Maturity onset diabetes of the young pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

The recognised forms of MODY are all due to ineffective insulin production or release by pancreatic β-cells. Several of the defects are mutations of transcription factor genes. One form is due to mutations of the glucokinase gene. For each form of MODY, multiple specific mutations involving different amino acid substitutions have been discovered. In some cases, there are significant differences in the activity of the mutant gene product that contribute to variations in the clinical features of the diabetes (such as degree of insulin deficiency or age of onset).

Cases of MODY in China appear to be largely unexplained by the genes associated with MODY in Western populations.

Genetics

They are inherited in an autosomal dominant fashion, and most patients therefore have other members of the family with diabetes; penetrance differs between the types (from 40% to 90%).

MODY 1: hepatocyte nuclear factor 4&alpha

MODY 1 is due to a loss-of-function mutation in the HNF4A gene on chromosome 20. This gene codes for HNF4-α protein also known as transcription factor 14 (TCF14). HNF4α controls function of HNF1α (see MODY 3; TCF1) and perhaps HNF1β (MODY 5) as well. This transcription network plays a role in the early development of the pancreas, liver, and intestines. In the pancreas these genes influence expression of, among others, the genes for insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.

Although pancreatic beta cells produce adequate insulin in infancy, the capacity for insulin production declines thereafter. Diabetes (persistent hyperglycemia) typically develops by early adult years, but may not appear until later decades. The degree of insulin deficiency is slowly progressive. Many patients with MODY 1 are treated with sulfonylureas for years before insulin is required.

Liver effects are subtle and not clinically significant. Many people with this condition have low levels of triglycerides, lipoprotein(a), apolipoproteins AII and CIII.

Mutations in the alternative promoter of HNF4A are linked to development of type 2 diabetes.

MODY 2: glucokinase

MODY 2 is due to any of several mutations in the GCK gene on chromosome 7 for glucokinase. 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 (e.g., 126-144 mg/dl, or 7-8 mM). This produces chronic, mild hyperglycemia which is usually asymptomatic. It is usually detected by accidental discovery of mild hyperglycemia (e.g., during pregnancy screening). An oral glucose tolerance test is much less abnormal than would be expected from the impaired (elevated) fasting glucose, since insulin secretion is usually normal once the glucose has exceeded the threshold for that specific variant of the glucokinase enzyme. It can usually be controlled by dietary measures (primarily avoiding large amounts of carbohydrate). The degree of hyperglycemia does not usually worsen with age and long-term diabetic complications are rare.

This type of MODY demonstrates the common circulation but complex interplay between maternal and fetal metabolism and hormone signals in the determination of fetal size. Because MODY2 is an autosomal dominant condition, an affected mother will pass it to 50% of her children. A small number of infants will have a new mutation not present in their mothers. If the mother is affected and the fetus is not, the maternal glucose will be somewhat high and the normal pancreas of the fetus will make lots of insulin, resulting in a large infant. If the fetus is affected but mother is not, glucoses will be normal and fetal insulin production will be low, resulting in intrauterine growth retardation. Finally, if both mother and fetus have the disease, the two defects will offset each other and fetal size will be unaffected.

When both GCK genes are affected the diabetes appears earlier and the hyperglycemia is more severe. A form of permanent neonatal diabetes has been caused by homozygous mutations in the GCK gene.

MODY 3: hepatocyte nuclear factor 1&alpha

MODY 3 is caused by mutations of the HNF1α gene, a homeobox gene on chromosome 12. This is the most common type of MODY in populations with European ancestry, accounting for about 70% of all cases in Europe. HNF1α is a transcription factor (also known as transcription factor 1, TCF1) that is thought to control a regulatory network (including, among other genes, HNF1α) important for differentiation of beta cells. Mutations of this gene lead to reduced beta cell mass or impaired function. MODY 1 and MODY 3 diabetes are clinically similar. About 70% of people develop this type of diabetes by age 25 years, but it occurs at much later ages in a few. This type of diabetes can often be treated with sulfonylureas with excellent results for decades. However, the loss of insulin secretory capacity is slowly progressive and most eventually need insulin.

This is the form of MODY which can most resemble ordinary type 1 diabetes, and one of the incentives for diagnosing it is that insulin may be discontinued or deferred in favor of oral sulfonylureas. Some people treated with insulin for years due to a presumption of type 1 diabetes have been able to switch to pills and discontinue injections. Long-term diabetic complications can occur if the glucose is not adequately controlled.

MODY 4: insulin promoter factor-1

MODY 4 arises from mutations of the IPF1 homeobox gene on chromosome 13. IPF1 is a transcription factor vital to the development of the embryonic pancreas. Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin.

MODY 4 is so rare that only a single family has been well-studied. A child born with pancreatic agenesis (absence of the pancreas) was found to be homozygous for IPF1 mutations. A number of older relatives who were heterozygous had mild hyperglycemia or diabetes. None were severely insulin-deficient and all were controlled with either diet or oral hypoglycemic agents.

MODY 5: hepatocyte nuclear factor 1&beta

HNF1β-related MODY is one of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas and several forms of renal disease. HNF1β, also known as transcription factor 2 (TCF2), is involved in early stages of embryonic development of several organs, including the pancreas, where it contributes to differentiation of pancreatic endocrine Ngn3⁺ cell progenitors from non-endocrine embryonic duct cells. The gene is on chromosome 17.

The degree of insulin deficiency is variable. Diabetes can develop from infancy through middle adult life, and some family members who carry the gene remain free of diabetes into later adult life. Most of those who develop diabetes show atrophy of the entire pancreas, with mild or subclincal deficiency of exocrine as well as endocrine function.

The non-pancreatic manifestations are even more variable. Kidney and genitourinary malformation and diseases may occur, but inconsistently even within a family, and the specific conditions include a range of apparently unrelated anomalies and processes. The most common genitourinary condition is cystic kidney disease, but there are many varieties even of this. Renal effects begin with structural alterations (small kidneys, renal cysts, anomalies of the renal pelvis and calices), but a significant number develop slowly progressive renal failure associated with chronic cystic disease of the kidneys. In some cases, renal cysts may be detected in utero. Kidney disease may develop before or after hyperglycemia, and a significant number of people with MODY5 are discovered in renal clinics.

With or without kidney disease, some people with forms of HNF1β have had various minor or major anomalies of the reproductive system. Male defects have included epididymal cysts, agenesis of the vas deferens, or infertility due to abnormal spermatozoa. Affected women have been found to have vaginal agenesis, hypoplastic, or bicornuate uterus.

Liver enzyme elevations are common, but clinically significant liver disease is not. Hyperuricaemia and early onset gout have occurred.

MODY 6: neurogenic differentiation 1

MODY 6 arises from mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. The gene is on chromosome 2 in a region of the p arm known as IDDM7 because it includes genes affecting susceptibility to type 1 diabetes. NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of beta cells and parts of the nervous system.

This is also one of the rarer forms of MODY. Only 3 kindreds with mutations causing MODY6 have been identified so far. In both, some of the members had more typical type 2 diabetes rather than MODY, and the reasons for the difference of expression have not been worked out. Most of the family members with diabetes were diagnosed after age 40, but a few required insulin for blood sugar control.

MODY 7: Kruppel-like factor 11

KLF11 has been associated with a form of diabetes that has been characterized as "MODY7" by OMIM.

MODY 8: Bile salt dependent lipase

CEL has been associated with a form of diabetes that has been characterized as "MODY8" by OMIM.

Permanent neonatal diabetes

A newly identified and potentially treatable form of monogenic diabetes is the neonatal diabetes caused by activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit of the beta cell K_ATP channel. This results in congenital impairment of insulin release but in the past has almost always been thought to be unusually early type 1 diabetes mellitus. The insulin deficiency results in intrauterine growth retardation with birth weight small for gestational age. The diabetes is usually diagnosed in the first 3 months of life due to continuing poor weight gain, polyuria, or diabetic ketoacidosis. Rare cases have been recognized as late as 6 months of age. Remarkably, this type of diabetes often responds well to sulfonylureas and insulin may not be necessary. More severe mutations in the KCNJ11 gene can cause early-onset diabetes which does not respond to the sulfonylurea drugs, as well as a syndrome of developmental delay and neurological features called the DEND syndrome. These forms of diabetes are very rare conditions, appearing in about 1/100,000 to 1/200,000 live births, and accounting for about 1/1000 of type 1 diabetes cases. Fewer than 5% of the cases assumed to exist have been diagnosed, and most diabetes clinics around the world are checking for KCNJ11 mutations in any persons who developed apparent insulin-dependent diabetes without the typical type 1 antibodies before 6 months of age. At least some of these people have been able to change from insulin to sulfonyurea pills after decades of injections.

Transient neonatal diabetes

Not all neonatal-onset diabetes is permanent, and not all forms of either the permanent or transient forms are understood. One of the transient forms appears to be a monogenic condition: that due to the mutations of the other subunit of the K_ATP channel, SUR1, which is encoded by the ABCC8 gene.

Associated conditions

Related homozygous disorders

By definition, the forms of MODY are autosomal dominant, requiring only one abnormal gene to produce the disease; the severity of the disease is moderated by the presence of a second, normal allele which presumably functions normally. However, a small number of people carrying two abnormal alleles have been identified. Unsurprisingly, combined (homozygous) defects of these genes are both much rarer and much more severe in their effects.

• Homozygous glucokinase deficiency causes severe congenital insulin deficiency resulting in persistent neonatal diabetes mellitus. About 6 cases have been reported worldwide. All have required insulin treatment from shortly after birth. The condition does not seem to improve with age.

• Homozygous IPF1 results in failure of the pancreas to form. Congenital absence of the pancreas, termed pancreatic agenesis, involves deficiency of both endocrine and exocrine functions of the pancreas.

Homozygous HNF4α, HNF1α, HNF1β, and NeuroD1 mutations have not yet been described. Those mutations for which a homozygous form has not been described may be extremely rare, or may result in clinical problems not yet recognized as connected to the monogenic disorder, or may be lethal for a fetus and not result in a viable child.