LADA & MODY DIABETES

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TYPE 1.5 Diabetes TYPE 1.5 Diabetes LADA & MODY LADA & MODY Dr KURIAN JOSEPH Dr KURIAN JOSEPH SMALL TOPIC PRESENTATIONS SMALL TOPIC PRESENTATIONS

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Transcript of LADA & MODY DIABETES

Page 1: LADA & MODY DIABETES

TYPE 1.5 DiabetesTYPE 1.5 DiabetesLADA & MODYLADA & MODY

Dr KURIAN JOSEPHDr KURIAN JOSEPHSMALL TOPIC PRESENTATIONSSMALL TOPIC PRESENTATIONS

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MODYMODY

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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

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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

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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)

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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.

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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.

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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.

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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

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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

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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

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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.

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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.

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LADALADA TYPE 1.5 DIABETESTYPE 1.5 DIABETES

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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

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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

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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

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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

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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.

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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)

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Thank youThank you

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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)

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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)

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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

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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

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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

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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