5% of all cases of diabetes mellitus in the US are due type 2 diabetes. a MODY-associated mutation and are therefore likely to develop diabetes. …
VERSION
2
MARCH
2005
Disease Reviews
IN ENDOCRINOLOGY
Testing You Can Count On
Monogenic Diabetes: MODY HNF4A, GCK, TCF1, IPF1, TCF2
Frequently Used Abbreviation: MODY: maturity-onset diabetes of the young
Introduction
An estimated 5 of all cases of diabetes mellitus in the US are due to autosomal dominant loss-offunction mutations in any one of at least six different genes1 Such autosomal dominant diabetes is generally known as MODY, or maturity-onset diabetes of the young, because differential diagnosis based on clinical presentation is only possible in young, non-obese individuals However, MODY can occur at any age and is caused by a limited capacity of the pancreas to release insulin, rather than by the insulin resistance typical of type 2 diabetes1,2 Treatment and clinical outlook for MODY depends on the exact genetic cause and may differ greatly from those of type 1 and type 2 diabetes While one subtype MODY2 can generally be managed by diet and exercise alone, others MODY1, 3, and 4 are highly responsive to sulfonylurea therapy; yet another MODY5 may require treatment for multiple organ abnormalities Genetic testing for MODY helps diagnose the exact subtype in
about 85 of all cases,2 enabling the physician to select the most appropriate treatment Among family members of MODY patients, genetic testing can identify asymptomatic individuals who harbor a MODY-associated mutation and are therefore likely to develop diabetes
Types and Causes of MODY
To date, loss-of-function mutations in any one of at least six different genes have been linked to the occurrence of MODY3-8 MODY Subtype MODY1 MODY2 MODY3 MODY4 MODY5 MODY6 Affected Gene HNF4A GCK TCF1 IPF1 TCF2 NEUROD1 Prevalence in the US and Europe uncommon common most common uncommon uncommon very rare
Affected Protein hepatocyte nuclear factor 4 glucokinase hepatic nuclear factor 1 insulin promotor factor 1 hepatic nuclear factor 1 Neurogenic differentiation factor 1
MODY 1, 3, 4, 5, and 6
These forms of MODY are due to loss-of-function mutations in the genes for the transcription factors HNF-4, HNF-1, IPF-1, HNF-1, or NeuroD1, respectively All of these transcription factors are involved in regulating transcription of the insulin gene, probably both directly and through regulating transcription of each other in a complicated
network9 Presence of any one of these mutations prevents
efficient stimulation of insulin gene transcription Consequently, not enough insulin is produced in response to high blood glucose Through an unknown mechanism, mutations in HNF-4, HNF-1, IPF-1, or HNF-1 eventually lead to complete -cell failure
Normal Physiology of Insulin Release
Blood glucose low Blood glucose high
ATP/ADP ratio low inside of cell K
Insulin
ATP/ADP ratio high inside of cell K
Insulin
Ca2 outside of cell
Ca2 outside of cell
K ions can flow out of the cell along their concentration gradient, leaving behind an excess of negative charges carried by intracellular proteins This excess of negative charges creates a negative membrane potential similar to the resting potential seen in nerve cells The negative membrane potential causes voltage-dependent Ca2 channels in the -cell membrane to remain shut and, consequently, the intracellular Ca2 concentration to remain low Under these conditions, no insulin is released from -cells When blood glucose levels are high, more glucose is taken up by the -cells, glycolysis is increased, and the intracellular ATP/ADP ratio rises The increased intracellular ATP/ADP ratio triggers closing of the KATP channels in the cell
membrane of the -cells Since K ions can no longer flow out of the cells, the membrane potential becomes more positive, causing the opening of voltage-gated Ca2 channels in the membrane of the -cells Ca2 ions flow in and stimulate the release of insulin from secretory vesicles stored in the cells
When blood glucose levels are low, glycolysis in -cells is limited by the sparse influx of glucose, and the intracellular ATP/ADP ratio is low Under these conditions, KATP channels in the membrane of -cells remain open, allowing K, but not Na ions, to freely pass through The cell membrane of -cells also contains energy-dependent ion pumps that pump Na ions out while pumping K ions in, thus creating opposing Na and K concentration gradients across the cellular membrane Through the KATP channels,
MODY2
MODY2 is caused by a loss-of-function mutation in the gene for the enzyme glucokinase, which catalyzes the first and rate-limiting step of glycolysis By determining the rate of ATP production in response to the blood glucose concentration, glucokinase functions as the -cells glucose sensor see Normal Physiology of Insulin Release Loss-of-function mutations in glucokinase reduce the efficiency
with which pancreatic -cells use glucose for ATP production, so that higher than normal blood glucose levels are necessary to generate an intracellular ATP concentration sufficient to trigger insulin release Of note, gain-of-function mutations in GCK do not lead to diabetes, but to the complementary condition, congenital hyperinsulinism10
Clinical Presentation of MODY
MODY often remains undetected and untreated for many years, since the classic symptoms of diabetes mellitus ie, frequent urination and excessive thirst and hunger develop only very gradually The initial sign of MODY usually is mild fasting hyperglycemia, which may be noticed during a routine visit to the doctor All types of MODY are characterized by non-ketotic hyperglycemia, which is often diagnosed during the second or third decade of life, but can occur at any age MODY is not necessarily associated with obesity; however, presence of obesity can lower the age of onset, since obesity-related insulin resistance raises insulin requirements Except
MODY1-associated defects in HNF-4 also affect fatty acid synthesis in the liver, reflecting the multiple roles of transcription factors in different tissues MODY2 is often
diagnosed in association
with pregnancy gestational diabetes, obesity, or old age
MODY5-associated defects in HNF-1 have been linked to renal cysts and other abnormalities in renal development, which can lead to chronic renal insufficiency and kidney failure In addition, internal genital abnor 
malities and atrophy of the pancreas, leading to exocrine as well as endocrine pancreatic deficiency, have been observed
MODY3-associated defects in HNF-1
also lead to decreased renal re-absorption of glucose, resulting in glycosuria
for MODY2, all types of MODY are characterized by glucose intolerance and progressive -cell failure and can lead to the long-term complications typical of diabetes MODY2 is associated with persistent mild fasting hyperglycemia and only mild glucose intolerance, which do not progress in severity with time and rarely lead to long-term problems The exact clinical presentation of MODY may vary depending on the underlying genetic cause
Genetic testing can establish a firm diagnosis of MODY in patients of any age, based on a single blood draw Genetic testing is also useful for family screening, as it can detect mutations associated with MODY in individuals who are
not yet diabetic In these individuals, increased vigilance and changes in lifestyle may help to prevent the persistence of unrecognized hyperglycemia
Treatment of MODY
MODY1, 3, and 4 usually respond very well to
oral sulfonylurea drugs Due to progressive -cell failure, a significant proportion of patients 30-40 for MODY1 and MODY3 will eventually require insulin therapy
Diagnosis of MODY
MODY should be suspected as a cause of non-ketotic hyperglycemia in patients of any age as well as in young or middle-aged obese individuals In children, MODY can be confused with early-stage type 1 diabetes11 MODY can be distinguished from type 1 diabetes by the absence of diabetes antibodies anti-insulin, anti-islet, anti-GAD In non-obese, but not in obese individuals, MODY can be differentiated from type 2 diabetes by the absence of insulin resistance MODY2 can be discriminated from the other types of MODY because it leads to only mild glucose intolerance Presence of renal disease can be indicative of MODY5, but may also be a sign of diabetic nephropathy
MODY2 generally has an excellent prognosis It is
non-progressive, rarely requires drug or insulin therapy, and can usually be managed by
exercise and diet alone
MODY5 may require several different treatments
because it leads to multiple organ abnormalities12 In overweight patients, who are likely to show insulin resistance, weight loss will improve hyperglycemia due to MODY
Figure 1: An approach to diagnosing MODY
Hyperglycemia
Ketotic
Non-Ketotic
Non-Obese Type 1 Diabetes: Insulin-replacement therapy
Obese
Any age2
50 years _
50 years
Yes
Diabetes antibodies
Type 2 Diabetes: Oral hypoglycemics usually only effective for a limited time period before insulin-replacement therapy becomes necessary Exercise to promote weight loss
No or borderline
Monogenic Diabetes MODY Evaluation Negative
Positive
Positive MODY MODY 1, 3, 4: Respond very well to oral hypoglycemics; insulin-replacement therapy usually not necessary until late stages 1 MODY 2: Non-progressive; can usually be managed with diet and exercise alone1 MODY 5: May require replacement of endocrine and exocrine pancreatic functions and therapy for other organ abnormalities12 If obese: Exercise to promote weight loss Family testing to help prevent the persistence of unrecognized hyperglycemia
False positive rate of 10
Proportion of MODY
cases expected to be very low
Genetics of MODY
MODY is inherited in an autosomal dominant manner It has been proposed that heterozygous loss-of-function mutations in transcription factors lead to MODY through haploinsufficiency, where the one remaining intact gene cannot compensate for the defective gene9,13 Homozygosity for MODY2-linked loss-of-function mutations in GCK or MODY4-linked loss-of-function
mutations in IPF1 does not lead to MODY, but to the more severe neonatal diabetes mellitus14,15
Genetic Testing for MODY
The Monogenic Diabetes MODY Evaluation allows identification of genetic defects linked to MODY1, MODY2, MODY3, MODY4, or MODY5 and can detect about 85 of all cases of MODY in the US population Genetic testing for MODY should be considered in all non-ketotic,
non-obese diabetes patients, regardless of age, as well as in all young or middle-aged non-ketotic, obese diabetes patients In addition, the Monogenic Diabetes MODY Evaluation permits family screening for MODY For the current number of MODY-associated variants in HNF4A, GCK, TCF1, IPF1, or TCF2, please visit: http://wwwcorrelagencom/endocrinetests/
How Is Genetic Testing for MODY Performed?
DNA for
sequencing is obtained from leukocytes present in a small blood sample The coding sequences of HNF4A, GCK, TCF1, IPF1, and TCF2 are amplified in a highly specific manner through a polymerase chain reaction PCR, and all PCR products are fully sequenced Sequencing results are interpreted, and a detailed result report is sent to the patients physician
Testing performed under license from
Correlagen, Inc 222 Third Street, Suite 1100, Cambridge, MA 02142 wwwcorrelagencom
For information on ordering the Monogenic Diabetes MODY Evaluation, Athena Diagnostics Customer Service Representatives are available from 8:30 am to 6:30 pm Eastern Time US Customers in the US and Canada please call toll-free
800-394-4493 x2
Non-US customers please call 508-756-2886 or fax 508-753-5601
wwwAthenaDiagnosticscom
References: 1 Fajans SS, et al 2001 N Engl J Med 345:971-80 2 Frayling TM, et al 2001 Diabetes 50 Suppl 1:S94-100 3 Yamagata K, et al 1996 Nature 384:458-60 4 Froguel P, et al 1993 N Engl J Med 328:697-702 5 Yamagata K, al 1996 Nature 384:455-8 6 Stoffers DA, et al 1997 Nat Genet 17:138-9 7 Horikawa Y, et al 1997 Nat Genet 17:384-5 8 Malecki MT, et al 1999 Nat Genet 23:323-8 9 Ferrer J 2002
Diabetes 51:2355-62 10 Meissner T, et al 1999 Hum Mutat 13:351-61 11 Moller AM, et al 1998 Diabetologia 41:1528-31 12 Bellanne-Chantelot C, et al 2004 Ann Intern Med 140:510-7 13 Thomas H, et al 2002 Biol Chem 383:1691-700 14 Njolstad PR, et al 2001 N Engl J Med 344:1588-92 15 Stoffers DA, et al 1997 Nat Genet 15:106-10 Athena Diagnostics and the Athena Diagnostics logo are registered trademarks of Athena Diagnostics, Inc Correlagen is a registered trademark of Correlagen, Inc ADX103SG-3/0AW-REV00
Source:athenadiagnostics.com
