LADA & MODY DIABETES
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Transcript of LADA & MODY DIABETES
TYPE 1.5 DiabetesTYPE 1.5 DiabetesLADA & MODYLADA & MODY
Dr KURIAN JOSEPHDr KURIAN JOSEPHSMALL TOPIC PRESENTATIONSSMALL TOPIC PRESENTATIONS
MODYMODY
Maturity-Onset Diabetes Maturity-Onset Diabetes of the Young (MODY)of the Young (MODY)
1975 Definition1975 Definition
Type-2 diabetes mellitus in the Type-2 diabetes mellitus in the youngyoung
plus plus
Autosomal dominant inheritanceAutosomal dominant inheritance
Current Definition of Current Definition of MODYMODY
Heterozygous Heterozygous monogenicmonogenic mutations mutations inin
one of the 6 different one of the 6 different genesgenes
Autosomal dominant inheritance Autosomal dominant inheritance Onset of diabetes early in life: Onset of diabetes early in life:
childhood, childhood, adolescence or young adulthoodadolescence or young adulthood
Primary defect in insulin secretionPrimary defect in insulin secretion
Monogenic Forms of Monogenic Forms of DiabetesDiabetes Forms Associated with Forms Associated with Insulin Resistance Insulin Resistance
Forms Associated withForms Associated with Defective Insulin Defective Insulin SecretionSecretion
Maturity-Onset diabetes of the young (MODY) Maturity-Onset diabetes of the young (MODY)
HNF-4HNF-4αα (MODY 1) (MODY 1)
Glucokinase (MODY 2)Glucokinase (MODY 2)
HNF-1HNF-1αα (MODY 3) (MODY 3)
IPF (MODY 4)IPF (MODY 4)
HNF-1HNF-1ββ (MODY 5) (MODY 5)
NeuroD1/BETA2 (MODY 6)NeuroD1/BETA2 (MODY 6)
MODY-Related Proteins MODY-Related Proteins [1/4][1/4]
GlucokinaseGlucokinase Expressed in Expressed in -cells and liver-cells and liver GSK catalyzes the formation of glucose-6-GSK catalyzes the formation of glucose-6-
phosphate from glucose.phosphate from glucose. Beta cells - “Glucose sensor” Control rate of Beta cells - “Glucose sensor” Control rate of
Glucose phosphorylationGlucose phosphorylation Liver – Helps in storage of glucose as Liver – Helps in storage of glucose as
glycogenglycogen Mild stable hyperglycemia Mild stable hyperglycemia Does not respond to Sulfonylureas. Does not respond to Sulfonylureas.
Liver-enriched transcription factors Liver-enriched transcription factors HNF-1 HNF-1, HNF-1, HNF-1, and HNF-4, and HNF-4
Expressed in liver, pancreatic islets, kidneys and Expressed in liver, pancreatic islets, kidneys and genitalia.genitalia.
In Beta cells they regulate In Beta cells they regulate
The expression of the insulin gene The expression of the insulin gene Proteins involved in glucose transport and Proteins involved in glucose transport and metabolism. metabolism.
Mutations results in defect of insulin secretion Mutations results in defect of insulin secretion response to glucose, leading to progressive response to glucose, leading to progressive decline in glycemic control. decline in glycemic control.
MODY 1 &3 responds to sulfonylurea MODY 1 &3 responds to sulfonylurea initially.initially.
MODY-Related Proteins MODY-Related Proteins
Transcription factor IPF-1Transcription factor IPF-1 Expressed in pancreatic isletsExpressed in pancreatic islets Central role in development of Central role in development of
pancreas. pancreas. Mediates glucose-induced Mediates glucose-induced
stimulation of insulin-gene stimulation of insulin-gene transcriptiontranscription
Exocrine pancreatic insufficiency Exocrine pancreatic insufficiency may occur.may occur.
MODY-Related Proteins MODY-Related Proteins
Transcription factor Neuro-D1 Transcription factor Neuro-D1 (BETA2)(BETA2) RareRare Expressed in pancreatic isletsExpressed in pancreatic islets Activates the transcription of the Activates the transcription of the
insulin geneinsulin gene Required for normal development Required for normal development
of the pancreatic isletsof the pancreatic islets
Phenotypic Expression Phenotypic Expression and Natural History of and Natural History of
MODYMODYRecognition at young ageRecognition at young age
1.Mild, asymptomatic increase in blood glucose in 1.Mild, asymptomatic increase in blood glucose in a child, a child, adolescent or young adolescent or young adult(<25 years)adult(<25 years)
2. Prominent family history of diabetes in 2-3 2. Prominent family history of diabetes in 2-3 generationsgenerations
3. Usually not associated with obesity3. Usually not associated with obesity
Not progressive, or slowly progressive Not progressive, or slowly progressive hyperglycemiahyperglycemia Hyperglycemia responsive to diet and/or oral Hyperglycemia responsive to diet and/or oral
anti-hyperglycemic agents for years to decadesanti-hyperglycemic agents for years to decades
When to suspect MODYWhen to suspect MODY a “type 1″ diabetes patient who has negative a “type 1″ diabetes patient who has negative
blood testing for autoantibodies.blood testing for autoantibodies. a “type 1″ diabetes patient who generates a a “type 1″ diabetes patient who generates a
significant amount of insulin for years beyond significant amount of insulin for years beyond diagnosis (detectable blood levels of c-peptide, diagnosis (detectable blood levels of c-peptide, proinsulin, and/ or insulin)proinsulin, and/ or insulin)
a “type 2″ diabetes patient who is normal weight a “type 2″ diabetes patient who is normal weight and shows no signs of insulin resistance.and shows no signs of insulin resistance.
a diabetes with family history of early onset a diabetes with family history of early onset diabetes for 2-3 generations.diabetes for 2-3 generations.
Diabetes paired with pancreatic insufficiency Diabetes paired with pancreatic insufficiency Individual or family history of diabetes paired Individual or family history of diabetes paired
with developmental kidney disease or kidney with developmental kidney disease or kidney cystscysts
Genetic TestingGenetic Testing
Only definitive way to confirm MODYOnly definitive way to confirm MODY blood or saliva blood or saliva Not all mutations cause diabetesNot all mutations cause diabetes Each child will have a 50% chance of Each child will have a 50% chance of
inheriting the gene inheriting the gene 11stst degree relatives have a 50% chance degree relatives have a 50% chance
of carrying the same gene mutationof carrying the same gene mutation Then they have a >95% chance of Then they have a >95% chance of
developing MODY at some time in their developing MODY at some time in their life.life.
Rx for MODYRx for MODY
Rx depends on the involved gene and other factorsRx depends on the involved gene and other factors
MODY 3 and 1 can be treated initially MODY 3 and 1 can be treated initially with with sulfonylureas, prompts the body to sulfonylureas, prompts the body to produce insulin.produce insulin.
Usually GCK-MODY requires no treatment Usually GCK-MODY requires no treatment at all. at all.
Other type of MODY Rx is unclear may Other type of MODY Rx is unclear may require require multiple daily Insulin injections.multiple daily Insulin injections.
LADALADA TYPE 1.5 DIABETESTYPE 1.5 DIABETES
LATENT AUTOIMMUNE LATENT AUTOIMMUNE DIABETES OF ADULTHOODDIABETES OF ADULTHOOD
Late-onset autoimmune diabetes of Late-onset autoimmune diabetes of adulthoodadulthood
Slow Onset Type 1 diabetesSlow Onset Type 1 diabetes Type 1.5 diabetes - Type 1 diabetes Type 1.5 diabetes - Type 1 diabetes
develops in adultsdevelops in adults Mistakenly diagnosed as T2DMMistakenly diagnosed as T2DM
Characteristics of LADACharacteristics of LADA
Adult age (usually over 30 years) at time of Adult age (usually over 30 years) at time of diagnosisdiagnosis
May initially appear to be non-obese Type 2 May initially appear to be non-obese Type 2 diabetesdiabetes
May initially be controlled with nutrition and May initially be controlled with nutrition and exerciseexercise
Patient gradually becomes dependent on insulinPatient gradually becomes dependent on insulin Positive for auto-antibodiesPositive for auto-antibodies Low C-peptide levels in the bodyLow C-peptide levels in the body Often does not have a family history of Type 2 Often does not have a family history of Type 2
diabetesdiabetes
Criteria for LADACriteria for LADA
I.I. Aged at least 30 years or olderAged at least 30 years or older
II.II. Positive for at least one of the auto-Positive for at least one of the auto-antibodies found in type 1 diabetes antibodies found in type 1 diabetes
III.III. Free from insulin treatment for the Free from insulin treatment for the first six months after diagnosis.first six months after diagnosis.
IV.IV. 20% of persons diagnosed as 20% of persons diagnosed as having non-obesity-related type 2 having non-obesity-related type 2 diabetes may actually have LADAdiabetes may actually have LADA
LADA Vs T2DMLADA Vs T2DM C-peptid levelsC-peptid levels
LADA have low level VS Normal or high in LADA have low level VS Normal or high in T2DMT2DM
Glutamic acid decarboxylase(GAD) Glutamic acid decarboxylase(GAD) autoantibodies – autoantibodies – Common in T1DMCommon in T1DM
Early age of onsetEarly age of onset Non obese individuals Non obese individuals No family history of early onset diabetesNo family history of early onset diabetes Ketosis prone Ketosis prone May requires insulin after initial 6 monthsMay requires insulin after initial 6 months
DiagnosisDiagnosis
Performing a GAD antibody test is Performing a GAD antibody test is the most common method of the most common method of diagnosing LADA. diagnosing LADA.
Islet cell antibodies (ICA) are also Islet cell antibodies (ICA) are also common.common.
ManagementManagement LADA often does not require insulin at the LADA often does not require insulin at the
time of diagnosis and may be managed time of diagnosis and may be managed with diet and exercise.with diet and exercise.
Due to destruction of the β-cells, they Due to destruction of the β-cells, they become insulin dependent more rapidly become insulin dependent more rapidly than “classic” type 2 diabetesthan “classic” type 2 diabetes
May require multiple daily Insulin May require multiple daily Insulin injections(after 6 months)injections(after 6 months)
Thank youThank you
Monogenic Forms of Monogenic Forms of DiabetesDiabetes Forms Associated with Insulin Resistance Forms Associated with Insulin Resistance
Mutation in the insulin receptor geneMutation in the insulin receptor gene
Type A insulin resistanceType A insulin resistance
LeprechaunismLeprechaunism
Rabson-Mendenhall SyndromeRabson-Mendenhall Syndrome Lipoatrophic diabetesLipoatrophic diabetes Mutations in the PPARMutations in the PPARγγ gene gene
Forms Associated with Defective Insulin Forms Associated with Defective Insulin SecretionSecretion
Mutations in insulin or proinsulin genesMutations in insulin or proinsulin genes
Mitochondrial gene mutationsMitochondrial gene mutations
Muturity-Onset diabetes of the young (MODY) Muturity-Onset diabetes of the young (MODY)
MODY MODY
Associated with Defective Insulin SecretionAssociated with Defective Insulin Secretion
HNF-4HNF-4αα (MODY 1) (MODY 1) Glucokinase (MODY 2)Glucokinase (MODY 2) HNF-1HNF-1αα (MODY 3) (MODY 3) IPF (MODY 4)IPF (MODY 4) HNF-1HNF-1ββ (MODY 5) (MODY 5) NeuroD1/BETA2 (MODY 6)NeuroD1/BETA2 (MODY 6)
MODY Vs T2DMMODY Vs T2DM
Mode of inheritanceMode of inheritance MODY: Monogenic, autosomal dominantMODY: Monogenic, autosomal dominant DM2: PolygenicDM2: Polygenic
Age of onsetAge of onset MODY: Childhood, adolescence, MODY: Childhood, adolescence, usually <25 usually <25
yearsyears DM2: Usually 40-60 years; DM2: Usually 40-60 years;
occasionally in obese adolescentsoccasionally in obese adolescents PedigreePedigree
MODY: Multi-generationalMODY: Multi-generational DM2: Rarely multi-generationalDM2: Rarely multi-generational
Distinguishing Clinical Characteristics Distinguishing Clinical Characteristics ofof
MODY and Type 2 DiabetesMODY and Type 2 Diabetes [2/2][2/2] PenetrancePenetrance
MODY: 80-95 %MODY: 80-95 % DM2: Variable (10-40 %)DM2: Variable (10-40 %)
Body habitusBody habitus MODY: Not obeseMODY: Not obese DM2: Usually obeseDM2: Usually obese
Dysmetabolic syndromeDysmetabolic syndrome MODY: AbsentMODY: Absent DM2: Usually presentDM2: Usually present
InvestigationsInvestigations
MODY should be considered in MODY should be considered in patients with 1.non-ketotic diabetes patients with 1.non-ketotic diabetes at presentationat presentation
2. Strong family history of diabetes 2. Strong family history of diabetes mellitus without pancreatic auto-mellitus without pancreatic auto-antibodies. antibodies.
MODY Vs T2DMMODY Vs T2DM
hyperinsulinaemia and high-normal c-hyperinsulinaemia and high-normal c-peptide in T2DMpeptide in T2DM
MODY vs T2DMMODY vs T2DM
Prominent family history of diabetes Prominent family history of diabetes in 2-3 generations in 2-3 generations
Childhood, adolescence, usually Childhood, adolescence, usually <25 years<25 years
Usually not associated with obesityUsually not associated with obesity