Hypoglycemia unawareness slide share

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