Maintenance of Homeostasis “Cellular Transport”. Homeostasis is… A biological balance.
Normal to Abnormal Glucose Homeostasis Sun H. Kim, M.D., M.S. Stanford University School of Medicine...
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Transcript of Normal to Abnormal Glucose Homeostasis Sun H. Kim, M.D., M.S. Stanford University School of Medicine...
Normal to Abnormal Glucose Homeostasis
Sun H. Kim, M.D., M.S.Stanford University School of MedicineOctober 22, 2015
Case16 year-old girl presents to the emergency room with
increased thirst, frequent urination, fatigue, and a 10-pound weight loss in the preceding 2-3 weeks.
Exam: BP 110/60, HR 130, RR 24◦ Drowsy◦ Kussmaul’s respiration (“breathing loud, rapid, and the respiratory movements strikingly
large”)
◦ Breath smelled “fruity”◦ Mucous membranes are dry
Case
Laboratory Findings: Normal Values
◦Glucose 650 mg/dL 70-99
◦Bicarbonate 10 mmol/L 20-30
◦pH 7.22 7.35-7.45
◦UA: +glucose, ketones none
Outline
Metabolic activities during prolonged starvation
Metabolic activities during diabetic ketoacidosis (DKA)
Metabolic activities during reversal of diabetic ketoacidosis (DKA)
Prolonged Starvation
Fuel Composition in 70kg MaleFuel Kg Calories
Fat (adipose triglycerides) 15 141,000
Protein (mainly muscle)(Only 1/3 can be used for fuel without comprising functions)
6 24,000
Glycogen (muscle) 0.150 600
Glycogen (liver) 0.075 300
Circulating fuels (plasma glucose, free fatty acids, triglycerides) <0.1 ~100
Cahill GF. NEJM 1970; 282:668-675
Fat: Best Source for Fuel Storage
Carbohydrate Protein Fat
Calories(kcal/gram) 4 4 9
Storage in body
Requires aqueous environment.
Performs nonfuel functions.
Does not require aqueous environment.
David Blaine
-Tower Bridge, London-Transparent Perspex box (2.1X2.1X 0.9m) suspended in air-44 days- “test personal endurance boundary”
David Blaine
30 yo MaleWeight 95.8 kg, Height 1.84 m, BMI 28.4◦Gained 6-7 kg prior to event
How much weight did he lose in 44 days?24.5 kg or 54 pounds
Obligate Users of Glucose
Brain◦Can adapt to using ketone bodies
Cornea, lensRed Blood CellsKidney Medulla
Glucose Utilization by Organ
Late StarvationEarly Starvation
Starvation: Brain’s Critical Adaptation
Cahill GF. Annu Rev Nutr 2006;26:1-22
Starvation: Effect on Glucose
0102030405060708090
100
0 3 10 17 24 31 38
Days of Starvation
Glu
co
se (
mg
/dL
)
Owen et al. JCI 1969; 48:574-583
Starvation: ↓Insulin and ↑Glucagon
0
5
10
15
20
25
30
35
40
0 3 5 7 14 21 28 35 42
Days of Starvation
Pla
sm
a I
nsu
lin
(µ
U/m
L)
Marliss et al. JCI 1970;49:2256-2270
40
80
120
160 Plasm
a Glucagon (µ
µg/m
L)
Glucagon
Insulin
Starvation: Liver
Glycogen
Glucose 6-P
Pyruvate
Acetyl CoA
Fatty acid
Glucose
Glucose
↓ Insulin, ↑Glucagon
Amino acids, glycerol, lactate
Ketone bodies Ketone bodies
Fatty acids
TCA
Starvation : Adipose Tissue↓ Insulin, ↑Glucagon
Triglycerides
Fatty acids Glycerol
Acetyl CoATCA
Fatty acids Glycerol
Starvation : Skeletal Muscle
Protein
Acetyl CoA
Amino Acids
Amino acidsTCA
Fatty acids
Ketone bodies
Fatty acids
Ketone bodies
Try to conserve
Glucose
Glut4
↓ Insulin, ↑Glucagon
Kidney
The kidney can also perform gluconeogenesis.After an overnight fast, the kidney releases 20-
25% of glucose into the circulation (with liver releasing 75-80% glucose).
As length of fast increases, the proportion of glucose from kidney increases.
Sources of Blood Glucoseafter Ingestion of 100g of Glucose
Brosnan JT and Watford M. Encyclopedia of Life Sciences, 2005; 1-6
Starvation: ↑Fatty Acids and Ketone Bodies
Owen et al. JCI 1969; 48:574-583
DB Update:Β-OH Butyrate=4.92 mmol/L at 44 daysFFA=1.53 mmol/L
Ketone Bodies
2 Acetyl CoA
Acetoacetyl CoA
3-Hydroxy-3-methylgutaryl CoA (HMG CoA)
Acetoacetate
β-Hydroxybutyrate
NADH + H+
NAD+
Acetone
CO2
Acetyl CoA
DB Update:He described sweet tastein his mouth, like “pear drops”on day 20.
Starvation: Ketone use
2 Acetyl CoA
Acetoacetyl CoA
3-Hydroxy-3-methylgutaryl
CoA (HMG CoA)
Acetoacetate
β-Hydroxybutyrate
NAD+
NADH + H+
Fatty AcidOxidation
Acetoacetate
β-Hydroxybutyrate
AcetoneCO2
β-Hydroxybutyrate
Acetoacetate
Acetoacetyl CoA
2 Acetyl CoA
Succinyl CoA
Succinate
NAD+
NADH + H+
Peripheral Tissue
Liver
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
↓ Insulin, ↑Glucagon
Starvation: Conservation of proteins
Brosnan JT and Watford M. Encyclopedia of Life Sciences, 2005; 1-6
Summary of Metabolic Changes during Prolonged Starvation
↓Glucose output by the liver and ↓glucose utilization
↑Ketogenesis and ↑ketone use by the body
Preservation of protein and ↓urea synthesis
DB UpdateBefore Fast End of Fast Change in Kg Change in % Body % of Initial
Weight 96 71.5 24.5 25.5%Fat mass 19.3 12.9 6.4 6.7 % 33.2 %Fat-free mass 76.7 58.6 18.1 18.8% 23.6%
Diabetic KetoacidosisSerious, acute complication of diabetesUsually associated with type 1 diabetes but can occur in
type 2 diabetesDue to insulin deficiency plus glucagon excess; in addition,
other counter-regulatory hormones (epinephrine, cortisol)
Precipitating factors usually present (infection, myocardial infarction, trauma, etc.)
Mortality ~5% in < 40 yo; up to 20% in elderly
Diabetic Ketoacidosis (DKA)
Porth Pathophysiology: Concepts of Altered Health States, 7 th ed.
DKA: Liver
Glycogen
Glucose 6-P
Pyruvate
Acetyl CoA
Fatty acid
Glucose↑↑↑
Glucose
No Insulin, ↑Glucagon
Amino acids, glycerol, lactate
Ketone bodies ↑↑↑ Ketone bodies
Fatty acids
TCA
DKA: Adipose Tissue No Insulin, ↑Glucagon
Triglyceride
Fatty acids Glycerol
Acetyl CoATCA
↑↑↑ Fatty acids Glycerol
DKA: Skeletal Muscle
Protein
Acetyl CoA
Amino Acids
Amino acidsTCA
No Insulin, ↑Glucagon
Fatty acids
Ketone bodies
Fatty acids
Ketone bodies
Glucose
Glut4
↑↑↑Glucose, Ketones, Fatty acids (blood)
Starvation vs. DKAStarvation DKA
Insulin and Glucagon
Plasma Glucose
Ketone bodies
Volume depletion
Starvation vs. DKAStarvation DKA
Insulin and Glucagon ↓Insulin↑Glucagon
Deficient Insulin↑Glucagon
Plasma Glucose Low normal(55-65 mg/dL)
High(>400 mg/dL)
Ketone bodies Slightly high Very high
Volume depletion Variable Usually
Clinical Features of DKA Polydipsia, polyuria Fatigue, nausea, and vomiting “Air hunger”; Kussmaul’s
respiration Fruity smell on breath Tachycardia Dehydration/volume depletion Mental Status Changes
Explanation of Clinical FeaturesHyperglycemia and hyperosmolality◦Polydipsia, polyuria◦Dehydration, tachycardia◦Mental status changes
Ketonemia and metabolic anion gap acidosis◦Air hunger◦ Fruity smell on breath◦Nausea◦Mental status changes
Polyuria: Renal Threshold for Glucose
Mather and Pollock. Kidney International 2011; 79:S1-S6.
Filtered glucose (plasma glucose X GFR)
Glu
cose
Exc
reti
on
(U
glu
cose
V)
Filtered Excreted
Reabsorbed
Tmglucose = 180-200mg/dL
SGLT2: Sodium Glucose Cotransporters
http://www.discoverymedicine.com/Edward-C-Chao/2011/03/23/a-paradigm-shift-in-diabetes-therapy-dapagliflozin-and-other-sglt2-inhibitors/
Clinical Relevance Sodium glucose co-transporter-2 inhibitors (SGLT2) have been
approved to treat type 2 DM.◦ Canagliflozin (Invokana)◦ Dapagliflozin (Farxiga)◦ Empagliflozin (Jardiance)
SGLT2 reduce hyperglycemia by increasing glucosuria (glucuretics).
SGLT2 is associate with weight loss.
Renal Threshold for Glucose
0 50 100 150 200 250 3000
25
50
75
100
125
Plasma Glucose (mg/dL)
Uri
nary
Glu
cose
Exc
retio
n (g
/day
)
NormalRTG ~180 mg/dL
Nair and Wilding. JCEM 2010;95:34
DM2
0 50 100 150 200 250 3000
25
50
75
100
125
Plasma Glucose (mg/dL)
Uri
nary
Glu
cose
Exc
retio
n (g
/day
)
NormalRTG ~180 mg/dL
DM2~240
Nair and Wilding. JCEM 2010;95:34
SGLT2 Inhibitors
0 50 100 150 200 250 3000
25
50
75
100
125
Plasma glucose (mg/dL)
Uri
nary
Glu
cose
Exc
retio
n (g
/day
)
SGLT2 Inh~70-90 mg/dL
Nair and Wilding. JCEM 2010;95:34
Hyperosmolality in DKA
Osmolality = 2 * Na +
Glucose
+
BUN
18 2.8Normal osmolality = 285-295 mOSM/L
Normal glucose contribution to osmolality:
4-6 mOSM/L (assume glucose 70-99 mg/dL)
During DKA:
>20 mOSM/L (assume glucose 400 mg/dL)
Effect of ↑Plasma Osm
ADH = antidiuretic hormone
Osmolality & Mental Status
1. Alert or mildly drowsy (26)2. Moderately drowsy, fully oriented (24)3. Very drowsy, partially oriented (14)4. Stuporous (3)5. Comatose (3)
Fulop et al. Lancet, 1973;2:635-639.
“Anion Gap” Metabolic Acidosis in DKA
Plasma Anion Gap = Na – (Cl + HCO3)
+ Ions - Ions
K, Ca, Mg Albumin,SO4, PO4
NaHCO3
Cl
Gap = 12
24
104
140
DKA
HCO3
Albumin,SO4, PO4,
Ketones10
Cl104
140 -(104+24)
Gap = 26
140 – (104+10)
Acidosis in DKA
HC03
pH = pK + log pCO2
↓HC03 (metabolic acidosis) leads to ↓pCO2 (respiratory alkalosis)-feelings of “air hunger”
↓blood pH when respiratory compensation becomes inadequate
Treatment of DKA
FluidsInsulinFind and treat precipitating factor
Reversal of DKA: Liver
Glycogen
Glucose 6-P
Pyruvate
Acetyl CoA
Fatty Acid
Triglycerides
VLDL
Glucose
Amino Acids
Glucose(from blood)
Amino Acids(from blood)
ProteinTCA
VLDL(to adipose tissue)
Glut2
Exogenous Insulin, ↓Glucagon
Ketone bodies
Reversal of DKA : Adipose Tissue
Glucose (from blood)
FFA: free fatty acids
VLDL: very low density lipoproteins
Glut 4: Insulin-dependent glucose transporter
Glucose
Acetyl CoAFFA
Glucose 6-P
Pyruvate
Glycerol-P
VLDL (from liver)
TCA
Glut4
Triglyceride
Lipoprotein Lipase
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Exogenous Insulin, ↓Glucagon
Reversal of DKA: Skeletal Muscle
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Protein
Glucose
Glucose 6-P
Pyruvate
Acetyl CoA
Amino Acids(from blood)
Amino acids
Glucose (from blood)
Glut4
Glycogen
TCA
Exogenous Insulin, ↓Glucagon
β-Hydroxybutyrate
Acetoacetate
Conclusions DKA is a serious metabolic
complication of insulin deficiency. It parallels metabolic changes in
starvation. However, without any insulin,
normal physiology becomes abnormal.
Case Presentation
45 year-old woman complains of frequent episodes of feeling nervous and sweaty in the last 6 months. At times she also feels confused. Symptoms appear to improve with eating. Her husband has diabetes and she once checked her glucose on his glucometer during one of the episodes. Her glucose was 45 mg/dL.
Normal
Glucose
Insulin
C-peptide
β-hydroxybutyrate
∆Glucose after glucagon
Insulinoma
Glucose
Insulin
C-peptide
β-hydroxybutyrate
∆Glucose after glucagon
Exogenous Insulin
Glucose
Insulin
C-peptide
β-hydroxybutyrate
∆Glucose after glucagon
Sulfonylurea-Induced
Glucose
Insulin
C-peptide
β-hydroxybutyrate
∆Glucose after glucagon
Hypoglycemia Case↓glucose 10min 20min 30min
Glucose 40 51 76 97
Insulin 54
C-peptide 5.05β-hydroxybutyrate 0.2
Hypoglycemia Case1.5 X 2.8 CM HYPERVASCULAR SOLID LESION IN
THE BODY OF THE PANCREAS.