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Diabetes

Diabetes. What is it?. Prevalence of Diabetes. 15.7 million people (5.9% of pop) 10.3 diagnosed 5.4 undiagnosed New cases per year: 798,000 Data from CDC. Types of Diabetes. Type 1 Aka insulin dependent or juvenile onset 5-10% of all diabetes cases Risk factors unclear, but include

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Diabetes

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  1. Diabetes What is it?

  2. Prevalence of Diabetes • 15.7 million people (5.9% of pop) • 10.3 diagnosed • 5.4 undiagnosed • New cases per year: 798,000 Data from CDC

  3. Types of Diabetes • Type 1 • Aka insulin dependent or juvenile onset • 5-10% of all diabetes cases • Risk factors unclear, but include • Autoimmune • Genetic • Environmental factors

  4. Types of Diabetes • Type 2 diabetes • Aka non-insulin dependent (a misnomer) or adult onset • 90-95% of all cases • Risk factors include • Age • Obesity • Family history • Prior history of gestational diabetes • Impaired glucose tolerance • Physical inactivity • Race/ethnicity • African American, Hispanic/Latino Americans, American Indians, Asian Americans/Pacific Islanders

  5. Types of Diabetes • Gestational diabetes • 2-5% of pregnancies • Linked with • Race/ethnicity • Obesity • Family history • Perhaps 40% of women with GD develop Type 2 • “Other specific types”—1-2% of diabetes • Other diseases • Drugs • Surgery • Malnutrition • Infections

  6. Complications of Diabetes • 2-4 x increase in heart disease • 2-4 x increase in strokes • 60-65% have high blood pressure • Leading cause of blindness in adults 20-74 yrs. • 12-24,000 new case/year • Primary cause of kidney disease

  7. Complications of Diabetes • 60-70% of diabetics have nervous system damage • Impaired sensation/pain in hands/feet • Slowed digestion • Carpal tunnel syndrome • >50% of lower limb amputations are diabetics

  8. Complications of Diabetes • Periodontal disease • Complications of pregnancy • Coma • General increase in disease susceptibility

  9. Cost • $98 billion (1997) • $44 billion in direct medical costs • $54 billion in indirect cost

  10. Treatment • Type 1 • Diet • Exercise • Glucose testing/insulin injection • Type 2 • Diet • Exercise • Glucose testing • Oral medication • Insulin injection

  11. Causes • Type 1 • Loss of pancreatic beta cells • Little or no insulin • Type 2 • May have very high insulin levels • Failure to respond to insulin • Insulin receptors • Glucose transporters • Failure to secret sufficient insulin

  12. Our Questions: • How does the pancreas sense glucose levels and secret insulin? • Metabolic coupling • Hormonal signals • How can this secretion be increased as needed? • What are some other disorders associated with insulin secretion?

  13. Mark J. Dunne, Karen E. Cosgrove, Ruth M. Shepherd and Carina Ämmälä (1999) “Potassium Channels, Sulphonylureas Receptors and Control of Insulin Release” Trends in Endocrinology and Metabolism 10(4):146-152.

  14. The K+ Channel • Pore formed by 4 copies of Kir6.2 • Part of large family • Related to voltage gated K+ channels

  15. SUR receptor • High affinity for sulfonylureas • 4 copies of SUR1 • Superfamily of ATP-binding cassette (ABC) proteins

  16. Sulfonylureas • Oral antidiabetic drugs • Increase insulin secretion

  17. Other effects of sulfonylureas • Inhibit Na/K ATPase • Inhibit and activate chloride channels • Potentiate Ca-dependent exocytosis

  18. Normal ligand of SUR1? • -endosulfine • 13 kD peptide • Expressed in • Muscle • Brain • Endocrine cells • Endogenous regulator of KATP channel?

  19. Other diseases associated with insulin secretion • Persistant hyperinsulinaemic hypoglycaemia of Infancy (PHHI) • Hyperinsulinaemic hypoglycaemia (HH)

  20. PPHI • Very rare (1:45,000) • Very low blood sugar in neonate • Risk of severe brain damage and mental retardation • Treat by • Decrease carbohydrate intake • Use drugs that inhibit insulin secretion • Diazoxide • Somatostatin • Pancreatectomy (95%) removal • At risk for diabetes later in life

  21. Genetics of PPHI • Not entirely clear • To date • >25 reported SUR1 defects • 3 KIR6.2 defects • Autosomal recessive • Abnormalities in • Trafficking • Assembly • Regulation

  22. Experimental Evidence • Cultured -cells from PPHI children • Spontaneously electrically active • No functional KATP channels • Resting membrane is close to threshold for Ca channels • Easily open • Trigger insulin secretion

  23. Experimental Evidence, con’t • Transgenic mice with ‘dominant negative’ form of Kir6.2 • No K channel activity • Developed hyperinsulinaemic hypoglycemia • Impaired KATP channel function • Depolarized resting membrane potentials • Elevated cytosolic [Ca] • High frequency of apoptotic -cells

  24. HH • Milder than PPHI • Episodic • Later in life (even adulthood) • Always responsive to diazoxide • Autosomally dominant inheritance • Not linked to SUR1 or KIR6.2

  25. Two forms of HH HH-GK • Defect in glucokinase • Rate-limiting step in pancreas • If mutation causes decrease in glucose sensitivity of GK • Maturity-onset diabetes of the young (MODY) • Autosomal dominant • GK-HH mutations increase glucose sensitivity

  26. Two forms of HH • GDH-HH • Hyperinsulinaemia with hyperammonaemia • Defects in glutamate dehydrogenase • Sporadic genetics or familial dominant • Defects in allosteric inhibition by GTP • Constantly “on” enzyme

  27. In liver, leads to increase ammonia production • In -cells, dietary leucine stimulates GDH • Increase flux of -kg into Kreb’s • Increases ATP production • Closes KATP channels • Response to diazoxide

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