Upload
mohamed-badr
View
895
Download
4
Tags:
Embed Size (px)
DESCRIPTION
Hypoglycemia unawareness
Citation preview
Hypoglycemia-Associated Autonomic
Failure HAAF
Pr Dr Mohamed A. BADRPr Dr Mohamed A. BADR
Diabetes and Metabolic UnitDiabetes and Metabolic Unit
Alex Faculty of medicineAlex Faculty of medicine
HYPOGLYCEMIAHYPOGLYCEMIA
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
HypoglycemiaHypoglycemia
““The Greatest Limiting The Greatest Limiting Factor In Diabetes Factor In Diabetes
Management”Management”
Since 1921 Since 1921
90 years after insulin discovery 90 years after insulin discovery
Insulin dark side !!!!!!!Insulin dark side !!!!!!!
Hypo is major barrier preventingHypo is major barrier preventing
insulin from achieving its full insulin from achieving its full
therapeutic promisetherapeutic promise
Add more, Hypo unawarenessAdd more, Hypo unawareness
Plz Think with mePlz Think with me
Is it the brain Is it the brain the primary site of the primary site of hypoglycemia detectionhypoglycemia detection
Tell me why would the body adapt to Tell me why would the body adapt to hypoglycemiahypoglycemia
WHERE IS THE GLUCOSE WHERE IS THE GLUCOSE SENSORSENSOR
WHAT MECHANISMS DOES IT WHAT MECHANISMS DOES IT USE TO ACTIVATE USE TO ACTIVATE
WHY DOES HYPOGLYCEMIA WHY DOES HYPOGLYCEMIA BEGET HYPOGLYCEMIABEGET HYPOGLYCEMIA
WHERE IS THE GLUCOSE WHERE IS THE GLUCOSE SENSORSENSOR
centralcentral
VMH ventromedial hypothalamus & VMH ventromedial hypothalamus & arcuate nuclei.arcuate nuclei.
Not only glucose but fuel glucose and Not only glucose but fuel glucose and lactate ,energy, metabolism, feeding , lactate ,energy, metabolism, feeding , satiety ,temperature and reproductionsatiety ,temperature and reproduction
Elsewhere in the brainElsewhere in the brain
peripheralperipheral
Portal tractPortal tract CarotidCarotid othersothers
Not only VMHNot only VMH
VMH may act as central integrator of VMH may act as central integrator of glucose sensing signals that are both glucose sensing signals that are both locally generated and come from network locally generated and come from network of sensors widely distributed throughout of sensors widely distributed throughout the body during hypoglycemiathe body during hypoglycemia
integrated informationintegrated information Activate downstream signalsActivate downstream signals to restore to restore
and maintain homeostasisand maintain homeostasis Counterregulatory hormonesCounterregulatory hormones
BrainBrain(central)(central)
PERIPHERALPERIPHERAL
Connection through neuronal, hormonal, Connection through neuronal, hormonal, mediator,humoral, othersmediator,humoral, others
PeripheralPeripheral mainly pancreas,liver, mainly pancreas,liver, gut,othersgut,others
What mechanism VMH use to What mechanism VMH use to activate counterregulationactivate counterregulation
SENSOR OF TWO TYPESSENSOR OF TWO TYPES
GLUCOSE EXCITED ATP-SENSITIVE KGLUCOSE EXCITED ATP-SENSITIVE K GLUCOSE INHIBITED AMP- KINASEGLUCOSE INHIBITED AMP- KINASE
HYPOGLYCEMIAHYPOGLYCEMIA
GLUCOSE SENSORGLUCOSE SENSOR
Hypoglycemic stressHypoglycemic stress
Provoke dual modulation of the Provoke dual modulation of the neuroendocrine response vianeuroendocrine response via
stimulation of endogenous corticotropin stimulation of endogenous corticotropin releasing factor CRF2 (inhibitory) releasing factor CRF2 (inhibitory)
and CRF1(stimulatory) receptorsand CRF1(stimulatory) receptors
WHY WOULD BRAIN ADAPT TO WHY WOULD BRAIN ADAPT TO RECURRENT HYP0GLYCEMIARECURRENT HYP0GLYCEMIA
PRECONDITIONINGPRECONDITIONING Protect brain from fuel deprivationProtect brain from fuel deprivation Protect the body from negative consequences of Protect the body from negative consequences of
recurrent stressrecurrent stress Response of acute effect differ from chronic Response of acute effect differ from chronic
repeated effectrepeated effect ADAPTATION protect brain from injuryADAPTATION protect brain from injury Use alterative fuelUse alterative fuel Type 1, type 2,\ normal and diabeticType 1, type 2,\ normal and diabetic Sleep, prior exerciseSleep, 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-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 EUGLYCEMIC HYPERINSULINEMICHYPERINSULINEMIC
CLAMPCLAMP 80 mg complete suppression of insulin80 mg complete suppression of insulin 70 mg inhibit glucose liberation &epinephr70 mg inhibit glucose liberation &epinephr 55 – 60 mg produces symptoms55 – 60 mg produces symptoms Compromised defense response activated Compromised defense response activated
only at very low level below 50 mg in only at very low level below 50 mg in patient on intensive insulin therapypatient on intensive insulin therapy
Awarness linked to a lowering level to Awarness linked to a lowering level to trigger epinephrine secretiontrigger epinephrine secretion
The Brain Fuel Transport Hypothesis
The Brain Metabolism Hypothesis
Alterations in brain metabolism that might beinvolved 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 toHypoglycemia 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 USA101:6217, 2004
Decreased Synaptic ActivityDecreased Synaptic ActivityDuring HypoglycemiaDuring Hypoglycemia
CNS Responses toHypoglycemia 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 USA101:6217, 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 USA101:6217, 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 ClampHypo Clamp
Synaptic ActivitySynaptic Activity
Interval hypoglycemia
ChallengeChallenge
Insulin have nothing to do in the brain Insulin have nothing to do in the brain DisagreeDisagree AgreeAgree Don’t knowDon’t know
Fruit flyFruit fly
The cells that produce insulin in the fruit flyThe cells that produce insulin in the fruit fly like other invertebrates are located in the like other invertebrates are located in the
brainbrain Claude Bernard experiment, induction of Claude Bernard experiment, induction of
diabetes in rabbit by needle puncture in diabetes in rabbit by needle puncture in the floor of 4the floor of 4thth ventricle ventricle
Occurrence of diabetes after extreme Occurrence of diabetes after extreme pshychic stresspshychic stress
Honey moonHoney moon
• 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.
Hypoglycemia Hypoglycemia Prevention StrategiesPrevention StrategiesContinuous Glucose Continuous Glucose
MonitoringMonitoring
Alarms to alert user/family of pending lows
APPLICATIONS OF NANOTECHNOLOGY IN DIABETES
A Big Part of the ProblemA Big Part of the Problem
CPOE
Change the scientific scope, Change the scientific scope, widening it, inclusion of other widening it, inclusion of other
domain don’t limit your mind in the domain don’t limit your mind in the same tract, sure researches must same tract, sure researches must
be redirected.be redirected.
Short messageShort message
THANK YOUTHANK YOU
THANK YOUTHANK YOU