Published on

Published in: Health & Medicine
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide


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