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BRAIN METABOLISMPresented by S Aryo No
High energy requirements (~10 mgkgmin)
Low energy reserves
The energy is needed to maintain the ionic gradient across nerve membranes
Brain Metabolism
Energy metabolism of the brain 2 of body weight 20 of energy
expenditure
GLUCOSE is the main fuel daily consumption 120g adopted starvation (3 weeks) oxidation of
ketones in the brain covers up to 50 of energy
Oxygen uptake Brain 20 of whole-body O2 consumption The most vulnerable to hypoxia
5 min of Ventrikel Fibrilationarrest may lead to irreversible brain damage
temperature dependent
Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life
Glucose oxidation provides more than 90 of the energy needed
Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation
The source of Brain Metabolism
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
High energy requirements (~10 mgkgmin)
Low energy reserves
The energy is needed to maintain the ionic gradient across nerve membranes
Brain Metabolism
Energy metabolism of the brain 2 of body weight 20 of energy
expenditure
GLUCOSE is the main fuel daily consumption 120g adopted starvation (3 weeks) oxidation of
ketones in the brain covers up to 50 of energy
Oxygen uptake Brain 20 of whole-body O2 consumption The most vulnerable to hypoxia
5 min of Ventrikel Fibrilationarrest may lead to irreversible brain damage
temperature dependent
Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life
Glucose oxidation provides more than 90 of the energy needed
Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation
The source of Brain Metabolism
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Energy metabolism of the brain 2 of body weight 20 of energy
expenditure
GLUCOSE is the main fuel daily consumption 120g adopted starvation (3 weeks) oxidation of
ketones in the brain covers up to 50 of energy
Oxygen uptake Brain 20 of whole-body O2 consumption The most vulnerable to hypoxia
5 min of Ventrikel Fibrilationarrest may lead to irreversible brain damage
temperature dependent
Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life
Glucose oxidation provides more than 90 of the energy needed
Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation
The source of Brain Metabolism
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Oxygen uptake Brain 20 of whole-body O2 consumption The most vulnerable to hypoxia
5 min of Ventrikel Fibrilationarrest may lead to irreversible brain damage
temperature dependent
Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life
Glucose oxidation provides more than 90 of the energy needed
Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation
The source of Brain Metabolism
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life
Glucose oxidation provides more than 90 of the energy needed
Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation
The source of Brain Metabolism
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Insulin independent GLUT1 (55 kd form)
localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium
GLUT3 GLUT1 (45 kd form)
transport glucose from interstitium into neurons and glial cells
Upregulation in chronically hypoglycemic rats
Transport of Glucose
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons
Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes
Brain Metabolism
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins
Neurite extension (axons dendrites) Synapse formation (connectivity)
1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation
Protein and fat in the brain
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Meski glukosa penting bagi otak namun kadarnya hanya sedikit
Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah
Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)
Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah
Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif
Protein metabolism
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik
Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin
dan sfingomielin dimetabolisme secara lambat di otak
Lipid metabolism
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly
more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are
consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency
Organs release glucose
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Hypoglycemia plasma glucose concentration below 50 mgdL
76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in
intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness
Hypoglycemia
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation
Liver1048708 senses glucose concentration in the absence of counterregulatory hormones
Hypoglycemia Sensors
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)
Architecture of Counterregulatory System
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+
influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons
Local increase in lactate increases blood flow
Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Functional imaging PET
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Ammonia handling in the brain NH3 is a waste product of deamination
reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism
Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys
Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Ammonia handling Clinical consequences liver disease impairs
brain function principle insufficient urea synthesis NH3
accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)
threatens live also by ICP
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Blood brain barrier selectivity Free permeability (passive diffusion)
small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones
Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids
Pinocytosis
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
Areas outside BBB Enables brain to sense and regulate blood
composition
Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
BBB ndash clinical significance CNS infection
BBB protects against bacteria entry but also antibodies and antibiotics
Kernikterus hyperbilirubinemia damages the brain in
neonates but not in adults Parkinsons disease
=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross
BBB) but its precursor L-DOPA is useful
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
CSF in diagnostics CNS infection
bacterial meningitis viscous and opalescent CSF WBC Glucose Lac
viral meningitis few cells protein Degenerative diseases
oligoclonal bands in multiple sclerosis others
Hematologic malignancy leucemic cells infiltrate CNS
![Journal 1967 [Owen] Brain Metabolism During Fasting](https://img.pdfslide.us/doc/110x75/577d27911a28ab4e1ea438f3/journal-1967-owen-brain-metabolism-during-fasting.jpg)