Diabete MODY
Diseases

Author: Luca Michele Martelli
Date: 07/11/2014

Description

Diabetes MODY

Diabetes MODY ( maturity onset diabetes of the young ) refers to any of several hereditary forms of diabetes caused by mutation in an autosomal dominant gene ( sex independent, so it is inherited from any of the parents). Patients with these forms of diabetes have impaired insulin secretion with minimal or no defect in insulin action. MODY is often referred to as “monogenic diabetes” to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combination of causes involving multiple genes and environment factors (wikipedia) . MODY 3 is the most common form which is associated with mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as HNF1alpha. A second form (called MODY 2) is associated with mutations in the glucokinase gene on chromosome 7p. The other forms are very rare. (monogenicdiabetes)

Currently MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. Prevalence of MODY is 1-5/10000. 50 of first-degree relatives will inherit the same mutation, giving them a greater than 95 lifetime risk of developing MODY themselves. For this reason, correct diagnosis of this condition is important. Typically patients present with a strong family history of diabetes (any type) and the onset of symptoms is in the second to fifth decade.(wikipedia)

Pathophysiology, symptoms, complications and treatment are different between distinct forms of diabetes MODY because they are characterized by mutation on diverse gene, so I describe the two most common forms of diabetes MODY: MODY 2 and MODY 3.

PATHOPHYSIOLOGY

MODY 2: MODY 2 is due to any of several mutations in the GCK gene on chromosome 7p for glucokinase. GCK is a hexokinase-like enzyme catalyzing the phosphorylation of glucose to glucose-6-phosphate, the first step in the metabolism of glucose. It is expressed principally in pancreatic b-cells and hepatocytes. Glucokinase serves as the glucose sensor for the beta cell. Normal glucokinase triggers insulin secretion as the glucose exceeds about 90 mg/dl (5 mM). These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose. The beta cells in MODY 2 have a normal ability to make and secrete insulin, but do so only above an abnormally high threshold (126–144 mg/dl, or 7-8 mM). This causes in patients with GCK mutations have chronic mild fasting hyperglycemia (5.5–9.0 mmol/l) from early childhood and probably from birth, which is usually asintomatic. (diabetesjournal )

MODY 3: MODY 3 is due by mutations of the hepatocyte nuclear 1 homeobox A gene on chromosome 12q, known as HNF1A. This codes for a transcription factor highly expressed in the liver and involved in the regulation of the expression of many liver-specific genes. Its role in insulin secretion is not well defined. The diabetes typically develops in the second to fourth decade of life and is generally beta cell antibody negative, C-peptide positive and not associated with features of insulin resistance. The main pathophysiological feature is a failure to augment insulin secretion in response to oral nutrients, which is why high postprandial glucose levels are characteristic of the condition. Metabolic control tends to deteriorate over time in undiagnosed patients despite insulin therapy, and typical late complications of diabetes can develop. (diapedia)

SIGNS AND SYMPTOMS

MODY 2: The insulin production is adequate; therefore, the glucose levels in these individuals rapidly return to normal when they are given an oral glucose load. Patients with MODY 2 have mild, stable fasting hyperglycemia (5.5–8.0 mmol/L) that shows little deterioration with age. Most patients with mutations in the GCK have a small increase in plasma glucose (<3 mmol/L in 70% of patients) 2 hours after an oral glucose load. The majority of patients with MODY due to GCK mutations maintain glycated hemoglobin (HbA1c level) below 8%. So these patients are generally asintomatic. (nejm)

MODY 3: Typically, patients with HNF1A mutations are characterized by a progressive β-cell failure and increasing hyperglycemia. The principal symptoms are: increased thirst (polydipsia), polyuria, weight loss, blurred vision, glycosuria, increased susceptibility to infection, low renal threshold for glucose ( is due to reduced expression of the high-affinity low-capacity glucose co-transporter 2 , leading to decreased resorption of glucose from the renal tubules), after 2 hours of an OGTT (oral glucose tolerance test) glucose level increased more than 6 mmol/ L higher than the fasting level, even the fasting glucose level is less than 6 mmol/L, dehydration, increased hunger ( there is plenty of sugar in the blood but the cells of the body of the body can not use it due to a lack of insulin), fatigue, extreme sensitivity to sulphonylurea drugs.
(diabetesjournal)

COMPLICATIONS

MODY 2: Evidence from observational studies (including a study of 95 GCK-MODY subjects exposed to hyperglycaemia for an average of 50 years) indicates that GCK-MODY patients do not develop microvascular diabetes-related complications. GCK-MODY patients typically have favourable cardiovascular risk factor profiles; however, no large studies have yet assessed long-term macrovascular outcomes. Neuropathic and kidney complications are very rare. (diapedia)

MODY 3: Patient with MODY 3 develop frequently complications caused by the progressive augmentation of hyperglcaemia;in particular are frequent microvascular disorders. Patients can also develop microalbuminuria and macroalbuminuria and chronic renal failure. Thirty-four percent of the MODY patients had mild retinopathy and 13 had severe non-proliferative or proliferative retinopathy. Neuropathy was observed frequently. Twenty-four percent of patients develop hypertension and 16 coronary heart desease. (diapedia)

DIAGNOSIS

There are some characteristic which suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients:
• Mild to moderate hyperglycemia (typically 130-250 mg/dl, or 7-14 mM) discovered before 30 years of age.
• A first degree relative with a similar degree of diabetes.
• Absence of positive antibodies or other autoimmunity in patient and family.
• Diabetes patient who shows no signs of insulin resistance.
• Absence of obesity (though obese people can get MODY), or other problems associated with type 2 diabetes or metabolic syndrome ( hypertension, hyperlipidemia, polycystic ovary syndrome).
• Individual or family history of diabetes with develop of kidney disease or kidney cysts.
• Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before 6 months of age.
• Diabetes patient with low level of insulin secretion.
The only definitive way to diagnosticate diabetes MODY is genetic testing. This type of testing will determine the exact type of MODY and can be done before a patient has any symptoms.
(wikipedia)

TREATMENT

MODY 2: Given the mild hyperglycemia, the absence of long-term microvascular complications, and the observation that treatment has little effect on glycemia in this group of patients, the general consensus is that the majority of these patients do not require treatment. The only exception is during pregnancy, in which insulin may be required to prevent excess fetal growth. Therefore MODY 2 is controlled by exercise and diet.(ncbi)

MODY 3: Patients with HNF1A gene mutations can initially be treated with diet. After it increase the insufficient of insulin production so it becomes necessary pharmacological treatment based on low-dose sulphonylureas are recommended as first-line pharmacological therapy for patients with HNF1A/HNF4A-MODY. A dose of gliclazide 40 mg will typically control diabetes (20 mg is often adequate). If hypogylcaemia occurs, the aim is to reduce the dose rather than discontinuing treatment where possible, as HbA1c may rise with metformin treatment. When sulphonylurea drugs begin to fail in HNF1A-MODY, there is no specific evidence base to recommend other treatments. It is reasonable to try other oral agents for example metformin. There are a few case reports of the successful use of GLP-1 agonists and DPP4 inhibitors. Most patients will transfer to insulin after sulphonylurea failure. In theory the addition of basal insulin to sulphonylureas should be effective.(diapedia)

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