Understanding MODY and LADA Diabetes: A Clinical Perspective
Explore the nuances of MODY and LADA diabetes, distinguishing them from common types like Type 1 and Type 2. Learn about their diagnostic considerations, clinical presentations, and management strategies through real case scenarios and expert insights.
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Presentation Transcript
MODY and LADA Diagnostic diabetes David Till Monogenic Diabetes Lead, ESHT Clinical Lead, Diabetes and Endocrinology, ESHT
Aims What are MODY and LADA When to think about them ie what does 'normal' diabetes look like, and what should prompt us to think this is different? When not to think about them sometimes we should act first and think later! What helps us consider the diagnosis? Examples of certain types Limitations of where we are What next?
What diabetes do we see normally Type 2 diabetes - 90% Type 1 diabetes 10% Monogenic diabetes represent about 0.2% of all DM (1-3% in under 30s?)
Clinical presentation of type 1 DM SYMPTOMATIC hyperglycaemia Osmotic diuresis symptoms thirst, polyuria, polydipsia Weight loss cardinal feature of absolute insulin deficiency; prompts me to want to start insulin now, and ask questions later Onset is usually over weeks if ignored for long enough, results in DKA Younger age children, adolescents, young adults
Case 1 44 year old male, BMI 25 3 month history of fatigue, nocturia PH Rheumatoid arthritis, FH primary hypothyroidism, vitiligo Random glucose 15, HbA1c 91 Modest weight loss Insulin commenced levemir 0.15 units/kg, rapid acting added shortly after GAD positive type 1/ LADA
LADA Latent Autoimmune Diabetes in Adults Diabetes 1.5 Older age group than type 1, but often normal BMI PH/FH autoimmune disease Slightly slower loss of B-cells, slowed further by early use of insulin
Presentation of type 2 diabetes ASYMPTOMATIC hyperglycaemia but can be symptomatic if ignored for long enough (even DKA) Usually middle-aged, older adults Associated with increased BMI There is often a family history Might be picked up by screening the at risk Often diagnosed at the time of a complication occurring macrovascular disease skin infection etc
MODY Maturity Onset Diabetes of the Young Misleading title; mimicking type 2 diabetes, but at a young age. (except we are seeing type 2 at younger ages now) - plus often labelled as type 1 better replaced with the term 'Monogenic diabetes' Represents a group of genetic conditions, in which glucose metabolism is affected Single gene defects, many AD (autosomal dominant) Generally, represent transcription factors in insulin production, and may lead to loss of B-cell function Represent about 0.2% of all DM (1-3% in under 30s?)
Why is it important to identify them? Genetic defect identification enables recognition of Phenotype and Pathophysiology Allows us to advise on Treatment/ response to treatment/ if treatment is even necessary Likely progression of the condition Risk of passing it on to other family members
Presentation hallmarks of MODY Age <25 Non-obese, so often treated as type 1 - (but they will still make their own insulin, and not have antibodies present) Non-insulin dependent type 1 but 'has holidays from insulin' Strong FH 90% have a parent with diabetes (cf <10% type 1, 50-60% type 2), across 2 or more generations Or labelled type 2, but why would a non-obese young person get type 2 diabetes?
Types of mongenicdiabetes Transcription factor mutations (MODY) Glucose sensor mutations (glucokinase) Syndromic diabetes Neonatal diabetes Insulin resistance syndromes
Transcription factors There is a progressive b-cell loss/ dysfunction HNF 1-alpha commonest form of MODY 2/3 of all cases Young, skinny, usually high sugars often labelled type 1 (is there a strong FH DM?) very sensitive to SU Subsequently may need MF/DPP-4 inhibitors, and basal insulin in later life They are at high risk of CV disease and microvascular complications HNF 4-alpha similar picture, FH, thin young adult, not sensitive to SU Macrosomic babies with postnatal hypoglycamia
Syndromic diabetes Young onset diabetes, but we don't think it's type 1 or type 2 AND Sensorineural deafness (early age, but non-congenital) Optic atrophy Renal cysts, uterine/liver/ pancreatic anatomical abnormalities usually present before the diabetes (HNF-1beta) Developmental delay And young onset diabetes Eg RCAD (renal cysts and diabetes HNF-1beta) Mitochondrial diabetes; a spectrum of conditions; MIDD mitochondrial inherited diabetes and deafness, DIDMOAD etc
Case 2 Female, Age 23 Fasting sugars high, post- prandial always to target no progression through 3rd trimester Slim, BMI 21 FH 'type 2 diabetes' - mum GTT performed (normal <5.5 fasting, <7.8 2 hrs) HbA1c mid 40s Mum, no meds T=0; glucose 6.2 6.2 Baby growth/ liquor volume normal T=120; glucose 7.1
Glucokinase mutation This is not diabetes- it is a glucose sensor disorder There is a higher set point for glucose homeostasis Fasting Plasma glucose runs 5.5-8, not 3.5-5.5, HbA1c 36-58 No risk No risk of microvascular complications no tx or monitoring required - important distinction for travel insurance etc... AD mutation impact on pregnancy depends on foetal inheritance... 'Incidental' finding, hence why found in pregnancy, on OGTT Pick it up a GDM if FPG>5.5, BMI <25 37% chance this is GCK All females age <30, BMI <25, GDM warrant consideration of monogenic 'diabetes'
Genetic causes of insulin resistance What is insulin resistance? (higher in puberty)) Is the patient obese? If yes, this is the cause of their resistance >3units/kg insulin/ day (People with type 1 diabetes need 0.3-1.3units/kg Are they actually taking their insulin? Compliance can be tested with inpatient insulin infusions Check c-peptide - >4000pmol/l - IR likely <200pmol/l - either type 1 + IR, or non-compliance How are their lipids normal? - insulin receptor defect Low HDL, high TG lipodystrophy can you see loss of s/c fat?
Diagnostic tools and decision aids History is key History is key FH NIDDM Age<25 at diagnosis Non-obese Autoantibodies C-peptide Online probability calculator - MODY calculator on the Exeter diabetesgenes.org site After this, consider genetic testing if appropriate This will only account for half We need to think about probabilities
Using the probability calculator Exeter Diabetes App (diabetesgenes.org) Starting point FH, dx age <25, NIDDM, non-obese Always Always - Use this before greatly improves the pick-up rate beforegenetic testing reminds you what questions to ask! And Do not Do not test if age >35 (is there a younger relative with DM) Only validated in Caucasian population before putting another ethnicity through the calculator, add 5 to their age, 5 to their BMI, and see if they still warrant further consideration Consider genetic testing if probability >20%, or >10% if patient is insulin treated
Limitations Using the calculator at diagnosis doesn't work - 'time to insulin' is a key variable Not validated in non-caucasian If diagnosed age>35, calculator is not effective are there younger family members with diabetes to assess preferentially?
Autoantibody panels -GAD65,IA2,ZnT8 HELPFUL IF POSITIVE HELPFUL IF POSITIVE TYPE 1 DIABETES Present before type 1 diabetes is manifest irrespective of age of onset 90% will have at least 1 ab May eventually fade but 80% still positive at 10yrs Not present in MODY 1 +ve abs 1 in 8200 will have MODY 2 +ve abs - <1 in 3,000,000 will be MODY (GAD is seen weakly in up to 15% without DM a higher lab cut-off is used - 99th centile)
C-peptide testing Endogenous insulin is formed from a Pro-peptide C-peptide is cleaved off in production Can be used as marker of body making insulin Measure a non-fasting non-hypoglycaemic - serum/ urine sample Still present at diagnosis of type 1 DM not valid test early on IS eventually lost in type 1 (3-5y post diagnosis). ADA suggests its use 3y post diagnosis Interpreting results is difficult difficult please ask for help HELPFUL IF UNDETECTABLE HELPFUL IF UNDETECTABLE likely type 1 diabetes
Genetic testing Funded on the NHS guidelines on the diabetes genes site, or the national genomic directory Consent is required Should be done in u-25s Once the gene is identified, other family members may be tested
Who to ask for help? Local trust monogenic diabetes lead consultant and DSN (ESHT, me! (David Till), Sarah Jones, Erwin Castro), or any friendly diabetes specialist nurse/ consultant! Call/ email/ ERS/ advice and guidance We feed in to the national diabetes monogenic programme - 7 regions nationally; Genetic diabetes nurse (Justin Veasey Sussex community Trust) Genomic medicine service Alliance lead (Ali Chakera BSUH) Contact Exeter directly they are super-helpful, very prompt to reply
Take homes Don't let this talk stop you treating the patient in front of you symptomatic hyperglycaemia needs glucose lowering therapy, weight loss needs insulin Refer children in whom you suspect diabetes straight to paediatrics LADA is late onset, slow burn type 1 refer to specialist Young thin adults with diabetes probably need referral to specialist either type 1 or MODY
