 1, 2, and 3 are common. In all three types, the pancreas,s ability of insulin production after meals is equal and same.

We can recognize these types, by the rising time of blood sugar. The MODY Form 1 and MODY Form 3 are common in features and affects, the ability of the beta cell to secrete insulin in response to rising mealtime blood sugars. In MODY, type 2, the fasting blood glucose level remains some high than normal, due to thermostat action. It is observed that insulin secretion remain normal but blood sugar level remains high.

3-The most common types of MODY

GENETICS

There are many types of diabetes MODY, according to the gene mutation and other factors. The mutation of the genes develops in the body under specific role, who effects the pancreatic β-cell. Ups and downs of insulin secretion some times can cause diabetes MODY.

The encoding of genes who mutates and develops the causes of various type of MODY are under:-

HNF4A (MODY 1)

[GCK (MODY 2)] glucosidase

HNF1α [HNF1A (MODY 3)]

[PDX1/IPF (MODY 4)] pancreatic and duodenal home box 1HNF1

β[HNF1B (MODY 5)]

[NEUROD1 (MODY 6)]neurogenic differentiation 1

[KLF11 (MODY 7)] Krüppel-like factor 11

[CEL (MODY 8)] carboxyl ester lipase

[PAX4 (MODY 9)] paired box gene 4

[INS (MODY 10)] insulin

[BLK (MODY 11)] B-lymphocyte kinase

[ABCC8 (MODY 12)] ATP -binding cassette, subfamily C, member 8

[KCNJ11 (MODY 13)]. potassium channel, inwardly rectifying, subfamily J, member 11

MODY 1 HNF4 ALPHA

MODY 1: Due to mutation HNF4; A gene from parent to the baby. HNF4 gene located on the long arm of chromosomes. The gene HNF4 expressed mainly in the liver but also in the pancreas and kidneys, is a transcription factor that affects glucose metabolism through various pathways. Gene HNF4 encodes a protein nuclear transcription factor binds to DNA as a homodimer.

This encoded protein by Gene HNF4, regulate the expression of different genes. Hepatocyte nuclear factor 1 alpha is also include in it. Where the transcription gene is concern, this gene may play role in the liver, kidney and intestines development. There are some mutations who may resembles of HNF1A-MODY.

Complication of Heterozygous

Due to Heterozygous mutations can develop fetal macrosomia. This can develop by increasing in utero insulin discharge. This condition can create temporary or permanent neonatal hypoglycemia.

Where the timing and reasons of neonatal hyperinsulinemia are concern, still unknown, The further research is going on.

Specific sub-types and their properties.

GCK-MODY (MODY 2)

Another gene that is cause of diabetes MODY is GCK (glucosidase). This gene is located on the short arm of choromosones,. When this gene transfers from parent to the baby at any time of his age the symptoms of diabetes can progress in the baby. GCK-MODY gene has relation to the liver and pancreas and modulating insulin secretion in the body.

Gene GCK-MODY plays key role to regulate enzyme in insulin secretion stimulation by glucose, acts as the glucose sensor of pancreas, Beta cells Pancreatic glucosidase play a vital role in modeling in insulin secretion. The role of GCK is to providing glucose phosphate to glycogen.

Hepatic glucopkinsase helps to facilitate the absorption and conversion of glucose act as an insulin. It is cause of hypoglycemia and hyperglycemia in individuals. In the time of baby birth this gene transfers from parent to the baby but does not make any progress. In pancreas beta cells, the reason of decreasing of GCK activity is due to mutation of this gene. In the any age of life this progress can resume and insulin production interrupted and baby can suffer diabetes MODY 2.

HNF1A-MODY (MODY 3)

HNF1A mutations are the most common causes of MODY 3. Diabetes MODY 3 progress in young individuals when a gene HNF1A (hepatocyte nuclear factor 1 alpha) mutates from parents to the baby. This gene HNF1A located on long arm of chromosomes 12. According to the scientist, in Hnf1a-knockout mutations, whenever, the insulin secretion decrease in the body, the diabetes may can develop.

HNF1A gene has relation to protein function. The appearance of HNF1A develops in β-cells of pancreas, in intestines and liver. HNF1A is a important element for INS and GLUT2. This appearance develop in β-cells when it matures.

An experience done on mice, in result it discovered the diabetes in mice and reduction of insulin secretion appeared in the mice.

Due to progress of β-cell dysfunction, in early age of adulthood, Heterozygous HNF1A mutations may occur and the diabetes may can develop.

The diagnosis of HNF1A-MODY in the children, is possible between 14 to 18 years of age. The diagnosis of HNF1A-MODY in the children younger than 10 is rear. In some people, destroy of pancreas beta-cell can observed before symptoms of diabetes appearance, instead of appearance, the blood sugar level did not go high.

It has been shown that the insulinogenic index of individual- also with an HNF1A mutation is lower than that of people without the mutation, with increased insulin sensitivity in the former group.

MODY 3 AND Insulin

During the early stage of diabetes, diabetic persons can control blood glucose by internal insulin and not dependent on artificial insulin. The children donot require low-dose insulin, due to better metabolic control, in this case, we donot observe ketoacidosis.

HNF1A mutations effect on baby weight

In the scientist thoughts that that HNF1A mutations don’t develop any effects on the birth weight of children. It is observed that for baby in utero β-cell functions are normal.

HNF1A mutations are the most common causes of MODY 3. Diabetes MODY 3 progress in young individuals when a gene HNF1A (hepatocyte nuclear factor 1 alpha) mutates from parents to the baby. This gene HNF1A located on long arm of chromosomes 12. This gene is related to protein function.

The appearance of HNF1A develops in β-cells of pancreas, in intestines and liver. HNF1A is a important element for INS and GLUT2. This appearance develop in β-cells when it matures.

Common causes of MODY 3

HNF1A mutations are the most common causes of MODY 3. Diabetes MODY 3 progress in young individuals when a gene HNF1A (hepatocyte nuclear factor 1 alpha) mutates from parents to the baby. This gene HNF1A located on long arm of chromosomes 12. This gene is related to protein function.

HNF1A mutation shows in the pancreatic β-cells, through liver and intestines.HNF1A is a basic factor of encoding of glucose carrier (INS and GLUT2 ), when encoding become mature of β-cells.

An experience done on mice, in result it discovered the diabetes in mices and reduction of insulin secretion appeared in the mice.

Complication of Heterozygous HNF1A

Heterozygous HNF1A mutations can cause diabetes with early-adulthood onset, via progressive β-cell dysfunction.The mean age of HNF1A-MODY diagnosis in children is 14 years (range 4–18 years), and it is rarely identified in children younger than 10 years.

In some people, destroy of pancreas beta-cell can observed before symptoms of diabetes appearance, instead of appearance, the blood sugar level did not go high.

It has been shown that the insulinogenic index of individual- also with an HNF1A mutation is lower than that of people without the mutation, with increased insulin sensitivity in the former group. These people do not need to exogenous insulin, In the early stage of diabetes.

Effects of HNF1A mutations

According to the diabetes specialists, HNF1A mutations don’t develop any effect on baby weight. During pregnancy, because in utero β-cell functions normal and do not develop effect on baby birth.

PDX1-MODY (MODY 4)

Another gene who is cause of diabetes MODY is PDX1. Full name is Pancreatic and Duodenal Homewood 1. PDX1-MODY gene is located on the long arm of chromosomes 12. When this gene transfer from parents to the baby is cause of diabetes MODY. Gene PDX1-MODY is related to pancreas and acts in pancreas development and gene transcriptions in the pancreas, including for insulin, glucose transporter 2 and glucosidase.

This gene plays important role in regulation of glucose development insulin gene expression. it is noted that all individual that found with diabetes MODY by transferring this gene was obese before the age of 12 years and hyperinsulinemia.

HNF1B-MODY (MODY 5)

HNF1B is a gene who is cause of diabetes MODY when transfer from parents to the baby. This gene is located on the long arm of chromosomes. Its full name is Hepatic Transcription Factoer 2. HNF1B-MODY gene is encoded a protein that binds DNA as a homodimer or a haterodimer with the hepatocyte related protein nuclear factoer 1-alpha.This gene HNF1B is related to the pancreas, liver, kidney and genital tract.

This gene is expressed in the early phase of embryonic development in the pancreas, kidneys, liver, and genital tract, and developmental abnormalities may therefore be encountered in all of these organs in individuals with HNF1B mutations. This type of diabetes MODY-5 renal complications are found in the diabetic individuals.

Complication of MODY 5

In the complication of MODY 5, 1st disease that appear is renal abnormality, due to renal cystic disease. Remaining all complication, follow the collecting-system abnormalities. In all sub types of MODY, the main complication develop in the body is β-cell dysfunction. On the contrary, other Type of MODY, HNF1B, who develop due to HNF1B mutation, creates two complications, insulin resistance and β-cell dysfunction.

Due to mutation this gene in baby, the baby birth weight individuals who developed early-adulthood diabetes have been reported to be approximately lower than normal. The individuals with diabetes MODY 5 mostly require insulin and depend on insulin. Heart diseases can also develop later in this type of diabetes.

NEUROD1-MODY (MODY 6)

Diabetes MODY type MODY 6, develops in the result of mutation of gene NEUROD 1. This gene is located on the long arm of chromosomes. After transfer this gene, NEUROD1, individuals with MODY may develop diabetes as children or adults and it is observed that majority of these individuals are obese. It is not necessary that this gene is cause of obesity but with mutation if individuals are obese, the risks of diabetes MODY 6 are more than individual those are not obese.

In the other words the obesity in mutation carriers might facilitate diabetes development. This gene relates to pancreas and INS expression. In the development of the pancreas and INS expression NEUROD1 is responsible to regulating gene. It regulates INS expression by binding to a complex promoter that is formed after dimerization with protein E47. It is noteable that ratio of this gene mutation is very rear and this gene is responsible for some complications like permanent neonatal diabetes, cerebellar hypoplasia, and vision, hearing, and learning problems in a small number of families.

KLF11-MODY (MODY 7)

Gene KLF11 is cause of MODY 7 due to its mutation. This gene is located on the short arm of chromosomes. This gene is related to pancreas and insulin regulation. KLF11 is expressed in pancreatic islet cells and β-cells. Similar to expression in exocrine cells, KLF11 mRNA expression in β-cells may be up regulated by transforming growth factor-β. Furthermore, due to hyperglycemia, declaration of KLF11 mRNA can increase in pancreatic beta-cells.

It has been shown that in the presence of high glucose levels, KLF11 can bind to and activate the insulin promoter in β-cells. It is reveals from this results that mutation and induction of KLF11 may can increase insulin declaration bete cells of pancreas.

Moreover, KLF11 regulates PDX1 transcription in pancreatic β-cells. Neve et al. first defined two rare variants of the KLF11 gene, which decreased its transcriptional activity, in three families with a history of early-onset T2DM.

CEL-MODY (MODY 8)

Another gene called CEL, who is cause of diabetes MODY-MODY 8. This gene CEL is located on the long arm of chromosomes 9. This gene is related to pancreas and mammary glands. The CEL gene is mainly expressed in mammary glands and pancreatic acinar tissue, but it is not expressed in β-cells.

The protein encoded by this gene is a glycoprotein secreted by the pancreas in the digestive tract and mammary glands infants. The protein of this gene play important role in hydrolysis and absorption of cholesterol and vitamins. Due to mutation of this gene, inherited disease, started characterize by exocrine pancreatic dysfunction during the childhood and diabetes mellitus in adulthood.

PAX4-MODY (MODY 9)

Individual suffers from diabetes MODY 9 due to mutation a gene called Paired box gene 4 (encoded by PAX4). This gene is located on the long arm of chromosomes. After transfer this gene PAX4 from parent to baby, first expressed in endocrine promoter cells in the early phase of embryonic life and is then selectively expressed in β- cells later in life.This gene plays an important role in the development and differentiation of the beta cells of pancreatic islets. PAX4 is required for the expression of PDX1 and Nkx 6.1, which are essential for the development of pancreatic β-cells.

INS-MODY (MODY 10)

An individual suffers from diabetes MODY when a gene INS (insulin) transforms from parent to the baby. This gene INS located on the short arm on chromosomes 11. The gene INS play important role to control glucose level in the blood. This gene INS generally cause of special form of diabetes MODY, neonatal diabetes. This form of diabetes MODY is a rear and its symptoms appeared in children some later age about 10 years of age and in adults.

Complication of INS-MODY

After mutation this gene some changes occur in the children later after birth, decreasing can start in the folding of proinsulin molecules or cause stress and beta cells opoptosis in the endoplasmic reticulum via endoplasmic reticulum protein retention. It is also observed that the same gene INS related to diabetes MODY mutation have been detected in the same families in some persons(group) but signs and diabetes severity was especially different from the other individuals (group A).

In some individuals beside with mild clinical signs some symptoms of polyurie, polydipsia and weight loss are detected. Diabetes has been reported to develop after 50 years of age in family members of individuals who were diagnosed between 9 and 44 years, and carrying the same mutation. While some individuals can have good metabolic control for years with oral antidiabetic medication, others might require insulin treatment.

BLK-MODY (MODY 11)

The gene BLK is cause of diabetes MODY 11. Due to mutation of this gene an individual can suffer diabetes MODY. This gene is duly being present in many cells and tissues, espoecially in pancreas beta cells, its presency is very essential. This gene plays important role in cellular multiplication and differentiation. Furthermore, BLK gene acts on insulin synthesis and secretion by increasing the expressions of PDX1 and Nkx 6.1, which are essential for the development of pancreatic beta cells.

In a newest investigating, it is discovered A71T mutation in 64 persons who were suffering from diabetes MODY, but causes were unknown. Another investigating was done on 4901 T2DM persons with MODY, and 4280 persons who have control normoglycemic, mutation was not found in any type of MODY.This was detected in 52 subjects in the normoglycemic control group.

ABCC8-MODY (MODY 12)

According to the a latest research, about 90 patients with similar symptoms of MODY3 or MODY1 but there is no signs of HNF1A or HNF4A mutations, further, 8% symptoms of mutations were present in the ABCC8 gene.

Differential, Diagnosis, And Significance of a Genetic Diagnosis

Diagnosis Diabetes MODY in form of diabetes 1 and diabetes 2 is a complicated matter, because many symptoms of diabetes type 1, diabetes 2 and diabetes MODY are same. It has been estimated that approximately 80% of individuals with MODY are incorrectly diagnosed with diabetes type 1 and diabetes type 2 at presentation. So correct diagnosis and considering that it is diabetes MODY not any other type, is very important.

The patient’s treatment depends on correct diagnosis. Diabetes MODY and type 1 associated to the children and mostly symptoms develop in the children, so it is very difficult to identify in which type of diabetes the child is suffering MODY or type 1. We can diagnose the type diabetes MODY through proper development of genes sequencing.

Genetic Diagnosis

The family having diabetes history, to diagnosis the diabetes MODY, (the persons not declared diabetes), must genetic consult with specialist before predictive genetic testing. It is more important in children before predictive genetic testing. Diagnostic genetic testing must offer the relative person of those people, who have already suffering from diabetes MODY.

The examination for monogenic diabetes, it is necessary to take blood sample who must be DNA isolated.

The DNA is dissected for changes in the qualities that reason monogenic diabetes. Strange outcomes can decide the quality in charge of diabetes in a specific individual or show whether somebody is probably going to build up a monogenic type of diabetes later on.

Hereditary testing can likewise be useful in choosing the most suitable treatment for people with monogenic diabetes. Pre-birth testing can analyze these conditions in unborn children. Most types of monogenic diabetes are brought about by overwhelming changes, implying that the condition can be passed on to youngsters when just one parent is influenced.

Conversely, if the transformation is a latent change, a sickness quality must be acquired from the two guardians for diabetes to happen. For passive types of monogenic diabetes, testing can show whether guardians or kin without ailment are bearers for passive hereditary conditions that could be acquired by their youngsters.

GENETIC TESTING FOR DIABETES MODY

Diagnostic testing of MODY must be examine, when clinical management start to happening.
When examine must take? when the uncertain situation developed, in diagnosis or in treatment option. In this situation, the examination must be tested in other liberties.

Children and young adults with mild hyperglycemia:

Testing for glucosidase gene mutations

  • Children and young adults with mild hyperglycemia: testing for glucosidase gene mutations
  • The finding of a raised fasting blood glucose in the range of 5.5 – 8 molls/l is unusual in children and young adults.
  • This result indicate to the point that they may be about to develop type 1 diabetes.
  • However, a considerable proportion of these patients will have a mutation in the glucosidase gene which is associated with stable hyperglycemia throughout life which does not require treatment and indeed responds very poorly to either tablets or insulin. This condition is very rare who is associated with any microvascular complications.

Diagnosis of a glucosidase mutation is suggested through following features :-

  1. It is observed that the fasting hyperglycemia is persistent and stable over a period of months or years.
  2. According to the diabetes specialist, in an oral glucose tolerance test the increment of glucose level is small. Although the specialists do not consider an absolute criterion of oral glucose tolerance test.
  3. Sometimes, the children having diabetes, but their parents were not diabetic person or suffering from mild type 2 diabetes.
  4. In case of, where the parent having diabetes symptoms or not, If their parent examined the fasting blood glucose level will be about 5.5 – 8 mmol/l. In some conditions, fasting blood glucose level raise with autosomal domination.

Gestational diabetes

testing for glucokinase gene mutations

As glucosidase patients have mild fasting hyperglycemia throughout life this often presents during pregnancy when routine testing is performed. Since these patients have a consistently raised fasting blood glucose they will have macrosomia children (as long as their child does not have the mutation).

The diagnosis of a glucosidase mutation is important not only as the child may subsequently be picked up as having a raised fasting blood glucose. When the symptoms of hyperglycemia appear in children, it may lead to type 1 diabetes.


When the glucosidase testing is suitable then we submit criteria as under :-

  • Persistently raised fasting blood glucose in the range of 5.5 – 8 mmol/l both before, during and after pregnancy.
  • An increment of <4.6 mmol/l on at least one oral glucose tolerance test (either during or after pregnancy).
  • Glucosidase must test in case of where, neither the symptoms of mild type 2 diabetes were not present in parents nor in family, the diabetes history found. Due to above reasons the doctor do not suggest the Diabetes diagnosis.

Children and young adults with diabetes and a strong family history of diabetes,

to know the 1A (HNF1A) gene mutations, the test of hepatocyte nuclear factor is necessary.

HNF1A Introduction

After recognition of HNF1A gene mutation, it is approved that a patient can live healthy and normal without insulin. But according to the diabetes specialists, 1/3 insulin require in every situation.

hypoglycemia controlling medicines like sulphonylureas but no more side effects noted. So unless they face any severe problem, they can take these medicines for long time.

Interestingly glycemic control in sulphonylureas is often better than that achieved on insulin. With a deep diagnosis, it can described that why diabetes mutates in families having diabetes history. This genetic mutation It may be possible about 50%. Diagnostic testing should be considered in the following situations:

  1. Good glycemic control outside a normally expected honeymoon period not on insulin (usually  years).
  2. The diabetes MODY shows some characteristics who reveal that sometimes, children can live without taking insulin e.g. Not developing ketoacidosis in the absence of insulin, good glycemic control on a small dose of insulin, or detectable C-peptide measured when on insulin.
  3. Family history of diabetes. This may be insulin treated and considered to be “type 1” diabetes. This would typically be diagnosed in the 20s, 30s or 40s.
  4. There may also In some rear cases, grandparents of such children, may be were suffered from diabetes. But usually, diabetes diagnosed after 45 yrs. be an affected grandparent although often these are diagnosed after 45 yrs.
  5. In case of examined in early stages of diabetes, by giving glucose orally, in result the blood glucose level will be high about >5 mmol/l.
  6. In some conditions, fasting blood glucose level be normal, but blood test must do after 2 hours after meals.
  7. Marked sensitivity to sulphonylureas resulting in hypoglycemia despite apparently poor control before starting OHA.

TREATMENT AND MANAGEMENT

Treatment and Management of diabetes MODY depend on forms and types of diabetes MODY. Some forms of MODY do not require drugs because they require only some management like exercise healthy diet and weight loss whereas some forms of MODY require drugs and insulin. Because all type of diabetes are life-long disease, so to keep the blood sugar level under control it require life-long Treatment and Management. To manage the diabetes MODY and keep the blood sugar level normal some steps must have to life long.

1- Maintain healthy body weight:

In case of diabetic person is obese or overweight, it is not a good sign. Being obese is very harmful for diabetic person. It is important to maintain the body mass index in the healthy range of 18.5 -24.9 to To stay fit. If diabetic person is overweight or obese, try to lose weight as early as possible.

2-Eat healthy:

It is advised to eat a balanced and healthy diet, which includes whole grain food, food rich in fiber such as fruits, vegetables, whole grains etc, with this diet must avoid all processed food, sugar products and fatty food.

Keep the eye on portion, quantity and calorie intake; extra calories than required even if as proteins impairs the blood sugar control and increases body weight. reduce the use of all type of sweets, salt and any quantity of alcoholic beverages etc.

Physical Activities:

The diabetes specialists suggest that diabetic persons continue daily 7/24 exercise about 30 minutes along with physical Activities. Daily exercise and regular physical activities can help to maintain blood sugar levels and body weight normal.


It is necessary to change the lifestyle, In case of these changes don’t maintain the blood sugar in the target range, its mean the medication must start. Where the changes in lifestyle can maintain the blood sugar in the target range, there no need to medication.You can use medication along with lifestyle modifications.

Learn more about the different types of diabetes:

Diabetes Types
Type 2 diabetesType 1 diabetesGestational diabetes
Diabetes TypesDrug-induced DiabetesDouble diabetes
Juvenile DiabetesBrittle DiabetesSecondary Diabetes
Diabetes InsipidusDiabetes MODYDiabetes LADA
Steroid-induced Diabetes

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