LADA & MODY DIABETES
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LADA & MODY DIABETES

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LADA & MODY DIABETES LADA & MODY DIABETES Presentation Transcript

  • TYPE 1.5 Diabetes LADA & MODY Dr KURIAN JOSEPH SMALL TOPIC PRESENTATIONS
    • MODY
  • Maturity-Onset Diabetes of the Young (MODY) 1975 Definition
    • Type-2 diabetes mellitus in the young plus
    • Autosomal dominant inheritance
  • Current Definition of MODY
    • Heterozygous monogenic mutations in
    • one of the 6 different genes
    • Autosomal dominant inheritance
    • Onset of diabetes early in life: childhood, adolescence or young adulthood
    • Primary defect in insulin secretion
  • Monogenic Forms of Diabetes
    • Forms Associated with Insulin Resistance
    • Forms Associated with Defective Insulin Secretion
    • Maturity-Onset diabetes of the young (MODY)
    • HNF-4 α (MODY 1)
    • Glucokinase (MODY 2)
    • HNF-1 α (MODY 3)
    • IPF (MODY 4)
    • HNF-1 β (MODY 5)
    • NeuroD1/BETA2 (MODY 6)
  •  
  • MODY-Related Proteins [1/4]
    • Glucokinase
      • Expressed in  -cells and liver
      • GSK catalyzes the formation of glucose-6-phosphate from glucose.
      • Beta cells - “Glucose sensor” Control rate of Glucose phosphorylation
      • Liver – Helps in storage of glucose as glycogen
      • Mild stable hyperglycemia
      • Does not respond to Sulfonylureas.
    • Liver-enriched transcription factors HNF-1  , HNF-1  , and HNF-4 
      • Expressed in liver, pancreatic islets, kidneys and genitalia.
      • In Beta cells they regulate
      • The expression of the insulin gene Proteins involved in glucose transport and metabolism.
      • Mutations results in defect of insulin secretion response to glucose, leading to progressive decline in glycemic control.
      • MODY 1 &3 responds to sulfonylurea initially.
  • MODY-Related Proteins
    • Transcription factor IPF-1
      • Expressed in pancreatic islets
      • Central role in development of pancreas.
      • Mediates glucose-induced stimulation of insulin-gene transcription
      • Exocrine pancreatic insufficiency may occur.
  • MODY-Related Proteins
    • Transcription factor Neuro-D1 (BETA2)
      • Rare
      • Expressed in pancreatic islets
      • Activates the transcription of the insulin gene
      • Required for normal development of the pancreatic islets
  • Phenotypic Expression and Natural History of MODY
    • Recognition at young age
      • 1.Mild, asymptomatic increase in blood glucose in a child, adolescent or young adult(<25 years)
    • 2. Prominent family history of diabetes in 2-3 generations
    • 3. Usually not associated with obesity
    • Not progressive, or slowly progressive hyperglycemia
      • Hyperglycemia responsive to diet and/or oral anti-hyperglycemic agents for years to decades
    • When to suspect MODY
    • a “type 1″ diabetes patient who has negative blood testing for autoantibodies.
    • a “type 1″ diabetes patient who generates a significant amount of insulin for years beyond diagnosis (detectable blood levels of c-peptide, proinsulin, and/ or insulin)
    • a “type 2″ diabetes patient who is normal weight and shows no signs of insulin resistance.
    • a diabetes with family history of early onset diabetes for 2-3 generations.
    • Diabetes paired with pancreatic insufficiency 
    • Individual or family history of diabetes paired with developmental kidney disease or kidney cysts
  • Genetic Testing
    • Only definitive way to confirm MODY
    •   blood or saliva 
    • Not all mutations cause diabetes
    • Each child will have a 50% chance of inheriting the gene 
    • 1 st degree relatives have a 50% chance of carrying the same gene mutation
    • Then they have  a >95% chance of developing MODY at some time in their life.
  • Rx for MODY
    • Rx depends on the involved gene and other factors
    • MODY 3 and 1 can be treated initially with sulfonylureas, prompts the body to produce insulin.
    • Usually GCK-MODY requires no treatment at all.
    • Other type of MODY Rx is unclear may require multiple daily Insulin injections.
    • LADA
    • TYPE 1.5 DIABETES
  • LATENT AUTOIMMUNE DIABETES OF ADULTHOOD
    • Late-onset autoimmune diabetes of adulthood
    • Slow Onset Type 1 diabetes
    • Type 1.5 diabetes - Type 1 diabetes develops in adults
    • Mistakenly diagnosed as T2DM
  • Characteristics of LADA
    • Adult age (usually over 30 years) at time of diagnosis
    • May initially appear to be non-obese Type 2 diabetes
    • May initially be controlled with nutrition and exercise
    • Patient gradually becomes dependent on insulin
    • Positive for auto-antibodies
    • Low C-peptide levels in the body
    • Often does not have a family history of Type 2 diabetes
  • Criteria for LADA
    • Aged at least 30 years or older
    • Positive for at least one of the auto-antibodies found in type 1 diabetes
    • Free from insulin treatment for the first six months after diagnosis.
    • 20% of persons diagnosed as having non-obesity-related type 2 diabetes may actually have LADA
  • LADA Vs T2DM
    • C-peptid levels
    • LADA have low level VS Normal or high in T2DM
    • Glutamic acid decarboxylase(GAD) autoantibodies – Common in T1DM
    • Early age of onset
    • Non obese individuals
    • No family history of early onset diabetes
    • Ketosis prone
    • May requires insulin after initial 6 months
  • Diagnosis
    • Performing a GAD antibody test is the most common method of diagnosing LADA.
    • Islet cell antibodies (ICA) are also common.
  • Management
    • LADA often does not require insulin at the time of diagnosis and may be managed with diet and exercise.
    •   Due to destruction of the β-cells, they become insulin dependent more rapidly than “classic” type 2 diabetes
    • May require multiple daily Insulin injections(after 6 months)
    • Thank you
  •  
  • Monogenic Forms of Diabetes
    • Forms Associated with Insulin Resistance
        • Mutation in the insulin receptor gene
        • Type A insulin resistance
        • Leprechaunism
        • Rabson-Mendenhall Syndrome
        • Lipoatrophic diabetes
        • Mutations in the PPAR γ gene
    • Forms Associated with Defective Insulin Secretion
    • Mutations in insulin or proinsulin genes
    • Mitochondrial gene mutations
    • Muturity-Onset diabetes of the young (MODY)
  • MODY
    • Associated with Defective Insulin Secretion
    • HNF-4 α (MODY 1)
    • Glucokinase (MODY 2)
    • HNF-1 α (MODY 3)
    • IPF (MODY 4)
    • HNF-1 β (MODY 5)
    • NeuroD1/BETA2 (MODY 6)
  • MODY Vs T2DM
    • Mode of inheritance
      • MODY: Monogenic, autosomal dominant
      • DM2: Polygenic
    • Age of onset
      • MODY: Childhood, adolescence, usually <25 years
      • DM2: Usually 40-60 years; occasionally in obese adolescents
    • Pedigree
      • MODY: Multi-generational
      • DM2: Rarely multi-generational
  • Distinguishing Clinical Characteristics of MODY and Type 2 Diabetes [2/2]
    • Penetrance
      • MODY: 80-95 %
      • DM2: Variable (10-40 %)
    • Body habitus
      • MODY: Not obese
      • DM2: Usually obese
    • Dysmetabolic syndrome
      • MODY: Absent
      • DM2: Usually present
  •  
  • Investigations
    • MODY should be considered in patients with 1.non-ketotic diabetes at presentation
    • 2. Strong family history of diabetes mellitus without pancreatic auto-antibodies.
    • MODY Vs T2DM
    •   hyperinsulinaemia and high-normal c-peptide in T2DM
  • MODY vs T2DM
    • Prominent family history of diabetes in 2-3 generations
    • Childhood, adolescence, usually <25 years
    • Usually not associated with obesity