42 HOW TO TREAT : MATURITY-ONSET DIABETES OF THE YOUNG
42 HOW TO TREAT : MATURITY-ONSET DIABETES OF THE YOUNG
8 NOVEMBER 2024 ausdoc . com . au
Box 4 . Safe targets for most adults with MODY
• First morning and pre-meal plasma glucose in the range 4-7mmol / L .
• Plasma glucose in the range of 5-9mmol / L after eating .
Source : Tattersall RB 1974 5
diabetes to maintain at least a moderate level of physical activity and fitness , as part of a healthy lifestyle . Additional support from GPs , nurses , educators , accredited dietitians and exercise physiologists , together with education programs , can greatly help patients with their self-management goals . In some types of MODY , patients may also need treatment for related conditions , such as kidney disease and gout . Because of associated abnormalities , undertake screening for kidney and eye disease in the first year following a diagnosis of diabetes , and repeat this at least annually , or more often depending on individual risk factors .
When MODY first presents during pregnancy , when compared to standard gestational diabetes , higher doses of insulin are sometimes needed to lower maternal glucose levels . It may be difficult to maintain normal pregnancy glucose targets . Notably , maternal hyperglycaemia can cause fetal hyperinsulinaemia , an increased risk of macrosomia
( excessive birthweight ) and poor perinatal outcomes , depending on the fetal genotype .
In some cases , fetal growth restriction can occur when maternal hyperglycaemia is aggressively treated with insulin and the fetus has not inherited the mother ’ s mutation . Therefore , a referral by the GP to an appropriate tertiary hospital for specialist antenatal care is recommended .
PROGNOSIS
PATIENTS with MODY who remain free of complications have very good health outcomes . In contrast , those individuals who develop complications , like kidney or heart disease , often experience poor health and premature mortality .
Prevention of complications through early and sustained control of glucose levels and mitigation of other risk factors is currently the best way to manage MODY .
CASE STUDIES
Case study one
MARK , 23 , an engineer , was diagnosed with type 1 diabetes at age 19 . He presented to ED following GP review and a four-week history of polyuria , polydipsia and elevated capillary blood glucose .
On examination , he was lean ( BMI 20kg / m 2 ), with pathology revealing a random plasma glucose of 14mmol / L ( normal less than 11.1mmol / L ), capillary ketones 0.3 ( normal less than 0.6 ), HbA1c 7.4 %, and negative
How to Treat Quiz .
1 . Which THREE statements regarding diabetes are correct ? a Type 2 diabetes results from a progressive decline in the insulin-producing capacity of the pancreas . b About 10 % of patients with MODY are misdiagnosed and incorrectly managed initially . c Type 1 diabetes results from the autoimmune destruction of the beta cells within their pancreatic islets . d MODY results from a genetic mutation resulting in the progressive ( non-autoimmune ) loss of the insulin-production capacity of the pancreas .
2 . At which ONE stage does MODY most commonly present ? a Later in adulthood . b Teenage years . c In pregnancy . d In childhood .
3 . Which TWO statements regarding the epidemiology of MODY are correct ? a The highest rates have been documented in Asian populations . b The documented prevalence of clinically diagnosed MODY varies widely according to the population and ethnicity . c It is estimated that approximately 1-5 % of women with gestation diabetes have undiagnosed MODY . d Unbiased genetic screening studies suggest that at least 100,000 Australians may carry a diabetes-causing mutation of a MODY gene .
4 . Which THREE statements regarding the pathogenesis of MODY are correct ? a Every individual with a mutated gene develops diabetes . b MODY is a monogenetic disorder . c MODY is the most common presentation of monogenic diabetes . d Changes in the function of many of the genes causing MODY are implicated in other forms of diabetes .
5 . Which THREE are features of MODY ? a Family history of diabetes . b Not insulin dependent . c High risk of diabetic ketoacidosis . d Typically younger than
25 years at diagnosis .
6 . In which TWO patient groups is testing for MODY indicated a Early-onset diabetes with no pancreatic autoantibodies ( anti- GAD-65 , anti-IA-2 and anti-ZnT8 ).
He was started on basal-bolus insulin therapy with four injections of insulin daily .
Mark was supported by his family , who had a strong history of diabetes , with his mother , maternal aunt and maternal grandfather all diagnosed with diabetes in their 20s .
Mark struggled to manage his diabetes appropriately and was frustrated with his inability to stabilise his blood glucose levels . He often experienced hypoglycaemic episodes despite regular meals , dietary
advice and support from a diabetes nurse educator . These issues were having a significant impact on his performance at work , personal relationships and overall wellbeing .
His GP referred him to an endocrinologist , who had a high clinical suspicion for MODY after taking a careful history and using a MODY probability calculator . Subsequent testing demonstrated a fasting paired serum glucose of 6.8mmol / L and C-peptide of 340pmol / L ( normal range 260-1270pmol / L via Alfred Pathology ) confirming preserved beta cell function and persistent
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dyslipidaemia . b Early-onset diabetes with no hypertension . c Clinical features of insulin resistance . d Absence of a family history of diabetes .
7 . Which TWO statements regarding the diagnosis of MODY are correct ? a Online risk calculators can assist in making a diagnosis of MODY . b Rapidly rising rates of type 2 diabetes in adolescents and young adults makes clinical differentiation from MODY more difficult . c The presence of islet antibodies will differentiate between type 1 diabetes and MODY . d Patients with MODY have a serum C-peptide level consistently exceeding 200pmol / L .
8 . Which THREE statements regarding the genetic testing for MODY are correct ? a International guidelines recommend that the correct diagnosis of MODY and determination of subtype should
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MATURITY ONSET DIABETES OF THE YOUNG
glycosuria in the absence of significant hyperglycaemia .
MODY-targeted genetic testing was performed and revealed an HNF1A ( MODY3 ) variant . Mark was switched from subcutaneous insulin to oral sulfonylurea monotherapy ( gliclazide MR 30mg daily ). This led to a significant reduction in hypoglycaemic events and an improvement in his glucose profile , HbA1c and overall quality of life . Subsequent cascade family genetic testing confirmed that his mother and maternal aunt also possessed the MODY3 variant .
In some types of MODY , patients may also need treatment for related conditions such as kidney disease .
Case study two
Emma was first diagnosed with ‘ mild ’ diabetes at the age of 27 , while undergoing pre-pregnancy planning with her GP . At that time , her HbA1c was elevated at 6.7 % ( 50mmol / mol ). She was a little overweight with a BMI of 27kg / m 2 . A presumptive diagnosis of early type 2 diabetes was made . Further history revealed her mother and grandmother also developed diabetes . Dietary and lifestyle modifications were recommended to ideally achieve an HbA1c of 6.0 % ( 42mmol / mol ) or less before conception , together with high-dose
be based on genetic testing . b There are currently no recommendations for genetic testing for MODY in Australia . c Most forms of MODY are inherited an autosomal dominant fashion . d If a family member is identified as a carrier of a mutated MODY gene , it is currently possible to prevent the onset of diabetes .
9 . Which THREE are appropriate in the management of MODY ? a Thiazolidinediones . b Standard oral glucose-lowering agents as required . c Diet and lifestyle modification . d Insulin therapy at a later stage .
10 . Which TWO statements regarding the management of MODY are correct ? a Patients with MODY3 may have an increased risk of diabetic complications . b When MODY first presents during pregnancy , lower doses of insulin are sometimes needed to maintain normal pregnancy glucose targets . c Most adults with MODY can safely target first morning and pre-meal plasma glucose in the range 5-9mmol / L . d Patients with MODY who remain free of complications have very good health outcomes . folic acid supplements and retinal screening .
When Emma did become pregnant , her blood glucose concentrations progressively rose , and she was started on subcutaneous insulin therapy . Despite improved glycaemic control , at 20 weeks ’ gestation her baby demonstrated a reduced growth pattern , with the estimated fetal weight at the 10th percentile . She was referred for specialist endocrinological review .
Although diabetes may be independently associated with placental dysfunction , her strong family history and asymptomatic initial presentation at an early age led to a suspicion of GCK MODY ( MODY2 ), which was confirmed after genetic testing . Had her baby not inherited Emma ' s GCK mutation , increased fetal insulin production would have acted to increase birth weight , insulin therapy would have been needed to prevent macrosomia , and delivery would have likely occurred at 38 weeks . However , in this case , where the fetus inherits the mother ’ s GCK mutation , glucose-lowering with insulin is not recommended , as it can result in fetal growth restriction . This is because the set-point for glucose-triggered insulin production is shifted ( see figure 5 ), so that higher blood glucose levels are required to trigger fetal insulin secretion .
CONCLUSION
SOME young people develop diabetes due to a single mutation that impairs the function of one of their genes . As awareness increases and genetic testing becomes more common , practitioners will also come to identify patients with MODY in their practices . Although the cause is different from type 1 or type 2 diabetes , people with MODY also need the continuing support of their GP to ensure optimal blood glucose control and mitigation of their risk ( s ) for future complications . Appropriate counselling , education and screening of family members for diabetes will also need to be undertaken .
RESOURCES
• Exeter Diabetes MODY Probability Calculator bit . ly / 3AgLm2k
• RACGP : Genomics in General Practice — Diabetes bit . ly / 46SqQ4p
• International Society of Paediatric and Adolescent Diabetes ( ISPAD ) Guidelines bit . ly / 3WDmzwD
• National Institute for Health Care and Excellence ( NICE ): Diabetes ( type 1 and type 2 ) in Children and Young People bit . ly / 3WDJc4k
• Guidelines for Genetic Testing in MODY bit . ly / 3yvEei4
• Endocrine Society : Monogenic Diabetes — Patient Resources https :// bit . ly / 3LWzhSs
• Queensland Genomics : Targeted Genetic Testing for MODY in Gestational Diabetes bit . ly / 3WREL7i
• Practical Diabetes : An Update on the Diagnosis and Management of Monogenic Diabetes bit . ly / 4dAI7Rp
References Available on request from howtotreat @ adg . com . au