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.