Download Antipsychotic Medications and Type 2 Diabetes

Glucose Homeostasis
during Feeding and Fasting
Sun H. Kim, M.D., M.S.
Stanford University School of Medicine
October 22, 2015
In-class Experiment
Continuous Glucose Monitoring
1. Small Sensor:
Measures glucose in the
interstitial fluid
 2. Transmitter: On top of
sensor, sends data
wirelessly (to iPhone)
 3. Display

Glucose challenge
Glucose (mg/dL)
Oral Glucose Tolerance Test
150
100
50
0
0
75 gm Glucose
30
60
Time (minutes)
90
120
OGTT Interpretation
Standard 75 gram OGTT
Fasting Glucose
Normal
<100 mg/dL
Impaired/Prediabetes 100-125 mg/dL
Diabetes ≥ 126 mg/dL
2-hour Glucose
<140 mg/dL
140-199 mg/dL
≥ 200 mg/dL
Outline

Main regulators of glucose homeostasis:

Metabolic activities during feeding:

Metabolic activities during fasting:

Other regulators of glucose
◦ insulin and glucagon
◦ ↑insulin and ↓glucagon
◦ ↓insulin and ↑glucagon
◦ GLP-1
◦ Counter-regulatory hormones
Glucose Tightly Regulated
Peterson DT and Reaven GM. Diabetes 1971; 20:729-33
Hormones involved in glucose control
↑ Glucose




Glucagon
Epinephrine
Growth Hormone
Cortisol
↓ Glucose



Insulin
Amylin
Incretins
◦ GLP-1 (glucagon-like peptide 1)
◦ GIP (gastric inhibitory polypeptide,
also glucose-dependent
insulinotropic peptide)
Insulin and Glucagon in
Response to a Meal
Unger RH. NEJM, 1971; 285: 443–449.
Pancreas
http://www.barnesjewish.org/healthinfo/content.asp?PageID=P00416
Pancreas (CT image)
http://img.medscape.com/pi/emed/ckb/endocrinology/116364-138564-126438-1685101.jpg
Pancreas
Bardeesy and DePinho. Nature Reviews Cancer 2002; 2:897-909
Islet of Langerhans: Endocrine Pancreas
Single
Islet
Paul Langerhans (1847-1888)
H & E stain of pancreas
http://education.vetmed.vt.edu/Curriculum/VM8054/Labs/Lab24/lab24.htm
Islet of Langerhans
α:
Glucagon
β:
Insulin
δ:
Somatostatin
Insulin Secretion
Gloyn et al. NEJM 2004;18:1838-49
Clinical Relevance
KATP Channel
Closed
Disease
Treatment for
KATP Channel
Open
Clinical Relevance
Disease
Treatment for
KATP Channel
Closed
Hypoglycemia
Diabetes
(e.g. sulfonylureas)
KATP Channel
Open
Diabetes
Hypoglycemia
(e.g. diazoxide)
Proinsulin
Insulin Action
Insulin: the “Anabolic” Hormone
Insulin Effects
Promotes storage of nutrients.
Nutrients
Glucose uptake in tissue (muscle, adipose tissue)
• Glucose storage as glycogen (glycogenesis)
• Glucose utilization (glycolysis)
Carbohydrate
•
Fat
•
Protein
•
Fat synthesis (lipogenesis)
• Fat storage as triglycerides in adipose tissue
Protein synthesis
Proglucagon
Proglucagon
GRPP
Glucagon
GLP-1
GLP-2
Pancreas α cells
GRPP
MPGF
Glucagon
Small Intestine
Glicentin
GRPP
GLP-1
Oxyntomodulin
GLP: glucagon-like peptide
GRPP: glicentin-related pancreatic peptide
MPGF: major proglucagon fragment
Fehmann et al. Endocrinology Reviews 1995; 16: 390-410
GLP-2
Glucagon Action
PKA: protein kinase A
R: regulatory subunits of PKA
C: catalytic subunits of PKA
http://web.indstate.edu/thcme/mwking/peptide-hormones.html
Glucagon: the “Catabolic” Hormone
Glucagon Effects
Promotes breakdown of nutrients.
Nutrients
Breakdown of glycogen to glucose (glycogenolysis)
• Formation of glucose from amino acids, lactate, and glycerol
(gluconeogenesis)
Carbohydrate
•
Fat
•
Protein
•
Breakdown of triglycerides to glycerol and free fatty acids (lipolysis)
• Breakdown of fatty acids (fatty acid oxidation)
• Formation of ketone bodies (ketogenesis)
Breakdown of protein to amino acids (proteolysis)
Clinical Relevance
• Insulin is used to treat
patients with diabetes.
• Is there a use for
glucagon?
Clinical Relevance: Bionic Pancreas
Russell et al. NEJM 2014; 371:313.
α- and β-cells in cultured islet cells
Domenico Bosco et al. Diabetes 2010;59:1202-1210
Green=alpha cells; Red=beta cells
In-class Experiment
Peppermint White Chocolate Mocha
Content
Calories
520 kcal
Total Fat
18 grams
Total Carbohydrates
78 grams
Protein
14 grams
Caffeine
150 mg
Mocha : Digested
Blood (or lymphatics)
Gut
Carbohydrate
Protein
Fat
Glucose
Amino acids
Triglycerides (within
Chylomicrons)
Mocha: ↑Insulin and ↓Glucagon
α:
Glucagon
β:
Insulin
δ:
Somatostatin
-Glucose and amino acids can stimulate insulin
secretion.
-Insulin and glucose inhibit glucagon secretion.
Mocha: Liver
↑Insulin, ↓Glucagon
Glycogen
Glucose
Glut2
Glucose 6-P
Amino Acids
Pyruvate
Glucose
(from gut)
Amino Acids
(from gut)
Protein
Acetyl CoA
TCA
Fatty Acid
Chylomicron
remnants
Triglycerides
VLDL
VLDL
(to adipose tissue)
TCA: Tricarboxylic Acid cycle (also
known as Kreb cycle, citric acid cycle)
VLDL: Very low density lipoprotein
Glut2: Insulin-independent glucose
transporter
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Mocha : Adipose Tissue
Glucose
(from gut)
Glut4
↑Insulin, ↓Glucagon
Glucose
Glucose 6-P
Glycerol-P
Pyruvate
Triglyceride
Acetyl CoA
FFA
FFA: free fatty acids
TCA
VLDL: very low density
lipoproteins
Glut 4: Insulin-dependent
glucose transporter
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Lipoprotein Lipase
VLDL (from
liver)
Chylomicrons
(from gut)
Mocha: Skeletal Muscle
↑Insulin, ↓Glucagon
Amino Acids
(from gut)
TCA
Acetyl CoA
Pyruvate
Amino acids
Glycogen
Glucose 6-P
Protein
Glucose
Glut4
Glucose (from gut)
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Fasting
Fasting: ↓Insulin and ↑Glucagon
α:
Glucagon
β:
Insulin
δ:
Somatostatin
-↓Glucose increases glucagon secretion;
insulin secretion is not stimulated.
Fasting State: Liver
↓ Insulin, ↑Glucagon
Glycogen
Glucose 6-P
Glucose
Pyruvate
Amino acids,
glycerol,
lactate
Acetyl CoA
Glucose
Ketone bodies
TCA
Fatty acid
Fatty acids
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Ketone
bodies
Fasting State: Adipose Tissue
TCA
Acetyl CoA
Triglyceride
Fatty acids
Fatty acids
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Glycerol
Glycerol
↓ Insulin, ↑Glucagon
Fasting State: Skeletal Muscle
↓ Insulin, ↑Glucagon
Amino Acids
Fatty acids
Fatty acids
Amino acids
TCA
Acetyl CoA
Protein
Ketone bodies
Adapted from Biochemistry, 4th Ed, Lippincott’s Illustrated Reviews 2007
Ketone
bodies
Factors that affect insulin secretion
Glucose (composition and content)
 Route of glucose delivery (PO or IV)
 Degree of insulin sensitivity

Factors Affecting Insulin Secretion
Insulin Resistant
140
80
120
70
Insulin (µIU/mL)
Glucose (mg/dL)
Insulin Sensitive
100
80
60
40
60
50
40
30
20
20
10
0
0
8am 10am noon 2pm
breakfast
lunch
4pm
8am
breakfast
10am noon
lunch
2pm
4pm
Insulin Suppression Test
250
200
150
Octreotide
Insulin
Glucose
Steady-State Plasma Glucose
Plasma Insulin (μIU/mL)
Plasma Glucose (mg/dL)
SSPG
100
SSPI
50
Steady-State Plasma Insulin
0
0
150
Time (min)
160
170
180
Distribution of Insulin Resistance in Nondiabetic Individuals
14
12
%
10
8
6
4
2
0
20
60
100
140
180
220
260
SSPG (mg/dL)
Insulin Resistance
300
340
Tertiles of Insulin Resistance
14
12
10
%
8
6
4
2
0
20
60
100
140
180
220
260
SSPG (mg/dL)
Insulin Resistance
300
340
Glucose-stimulated Insulin Secretion (GS-IS)
900
GS-IS (pmol/min)
800
700
600
Insulin Resistant
500
400
300
200
Insulin Sensitive
100
0
5
6
7
Glucose (mmol/L)
8
9
Clinical Relevance

Insulin dosing in individuals with diabetes
◦ Insulin: carbohydrate ratio
◦ Insulin sensitivity factor (amount decrease in glucose per 1
unit of insulin)
Clinical Relevance: Insulin Dosing
Insulin Sensitive
Insulin Resistant
Glucose (mg/dL)
Insulin dose
Glucose (mg/dL)
Insulin dose
< 70
Eat
<70
Eat
71-130
1 unit: 20 gm CHO
(4 units for Mocha)
71-130
1 unit: 5 gm CHO
(16 units for Mocha)
131-150
0
131-150
+1
151-250
+1
151-175
+2
251-300
+2
176-200
+3
301-400
+3
201-225
+4
>400
+4
226-250
+5
251-275
+6
Other Regulators of Insulin Secretion

Incretins: ↓Glucose
◦ GLP-1
Incretin Effect
Perley MJ and Kipnis DM. JCI 1967;46:1954-1962
Incretin Effect

GLP-1:
◦ Synthesized and secreted by L-cells in intestine
(mainly ileum and colon)
◦ Stimulates glucose-dependent insulin secretion
◦ Inhibits glucagon secretion
◦ Slows gastric emptying
Exenatide (Byetta)

Synthetic version of exendin-4, a
hormone found in the saliva of
Gila monster

53% amino acid homology to GLP1

Currently approved for treatment
of type 2 diabetes (2005)
Heloderma suspectum
“Gila monster”
Incretin-based Therapies for Type 2 Diabetes

GLP-1 Mimetics:
◦ Exenatide (Byetta)
◦ Liraglutide (Victoza)

Albiglutide (Tanzeum)
Dulagutide (Trulicity)
Dipeptidyl peptidase 4 Inhibitors (DPP4),
enzyme responsible for GLP-1 inactivation
◦ Sitagliptin (Januvia)
◦ Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
Regulators of Insulin Secretion
GLP-1
Insulin Secretion Rate (pmol/L)
Pharmacologic Treatment with GLP-1 (liraglutide)
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Baseline
5
6
7
Glucose (mmol/L)
8
9
Insulin Secretion Rate (pmol/L)
Pharmacologic Treatment with GLP-1 (liraglutide)
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Baseline
After
5
6
7
Glucose (mmol/L)
8
9
Gastric Bypass
BMI (kg/m2)
50
45
34%
11%
40
35
30
Baseline
25
1 month
20
9 month
15
10
5
0
Baseline
1 month
9 month
GLP-1 (pmol/l)
Gastric Bypass
160
140
120
100
80
60
40
20
0
Baseline
0
30
60
90
9month
120 150 180 210 240
Time (minutes)
75-gram glucose
1month
Control of Prandial Glucose
Ahren B. Nature Reviews 2009; 8:369-85.
Other Regulators of Glucose

Counter-regulatory Hormones (beside
glucagon): ↑Glucose
◦ Epinephrine: ↑glycogenolysis, ↑lipolysis, ↓insulin
secretion, ↓insulin-mediated glucose uptake
◦ Growth Hormone: ↓insulin-mediated glucose
uptake, ↑hepatic glucose production
◦ Cortisol: ↓insulin-mediated glucose uptake,
↑hepatic glucose production
Responses to Hypoglycemia
Blood Glucose (mg/dL)
80
↓Insulin secretion
70
↑Glucagon; ↑Epinephrine
↑Growth Hormone
60
↑Cortisol
50
Adrenergic symptoms begin: anxiety, palpitations, tremor,
sweating
Neuroglycopenic symptoms begin: headache, confusion, slurred
speech, seizures, coma, death
40
Service FJ. NEJM 1995; 332:1144-1152
Outline Revisted

Main regulators of glucose homeostasis:
 insulin and glucagon

Metabolic activities during feeding:
 ↑insulin and ↓glucagon

Metabolic activities during fasting:
 ↓insulin and ↑glucagon

Other regulators of glucose
◦ GLP-1
◦ Counter-regulatory hormones
BEFORE
AFTER
Necrolytic Migratory Erythema
McGevna L, Tavakkol Z. N Engl J Med 2010;362:e1.