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Hypoglycemia-Associated Autonomic Failure HAAF Pr Dr Mohamed A. BADR Diabetes and Metabolic Unit Alex Faculty of medicine
HYPOGLYCEMIA <ul><li>Hypoglycemia in diabetes is iatrogenic, the result of episodes of relative or absolute therapeutic hy...
Hypoglycemia <ul><li>“ The Greatest Limiting Factor In Diabetes Management” </li></ul>
Since 1921  <ul><li>90 years after insulin discovery  </li></ul><ul><li>Insulin dark side !!!!!!! </li></ul><ul><li>Hypo i...
Plz Think with me <ul><li>Is it the brain  the primary site of hypoglycemia detection </li></ul><ul><li>Tell me why would ...
WHERE IS THE GLUCOSE SENSOR WHAT MECHANISMS DOES IT USE TO ACTIVATE  WHY DOES HYPOGLYCEMIA BEGET HYPOGLYCEMIA
WHERE IS THE GLUCOSE SENSOR central <ul><li>VMH ventromedial hypothalamus & arcuate nuclei. </li></ul><ul><li>Not only glu...
peripheral <ul><li>Portal tract </li></ul><ul><li>Carotid </li></ul><ul><li>others </li></ul>
Not only VMH <ul><li>VMH may act as central integrator of glucose sensing signals that are both locally generated and come...
Brain (central) PERIPHERAL <ul><li>Connection  through neuronal, hormonal, mediator,humoral, others </li></ul><ul><li>Peri...
What mechanism VMH use to activate counterregulation   SENSOR OF TWO TYPES <ul><li>GLUCOSE EXCITED  ATP-SENSITIVE K </li><...
HYPOGLYCEMIA
GLUCOSE SENSOR
Hypoglycemic stress <ul><li>Provoke dual modulation of the neuroendocrine response via </li></ul><ul><li>stimulation of en...
WHY WOULD BRAIN ADAPT TO RECURRENT HYP0GLYCEMIA <ul><li>PRECONDITIONING </li></ul><ul><li>Protect brain from fuel deprivat...
Hypoglycemia-Associated Autonomic Failure <ul><li>The mechanism(s) of the key component of HAAF </li></ul><ul><li>in diabe...
HYPOGLYCEMIA
HYPOGLYCEMIA
Hypoglycemia-Associated Autonomic Failure
Half Severe Hypo in DCCT occurred  patient sleep
Hypoglycemia-Associated Autonomic Failure <ul><li>Although the causative alteration could be in </li></ul><ul><li>the affe...
The Systemic Mediator Hypothesis <ul><li>Cortisol elevations comparable to those that occur </li></ul><ul><li>during hypog...
EUGLYCEMIC HYPERINSULINEMIC CLAMP <ul><li>80 mg complete suppression of insulin </li></ul><ul><li>70 mg inhibit glucose li...
The Brain Fuel Transport Hypothesis
The Brain Metabolism Hypothesis <ul><li>Alterations in brain metabolism that might be </li></ul><ul><li>involved in the pa...
CNS Responses to Hypoglycemia in Humans <ul><li>Measurements of rCBF with [150]water and PET </li></ul><ul><li>in humans i...
Decreased Synaptic Activity During Hypoglycemia
CNS Responses to Hypoglycemia in Humans cont <ul><li>and an increase in synaptic activity in a </li></ul><ul><li>discrete ...
Hypothesis <ul><li>We reasoned that if any of the components of </li></ul><ul><li>this hypoglycemia-induced brain synaptic...
Interval hypoglycemia <ul><li>Interval hypoglycemia did not alter synaptic </li></ul><ul><li>activities in any brain regio...
Hypo Clamp
Synaptic Activity   Interval hypoglycemia
Challenge <ul><li>Insulin have nothing to do in the brain  </li></ul><ul><li>Disagree </li></ul><ul><li>Agree </li></ul><u...
Fruit fly <ul><li>The cells that produce insulin in the fruit fly </li></ul><ul><li>like other invertebrates are located i...
 
HYPOGLYCEMIA RISK REDUCTION
<ul><li>Team of Diabetes Educators w/Personal Connection to Diabetes </li></ul><ul><li>Provide Advanced Education & BG Man...
Hypoglycemia Risk Reduction in Diabetes <ul><li>1. Address the issue of hypoglycemia in every </li></ul><ul><li>patient co...
Hypoglycemia Risk Reduction in Diabetes <ul><li>3. Consider the conventional risk factors, and adjust the regimen accordin...
 
Approaches to the Problem of Nocturnal Hypoglycemia <ul><li>1. CSII or MDI (basal bolus) with insulin analogues </li></ul>...
Hypoglycemia  Prevention Strategies <ul><li>Continuous Glucose  </li></ul><ul><li>  Monitoring </li></ul><ul><li>Alarms to...
 
 
 
A Big Part of the Problem CPOE Documentation
Change the scientific  scope, widening it, inclusion of other domain don’t limit  your mind in the same tract, sure resear...
 
THANK YOU
THANK YOU
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Hypoglycemia unawareness slide share

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Hypoglycemia unawareness

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  1. 2. Hypoglycemia-Associated Autonomic Failure HAAF Pr Dr Mohamed A. BADR Diabetes and Metabolic Unit Alex Faculty of medicine
  2. 3. HYPOGLYCEMIA <ul><li>Hypoglycemia in diabetes is iatrogenic, the result of episodes of relative or absolute therapeutic hyperinsulinemia. </li></ul><ul><li>Marked insulin excess alone can cause </li></ul><ul><li>hypoglycemia. Nonetheless, the integrity of the </li></ul><ul><li>physiological and behavioral defenses against </li></ul><ul><li>falling plasma glucose concentrations typically </li></ul><ul><li>determines whether a given episode of </li></ul><ul><li>therapeutic hyperinsulinemia does or does not result in an episode of clinical hypoglycemia </li></ul>Hypoglycemia is brain specific
  3. 4. Hypoglycemia <ul><li>“ The Greatest Limiting Factor In Diabetes Management” </li></ul>
  4. 5. Since 1921 <ul><li>90 years after insulin discovery </li></ul><ul><li>Insulin dark side !!!!!!! </li></ul><ul><li>Hypo is major barrier preventing </li></ul><ul><li>insulin from achieving its full </li></ul><ul><li>therapeutic promise </li></ul><ul><li>Add more, Hypo unawareness </li></ul>
  5. 6. Plz Think with me <ul><li>Is it the brain the primary site of hypoglycemia detection </li></ul><ul><li>Tell me why would the body adapt to hypoglycemia </li></ul>
  6. 7. WHERE IS THE GLUCOSE SENSOR WHAT MECHANISMS DOES IT USE TO ACTIVATE WHY DOES HYPOGLYCEMIA BEGET HYPOGLYCEMIA
  7. 8. WHERE IS THE GLUCOSE SENSOR central <ul><li>VMH ventromedial hypothalamus & arcuate nuclei. </li></ul><ul><li>Not only glucose but fuel glucose and lactate ,energy, metabolism, feeding , satiety ,temperature and reproduction </li></ul><ul><li>Elsewhere in the brain </li></ul>
  8. 9. peripheral <ul><li>Portal tract </li></ul><ul><li>Carotid </li></ul><ul><li>others </li></ul>
  9. 10. Not only VMH <ul><li>VMH may act as central integrator of glucose sensing signals that are both locally generated and come from network of sensors widely distributed throughout the body during hypoglycemia </li></ul><ul><li>integrated information </li></ul><ul><li>Activate downstream signals to restore and maintain homeostasis </li></ul><ul><li>Counterregulatory hormones </li></ul>
  10. 11. Brain (central) PERIPHERAL <ul><li>Connection through neuronal, hormonal, mediator,humoral, others </li></ul><ul><li>Peripheral mainly pancreas,liver, gut,others </li></ul>
  11. 12. What mechanism VMH use to activate counterregulation SENSOR OF TWO TYPES <ul><li>GLUCOSE EXCITED ATP-SENSITIVE K </li></ul><ul><li>GLUCOSE INHIBITED AMP- KINASE </li></ul>
  12. 13. HYPOGLYCEMIA
  13. 14. GLUCOSE SENSOR
  14. 15. Hypoglycemic stress <ul><li>Provoke dual modulation of the neuroendocrine response via </li></ul><ul><li>stimulation of endogenous corticotropin releasing factor CRF2 (inhibitory) </li></ul><ul><li>and CRF1(stimulatory) receptors </li></ul>
  15. 16. WHY WOULD BRAIN ADAPT TO RECURRENT HYP0GLYCEMIA <ul><li>PRECONDITIONING </li></ul><ul><li>Protect brain from fuel deprivation </li></ul><ul><li>Protect the body from negative consequences of recurrent stress </li></ul><ul><li>Response of acute effect differ from chronic repeated effect </li></ul><ul><li>ADAPTATION protect brain from injury </li></ul><ul><li>Use alterative fuel </li></ul><ul><li>Type 1, type 2, normal and diabetic </li></ul><ul><li>Sleep, prior exercise </li></ul>
  16. 17. Hypoglycemia-Associated Autonomic Failure <ul><li>The mechanism(s) of the key component of HAAF </li></ul><ul><li>in diabetes – the attenuated CNS-mediated </li></ul><ul><li>sympathoadrenal response to falling glucose </li></ul><ul><li>levels that causes hypoglycemia unawareness </li></ul><ul><li>and, in the setting of absent decrements in insulin </li></ul><ul><li>and absent increments in glucagon, </li></ul><ul><li>Defective glucose counterregulation </li></ul><ul><li>Cryer PE. Diabetes 54:3592, 2005. </li></ul><ul><li>Cryer PE. J Clin Invest 116:1470, 2006 </li></ul>
  17. 18. HYPOGLYCEMIA
  18. 19. HYPOGLYCEMIA
  19. 20. Hypoglycemia-Associated Autonomic Failure
  20. 21. Half Severe Hypo in DCCT occurred patient sleep
  21. 22. Hypoglycemia-Associated Autonomic Failure <ul><li>Although the causative alteration could be in </li></ul><ul><li>the afferent or efferent components of the </li></ul><ul><li>sympathoadrenal system, it is often assumed </li></ul><ul><li>to reside in the CNS. </li></ul><ul><li>Suggested possibilities include: </li></ul><ul><li>1. The systemic mediator hypothesis </li></ul><ul><li>2. The brain fuel transport hypothesis </li></ul><ul><li>3. The brain metabolism hypothesis </li></ul><ul><li>Cryer PE. Diabetes 54:3592, 2005. </li></ul><ul><li>Cryer PE. J Clin Invest 116:1470, 2006. </li></ul>
  22. 23. The Systemic Mediator Hypothesis <ul><li>Cortisol elevations comparable to those that occur </li></ul><ul><li>during hypoglycemia do not reduce the </li></ul><ul><li>adrenomedullary epinephrine or neurogenic symptom </li></ul><ul><li>responses to subsequent hypoglycemia,1,2 and </li></ul><ul><li>inhibition of the cortisol response (with metyrapone) </li></ul><ul><li>does not prevent the effect of hypoglycemia to </li></ul><ul><li>reduce the sympathoadrenal (or other) responses to </li></ul><ul><li>subsequent hypoglycemia.2 </li></ul><ul><li>1Raju B, et al. Diabetes 52:2083, 2003. </li></ul><ul><li>2Goldberg PA, et al. Diabetes 55:1121, 2006 </li></ul>
  23. 24. EUGLYCEMIC HYPERINSULINEMIC CLAMP <ul><li>80 mg complete suppression of insulin </li></ul><ul><li>70 mg inhibit glucose liberation &epinephr </li></ul><ul><li>55 – 60 mg produces symptoms </li></ul><ul><li>Compromised defense response activated only at very low level below 50 mg in patient on intensive insulin therapy </li></ul><ul><li>Awarness linked to a lowering level to trigger epinephrine secretion </li></ul>
  24. 25. The Brain Fuel Transport Hypothesis
  25. 26. The Brain Metabolism Hypothesis <ul><li>Alterations in brain metabolism that might be </li></ul><ul><li>involved in the pathogenesis of HAAF include … </li></ul><ul><li>• Glycogen </li></ul><ul><li>Supercompensation </li></ul><ul><li>• ↓ AMPK activation </li></ul><ul><li>• ↓ Hippocampal activation </li></ul><ul><li>• ↑ KATP channel closure </li></ul><ul><li>• ↓ Insulin signaling </li></ul><ul><li>• ↓ PVN activity </li></ul><ul><li>• ↑ CBF </li></ul><ul><li>• ↑ CRH or urocortin </li></ul><ul><li>• ↓ CMRGlc </li></ul><ul><li>• ↑ GK • ↑ GABAergic tone </li></ul><ul><li>Lactate </li></ul>
  26. 27. CNS Responses to Hypoglycemia in Humans <ul><li>Measurements of rCBF with [150]water and PET </li></ul><ul><li>in humans indicate that hypoglycemia causes: </li></ul><ul><li>A small (6-8%) generalized decrease in brain </li></ul><ul><li>synaptic activity and a sharp decrease (25%) in </li></ul><ul><li>the hippocampi … </li></ul>Teves D, et al. Proc Natl Acad Sci USA 101:6217, 2004
  27. 28. Decreased Synaptic Activity During Hypoglycemia
  28. 29. CNS Responses to Hypoglycemia in Humans cont <ul><li>and an increase in synaptic activity in a </li></ul><ul><li>discrete system of interconnected brain regions </li></ul><ul><li>including the medial prefrontal cortex, the lateral orbital prefrontal cortex, the thalamus, the globus pallidus and the periaqueductal grey </li></ul>Teves D, et al. Proc Natl Acad Sci USA 101:6217, 2004
  29. 30. Hypothesis <ul><li>We reasoned that if any of the components of </li></ul><ul><li>this hypoglycemia-induced brain synaptic </li></ul><ul><li>activation pattern were involved in the </li></ul><ul><li>suppression of the sympathoadrenal response </li></ul><ul><li>to subsequent hypoglycemia – the key feature </li></ul><ul><li>of HAAF – they would be altered following a </li></ul><ul><li>period of hypoglycemia. Alternatively, if they </li></ul><ul><li>were not involved they would not be altered </li></ul>Teves D, et al. Proc Natl Acad Sci USA 101:6217, 2004
  30. 31. Interval hypoglycemia <ul><li>Interval hypoglycemia did not alter synaptic </li></ul><ul><li>activities in any brain regions during euglycemia. </li></ul><ul><li>However, interval hypoglycemia resulted in greater synaptic activity during hypoglycemia (P=0.004),on Day 2 in the dorsal midline thalamic nuclei, a region that includes the paraventricular nucleus of the thalamus (PVNT), and did so only in that region. </li></ul>1Arbelaez AM, et al. Diabetes 57:470, 2008. 2Segel S, et al. Diabetes 50:1911, 2001
  31. 32. Hypo Clamp
  32. 33. Synaptic Activity Interval hypoglycemia
  33. 34. Challenge <ul><li>Insulin have nothing to do in the brain </li></ul><ul><li>Disagree </li></ul><ul><li>Agree </li></ul><ul><li>Don’t know </li></ul>
  34. 35. Fruit fly <ul><li>The cells that produce insulin in the fruit fly </li></ul><ul><li>like other invertebrates are located in the brain </li></ul><ul><li>Claude Bernard experiment, induction of diabetes in rabbit by needle puncture in the floor of 4 th ventricle </li></ul><ul><li>Occurrence of diabetes after extreme pshychic stress </li></ul><ul><li>Honey moon </li></ul>
  35. 37. HYPOGLYCEMIA RISK REDUCTION
  36. 38. <ul><li>Team of Diabetes Educators w/Personal Connection to Diabetes </li></ul><ul><li>Provide Advanced Education & BG Management Coaching </li></ul><ul><li>Full Remote Access (phone, e-mail, skype, text, etc.) </li></ul><ul><li>Type-1 Diabetes Focus, Children & Adults </li></ul>
  37. 39. Hypoglycemia Risk Reduction in Diabetes <ul><li>1. Address the issue of hypoglycemia in every </li></ul><ul><li>patient contact. </li></ul><ul><li>2. Apply the Principles of Aggressive Therapy: </li></ul><ul><li>• Patient education and empowerment </li></ul><ul><li>• Frequent SMBG </li></ul><ul><li>• Flexible insulin (or other drug) regimens </li></ul><ul><li>• Rational individualized glycemic goals </li></ul><ul><li>• Ongoing professional guidance and support </li></ul><ul><li>Hot line </li></ul>
  38. 40. Hypoglycemia Risk Reduction in Diabetes <ul><li>3. Consider the conventional risk factors, and adjust the regimen accordingly. </li></ul><ul><li>4. Consider the possibility of compromised </li></ul><ul><li>glucose counterregulation and seek a history of hypoglycemia unawareness. </li></ul><ul><li>• Consider 2-3 weeks of scrupulous avoidance of iatrogenic hypoglycemia. </li></ul>
  39. 42. Approaches to the Problem of Nocturnal Hypoglycemia <ul><li>1. CSII or MDI (basal bolus) with insulin analogues </li></ul><ul><li>2. Bedtime snacks </li></ul><ul><li>3. Sustained exogenous glucose delivery overnight </li></ul><ul><li>• Uncooked cornstarch </li></ul><ul><li>• α-Glucosidase inhibitor with the evening meal </li></ul><ul><li>4. Sustained endogenous glucose production </li></ul><ul><li>overnight </li></ul><ul><li>• Glucagon stimulating amino acid alanine </li></ul><ul><li>• Glucagon infusion </li></ul><ul><li>• Epinephrine simulating β2-adrenergic agonist </li></ul><ul><li>terbutaline </li></ul>
  40. 43. Hypoglycemia Prevention Strategies <ul><li>Continuous Glucose </li></ul><ul><li> Monitoring </li></ul><ul><li>Alarms to alert user/family of pending lows </li></ul><ul><li>APPLICATIONS OF NANOTECHNOLOGY IN DIABETES </li></ul>
  41. 47. A Big Part of the Problem CPOE Documentation
  42. 48. Change the scientific scope, widening it, inclusion of other domain don’t limit your mind in the same tract, sure researches must be redirected. <ul><li>Short message </li></ul>
  43. 50. THANK YOU
  44. 51. THANK YOU
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