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Hypoglycemia unawareness

Hypoglycemia unawareness

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Hypoglycemia unawareness slide share Hypoglycemia unawareness slide share Presentation Transcript

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