MATURITY ONSET DIABETES OF THE YOUNG - 3

VARSHIL MEHTAINT. ROTATING M4

STUDENT

OBJECTIVES

• DEFINITION• BACKGROUND• CLASSIFICATION• MODY TYPE 3

HISTORY• ELLIOT JOSLIN OBSERVED BEFORE THE DISCOVERY OF INSULIN THAT SOME

YOUNG PATIENTS WITH DIABETES AND A STRONG FAMILY HISTORY OF THE CONDITION SURVIVED MUCH LONGER THAN EXPECTED.

• SIMILAR CLINICAL REPORTS MAY BE TRACED IN THE SUBSEQUENT LITERATURE, BUT THE HISTORY OF MODY REALLY BEGAN IN 1974 WHEN TATTERSALL AND PYKE DESCRIBED THREE FAMILIES WITH EARLY ONSET DIABETES TRANSMITTED AS AN AUTOSOMAL DOMINANT TRAIT, RESPONSIVE TO SULPHONYLUREAS, AND WITH A RELATIVELY BENIGN PROGNOSIS.

• FAJANS HAD INDEPENDENTLY DESCRIBED A GROUP OF PATIENTS DIAGNOSED WITH DIABETES UNDER THE AGE 25 YEARS WHO HAD NOT PROGRESSED TO INSULIN AFTER MANY YEARS ON SULPHONYLUREAS.

• TATTERSALL AND FAJANS JOINED FORCES TO COIN THE SOMEWHAT UNFORTUNATE TERM MATURITY ONSET DIABETES OF THE YOUNG (MODY), WHICH THEY DEFINED AS 'FASTING HYPERGLYCAEMIA DIAGNOSED UNDER AGE 25 WHICH COULD BE TREATED WITHOUT INSULIN FOR MORE THAN TWO YEARS'.

4

• MATURITY ONSET DIABETES OF THE YOUNG (MODY) IS A CLINICALLY GROUP OF HETEROGENEOUS DISORDER CHARACTERIZED BY NON-INSULIN DEPENDENT DIABETES DIAGNOSED AT A YOUNG AGE (<25 YEARS) WITH AUTOSOMAL DOMINANT TRANSMISSION AND LACK OF AUTOANTIBODIES

DEFINITION-MODY

• EARLY ONSET DIABETES (<25 years)• NON-INSULIN DEPENDENT • AUTOSOMAL DOMINANT INHERITANCE • CAUSED BY A SINGLE GENE DEFECT ALTERING BETA

CELL FUNCTION • OBESITY UNUSUAL• PRIMARY DEFECT IN INSULIN SECRETION

BACKGROUND

CLASSIFICATION

MATURITY ONSET DIABETES OF THE YOUNG - 3

• COMMONEST CAUSE OF MODY

• MAY BE MISDIAGNOSED AS TYPE 1

• TYPICALLY DEVELOPS BEFORE 25 YEARS

• FBG MAYBE NORMAL INITIALLY

• LARGE RISE (>5MMOL/L) IN OGTTWORSENING GLYCAEMIA WITH AGE

• LOW RENAL THRESHOLD (GLYCOSURIA)

• NOT OBESE (USUALLY)• PARENTS AND

GRANDPARENTS USUALLY DIABETIC

INTRODUCTION

• HNF1 HOMEOBOX A (HEPATOCYTE NUCLEAR FACTOR 1 HOMEOBOX A), ALSO KNOWN AS HNF1A, IS A HUMAN GENE WHICH IS LOCATED ON CHROMOSOME 12Q24.2

• THE PROTEIN ENCODED BY THIS GENE IS A TRANSCRIPTION FACTOR THAT IS HIGHLY EXPRESSED IN THE PANCREAS.

• IT REGULATES EXPRESSION OF THE INSULIN GENE AND OTHER GENES ENCODING PROTEINS INVOLVED IN GLUCOSE TRANSPORT AND METABOLISM.

• HNF1 A MUTATIONS MAY CONTRIBUTE TO ABNORMAL PANCREATIC ISLET CELL DEVELOPMENT DURING FETAL LIFE, AS WELL AS IMPAIRED TRANSCRIPTIONAL REGULATION OF GENES INVOLVED IN NORMAL ISLET CELL FUNCTION

• ITS MUTATIONS ALSO INFLUENCE EXPRESSION OF HNF4A(MODY1). THIS SUGGESTS THAT THE MODY TRANSCRIPTION FACTORS FORM A REGULATOR NETWORK THAT IS NECESSARY TO MAINTAIN GLUCOSE HOMOSTASIS.

HNF1A

PATHOPHYSIOLOGY• MODY3 is caused by mutation in the hepatic transcription factor-

1 gene (TCF1) on chromosome 12q24.2.

CLINICAL PRESENTATION• MILD TO MODERATE HYPERGLYCEMIA (TYPICALLY 130–250 MG/DL, OR 7–

14 MMOL/L) DISCOVERED BEFORE 25 YEARS OF AGE. HOWEVER, ANYONE UNDER 50 CAN DEVELOP MODY.

• A FIRST-DEGREE RELATIVE WITH A SIMILAR DEGREE OF DIABETES.

• USUAL DIABETIC SYMPTOMS LIKE POLYUREA, POLYDYPSIA & POLYPHAGIA.

• ABSENCE OF POSITIVE ANTIBODIES OR OTHER AUTOIMMUNITY (E.G., THYROIDITIS) IN PATIENT AND FAMILY.

• PERSISTENCE OF A LOW INSULIN REQUIREMENT (E.G., LESS THAN 0.5 U/KG/DAY) PAST THE USUAL "HONEYMOON" PERIOD.

• ABSENCE OF OBESITY (ALTHOUGH OVERWEIGHT OR OBESE PEOPLE CAN GET MODY) OR METABOLIC SYNDROME (E.G.,HYPERTENSION, HYPERLIPIDEMIA, POLYCYSTIC OVARY SYNDROME).

• INSULIN RESISTANCE VERY RARELY HAPPENS.• CYSTIC KIDNEY DISEASE IN PATIENT OR CLOSE RELATIVES.• ON-TRANSIENT NEONATAL DIABETES, OR APPARENT TYPE 1

DIABETES WITH ONSET BEFORE SIX MONTHS OF AGE.• LIVER ADENOMA OR HEPATOCELLULAR CARCINOMA IN MODY TYPE 3• THE DIAGNOSIS OF MODY IS CONFIRMED BY SPECIFIC GENE TESTING

AVAILABLE THROUGH COMMERCIAL LABORATORIES.

CLINICAL PRESENTATION

• THE MAJORITY OF PATIENTS WITH GENETICALLY PROVEN MONOGENIC DIABETES ARE INITIALLY INCORRECTLY DIAGNOSED AS TYPE 1 OR TYPE 2 DIABETES.

• IT IS IMPORTANT TO CORRECTLY DIAGNOSE MONOGENIC DIABETES AS IT CAN PREDICT THE CLINICAL COURSE OF THE PATIENT, EXPLAIN OTHER ASSOCIATED CLINICAL FEATURES AND MOST IMPORTANTLY GUIDE THE MOST APPROPRIATE TREATMENT.

• IN ADDITION, MAKING A DIAGNOSIS WILL HAVE IMPLICATIONS FOR OTHER FAMILY MEMBERS OFTEN CORRECTING THE DIAGNOSIS AND TREATMENT FOR OTHER DIABETIC FAMILY MEMBERS AS WELL AS ALLOWING APPROPRIATE GENETIC COUNSELING

WHY DIAGNOSE MODY?

Diabetes in Young Adults (15-30 years)

Age of diagnosis 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

Type 2

Type 1

MODY

MIDD

• FEATURES IN CHILDREN INITIALLY THOUGHT TO HAVE TYPE 1 DIABETES THAT SHOULD SUGGEST A POSSIBLE DIAGNOSIS OF MONOGENIC DIABETES ARE SHOWN BELOW. NONE OF THESE ARE ABSOLUTE AND SHOULD BE CONSIDERED AS TOGETHER RATHER THAN IN ISOLATION(C) 3. THE APPROXIMATE PERCENTAGE OF PATIENTS WITH TYPE 1 DIABETES IS GIVEN IN BRACKETS

• A DIAGNOSIS OF DIABETES BEFORE 6 MONTHS (B) (<1% TYPE 1 IAFUSCO, 2002 #2514 )

• FAMILY HISTORY OF DIABETES WITH A PARENT AFFECTED (C) (2-4%4)

WHEN TO SUSPECT A DIAGNOSIS OF TYPE 1 DIABETES IN CHILDREN MAY NOT BE CORRECT?

• EVIDENCE OF ENDOGENOUS INSULIN PRODUCTION OUTSIDE THE ‘HONEYMOON’ PHASE (AFTER 3 YEARS OF DIABETES) WITH DETECTABLE C PEPTIDE (>200NMOL/L) WHEN GLUCOSE > 8 MMOL/L. (1-5% TYPE 1).

• WHEN PANCREATIC ISLET AUTOANTIBODIES ARE ABSENT, ESPECIALLY IF MEASURED AT DIAGNOSIS (3-30% TYPE 1 PATIENTS.

WHEN TO SUSPECT A DIAGNOSIS OF TYPE 1 DIABETES IN CHILDREN MAY NOT BE CORRECT?

WHEN TO SUSPECT A DIAGNOSIS OF TYPE 2 DIABETES IN CHILDREN MAY NOT BE CORRECT?

• NOT MARKEDLY OBESE OR DIABETIC FAMILY MEMBERS WHO ARE NORMAL WEIGHT (20%)

• ACANTHOSIS NIGRICANS NOT DETECTED (10%)

• ETHNIC BACKGROUND FROM A LOW PREVALENCE TYPE 2 DIABETES RACE E.G. EUROPEAN CAUCASIAN (0-45%)

• NO EVIDENCE OF INSULIN RESISTANCE WITH FASTING C PEPTIDE WITHIN THE NORMAL RANGE (0-20%8-11)

1. CLINICAL BASIS2. GENETIC TESTING3. NON GENETIC TESTING

DIAGNOSIS

Tattersall (QJM 1974)

• Early-onset diabetes

• Not insulin-dependent diabetes

• Autosomal dominant inheritanceCaused by a single gene defect altering beta-cell function, obesity unusual

Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members

Must be diabetes in one parent (2 generations) and ideally a grandparent or child ( 3 generations)

ON CLINICAL BASIS

Off insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis

WHEN THERE IS A HIGH INDEX OF SUSPICION I.E.1. FAMILIAL DIABETES WITH AUTOSOMAL DOMINANT PATTERN OF

INHERITANCE (>2 GENERATIONS), 2. ONSET <25 YEARS, 3. NON-OBESE, 4. NEGATIVE ISLET AUTOANTIBODIES

GENETIC TESTING

MODY

Variable

Not present

Usually detectable

(0-1 nmol/l)

normal (HDL>1.2 MODY3)

Type 1

Variable

>95% diagnosis

not

measurable > 3-5 years

(<0.33nmol/l)

normal

Glycaemia

Autoantibodies ICA, IA2 or GAD

C peptide

Lipids

Type 2Variable

unusual

detectable

may be high(>1nmol/l)

HDL low TG high

NON GENETIC TESTING

Diagnostic Testing : why do it?HNF1a:very sensitive to sulphonylureas

4

6

8

10

12

8 9 10 11 12 13

Glibenclamide stopped Metformin started

Glibenclamide started Metformin stopped

HbA1c(%)

Years since diagnosis(Pearson et al Diab Med 2000)

• RECENT WORK DONE BY TIM J, MCDONALD… SHOWED THAT HIGH SENSITIVITY C-REACTIVITY LEVELS ARE LOWER IN HNFA1 THAN TYPE 1, TYPE 2 SIABETES OR GLUCOKINASE (GCK) – MODY (DIABETES CARE JOURNAL)

• METHOD : HS-CRP LEVELS WERE ASSESSED IN 750 PATIENTS (220 HNF1A, 245 GCK, 54 HNF4A, 21 HNF1B, 53 TYPE 1 AND 157 TYPE 2 DIABETES.

• RESULTS : HS-CRP WAS LOWER IN HNF1A-MODY (MEDIAN 0.3 [0.1-0.6]) THAN TYPE 2 DIABETES ( MEDIAN 1.40 [ 0.60-3.45] MG/L) THAN TYPE 1 (1.10 [0.50-1.85] MG/DL) THAN HNF1B-MODY (0.60 [0.10-2.8] MG/DL) THAN GCK-MODY(0.60 [0.30-1.8]MG/DL)

• CONCLUSION: HS-CRP LEVELS ARE LOWER IN HNF1A-MODY THAN OTHER FORMS OF DIABETES AND MAY BE USED A S A BIOMARKER TO SELECT PATIENTS FOR DIAGNOSTIC HNF1A GENETIC TESTING.

HIGH SENSITIVE CRP

• RECENT WORK DONE S. A. MUGHAL, R. PARK… SHOWED THAT SERUM APOM LEVELS ARE LOWER IN HNFA1 THAN TYPE 1. (DIABETES MED JOURNAL)

• METHOD : APO M LEVELS WERE ASSESSED IN 69 HNF1A, 50 TYPE 1, 120 TYPE 2 DIABETES AND 100 HEALTHY CONTROL.

• RESULTS : MEAN SERUM APO M CONCENTRATION WAS SIGNIFICANTLY LOWER FOR SUBJECTS WITH HNF1A-MODY [0.86(0.29)] THAN THOSE WITH TYPE 1 AND CONTROL SUBJECTS [1.34(0.22)

• CONCLUSION: APO M LEVELS ARE LOWER IN HNF1A-MODY THAN IN CONTROLS. ALSO IT PROVIDES A GOOD DISCRIMINATION BETWEEN HNF1A MODY AND TYPE 1 DIABETIC PATIENTS.

APOLIPOPROTEIN M

• USE BOTH DIAGNOSTIC CRITERIA AND CLINICAL INFORMATION AND NON-GENETIC INVESTIGATION TO SUGGEST A DIAGNOSIS

• GENETIC TESTING MAKES DIAGNOSIS : DEFINES MODY, DEFINES SUBTYPE HELPS WITH COUNSELLING, PROGNOSIS AND TREATMENT

• BUT ….EXPENSIVE - ONLY DO IF ALTER MANAGEMENT

• TEST ORDERED GUIDED BY CLINICAL CRITERIA AS TO LIKELY GENE.

DISCUSS EACH CASE BEFORE TESTING

DIAGNOSIS CONCLUSION

MANAGEMENT• Unfortunately, chronic hyperglycemia of any cause can

eventually cause blood vessel damage and the microvascular complications of diabetes.

• The principal treatment goals for people with MODY — keeping the blood sugars as close to normal as possible ("good glycemic control"), while minimizing other vascular risk factors — are the same for all known forms of diabetes.

PRIMARY MANAGEMENT• PATIENTS WITH HNF-1a GENE MUTATIONS CAN INITIALLY BE TREATED WITH

DIET AND EXERCISE ALTHOUGH THEY WILL HAVE MARKED POST PRANDIAL HYPERGLYCAEMIA HIGH CARBOHYDRATE FOOD AS THE BETA-CELL DEFECT RESULTS IN INSUFFICIENT INCREASE IN INSULIN SECRETION WITH HYPERGLYCAEMIA.

• MOST PATIENTS WILL NEED PHARMACOLOGICAL TREATMENT AS THEY SHOW PROGRESSIVE DETERIORATION IN GLYCAEMIC CONTROL THROUGHOUT LIFE AND ARE AT RISK OF CONSIDERABLE MICRO-VASCULAR AND MACRO-VASCULAR COMPLICATIONS.

• THE CURRENT INTERNATIONAL SOCIETY FOR PEDIATRIC AND ADOLESCENT DIABETES/INTERNATIONAL DIABETES FEDERATION (ISPAD/IDF) GUIDELINES PUBLISHED IN 2009 SUGGEST SWITCHING PATIENTS WITH PROFEN HNF1A MUTATION (HNF1A–MODY) FROM INSULIN TO SULFONYLUREA.

• DESPITE THIS, 40% OF HNF1A PATIENTS WITH PAEDIATRIC AND ADOLESCENT-ONSET DIABETES CONTINUED TO RECEIVE INSULIN TREATMENT.

• INSULIN TREATMENT WAS ASSOCIATED WITH HIGHER HBA1C AND A HIGHER RISK OF HYPOGLYCAEMIA.

1. SULPHONYLYUREAS• THE FIRST TREATMENT TO BE USED IN CHILDREN WHO ARE NOT

CONTROLLED ON INSULIN SHOULD BE LOW DOSE SULPHONYLUREAS WHICH RESULTS IN A 4 FOLD GREATER LOWERING OF GLUCOSE THAN METFORMIN.

• THESE PATIENTS ARE EXTREMELY SENSITIVE TO SULPHONYLUREAS AND AS LONG AS THEY DO NOT HAVE PROBLEMS WITH HYPOGLYCAEMIA CAN BE MAINTAINED ON THESE FOR MANY DECADES .

• GLYCAEMIC CONTROL IN SULPHONYLUREAS IS OFTEN BETTER THAN THAT ACHIEVED ON INSULIN ESPECIALLY IN CHILDREN AND YOUNG ADULTS.

• THE DOSE OF SULPHONYLUREAS SHOULD INITIALLY BE LOW (¼ - OF THE NORMAL STARTING DOSE IN ADULTS) TO AVOID HYPOGLYCAEMIA .

• IF THERE IS HYPOGLYCAEMIA DESPITE DOSE TITRATION OF A ONCE OR TWICE DAILY SULPHONYLUREA PREPARATION SUCH AS GLICLAZIDE A SLOW RELEASE PREPARATION OR MEAL TIME DOSES WITH A SHORT ACTING AGENTS LIKE NATEGLINIDE MAY BE CONSIDERED.

PHARMACOLOGICAL RX

2. MEGLITINIDE ANALOGUES

• MARIANNE BECKER, ANGELA GALLER AND KLEMENS RAILE HAD PUBLISHED CASE REPORTS SUGGESTING THAT MEGLITINIDES CAN BE USED AS SINGLE OR COMBINED BASED THERAPY FOR MODY 3 PATIENTS.

• The Hba1c with the use of meglitinide was 51 mmol/mol , 6.8% whereas with insulin was 58 mmol/mol, 7.5%.

• In combination with Insulin Hba1c was 55 mmol/ml and 7.2%

PHARMACOLOGICAL RX

3. GLUCAGON LIKE PEPTIDE – 1 RECEPTOR AGONIST THERAPY

• Maricor, Charles, Christine, kevin published a Case study report of three patients saying that GLP-1 receptor agonist therapy may be of value in managing glycemia in patients with MODY 3

• In all 3 patients C-peptide levels went 3-fold after 3 days of liraglutide.• They also experienced significant weight loss (10-15%)• Hb1ac was 7.4%, 6.4 % and 6.8 % respectively.• With the help of GLP 1, they were able to discontinue Insulin.

1. UPTODATE2. YAMAGATA, K; ODA, N; KAISAKI, PJ; MENZEL, S; FURUTA, H; VAXILLAIRE, M;

SOUTHAM, L; COX, RD; LATHROP, GM; BORIRAJ, VV; CHEN, XN; COX, NJ; ODA, Y; YANO, H; LEBEAU, MM; YAMADA, S; NISHIGORI, H; TAKEDA, J; FAJANS, SS; HATTERSLEY, AT; IWASAKI, N; HANSEN, T; PEDERSEN, O; POLONSKY, KS; TURNER, RC; VELHO, G; CHEVRE, JC; FROGUEL, P; BELL, GI. (1996) "MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1 ALPHA GENE IN MATURITY-ONSET DIABETES OF THE YOUNG (MODY3)." NATURE 384(6608): 455-458.

3. MARIANNE BECKER, MD, ANGELA GALLER, MD, AND KLEMENS RAILE, MD “MEGLITINIDE ANALOGUES IN ADOLESCENT PATIENTS WITH HNF1A-MODY (MODY 3)” PEDIATRICS VOLUME NO. 133 NO.3 MARCH 1, 2014. PP. E775-E779

4. MCDONALD TJ, SHIELDS BM, LAWRY J, ET AL. HIGH-SENSITIVITY CRP DISCRIMINATES HNF1A-MODY FROM OTHER SUBTYPES OF DIABETES. DIABETES CARE2011;34(8):1860-1862. DOI:10.2337/DC11-0323.

REFERENCES