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Glucose Regulation in the Body: New Understandings for Management Curtis Triplitt, PharmD, CDE Texas Diabetes Institute Assistant Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX 1

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Glucose Regulation in the Body:

New Understandings for Management

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute

Assistant Professor, Medicine/Diabetes

University of Texas Health Science Center at San Antonio

San Antonio, TX

1

2

Faculty InformationPresenter

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute

Assistant Professor, Medicine/Diabetes

University of Texas Health Science Center at San Antonio

San Antonio, TX

Q&A Moderator

Jeff D. Prescott, PharmD, RPh

Vice President, Clinical and Scientific Affairs

American Journal of Managed Care

This activity is supported by an educational grant from

Bristol-Myers Squibb and AstraZeneca LP.

3

Disclosures

Curtis Triplitt, PharmD, CDE, has disclosed the following commercial

financial relationships:

Consultant/Advisory Board: Roche, Takeda Pharmaceuticals

Speaker’s Bureau: Amylin, Eli Lilly, Pfizer

The planning staff from Pharmacy Times Office of Continuing

Professional Education have no relevant financial relationships to

disclose related to this program.

The contents of this webinar may include information regarding the use

of products that may be inconsistent with or outside the approved

labeling for these products in the United States. Physicians should note

that the use of these products outside current approved labeling is

considered experimental and are advised to consult prescribing

information for these products.

4

Educational Objectives

After completion of this activity, participants should be better able

to:

• Examine pathophysiology of diabetes and different mechanisms

involved in maintaining glucose balance

• Explain new understandings in defects of glucose balance and

their role in the pathophysiology of diabetes

• Review the role of different organ systems in maintaining

glucose homeostasis

5

Pharmacy Accreditation

Pharmacy Times Office of Continuing

Professional Education is accredited by the

Accreditation Council for Pharmacy Education

(ACPE) as a provider of continuing pharmacy

education. This enduring activity is approved for 1

contact hour (0.1 CEU) under the ACPE universal

activity number 0290-9999-11-046-H01-P. This

activity is available for CE credit through October

19, 2013.

Type of Activity: Knowledge

Glucose Regulation in the Body: New

Understandings for Management

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute

Assistant Professor, Medicine/Diabetes

University of Texas Health Science Center at San Antonio

San Antonio, TX

6

7

Glucose Regulation in Diabetes

1. How is glucose tightly regulated in normal healthy people?

2. What are the problems that cause glucose regulation to be

abnormal in diabetes?

3. How can each of these 8 key abnormalities be addressed in

diabetes?

8

The “Lingo”

• Gluconeogenesis: making glucose

• Glycogen: stored glucose

• Glycogenolysis: breaking down stored glucose

• FFA: free fatty acid

• Ra: rate of appearance of glucose

• Rd: rate of disappearance of glucose

• NGT: normal glucose tolerance

• IGT: impaired glucose tolerance

• T2DM: type 2 diabetes mellitus

• GLP-1: glucagon-like peptide-1

• GIP: glucose-dependent insulinotropic polypeptide

9

Glucose

REASN14-6/2000

Pathogenesis of Type 2 Diabetes: Insulin

Resistance and -Cell Dysfunction

-Cell Dysfunction

Pancreas Liver Muscle Fat

Insulin Resistance

REASN14-6/2000

Pathogenesis of Type 2 Diabetes: Insulin

Resistance and -Cell Dysfunction

-Cell Dysfunction

Pancreas Liver Muscle Fat

Insulin Resistance

GLUCOSE

INPUTS

1. Gut (meals)

2. Liver (makes and

stores glucose)

3. Muscle (storage)

GLUCOSE

BLOOD

VESSEL

REASN14-6/2000

Pathogenesis of Type 2 Diabetes: Insulin

Resistance and -Cell Dysfunction

-Cell Dysfunction

Pancreas Liver Muscle Fat

Insulin Resistance

Insulin-Sensitive

Tissues

The rate of movement of glucose out of the circulation is called

the glucose disposal rate (Rd)

The rate of glucose appearance into the blood is called Ra

which is mainly from the liver or a meal

10

Normal, Hyper-, and Hypoglycemic States

Ra = the rate of appearance of glucose

into the blood

Rd = the rate of disappearance of

glucose from the blood

When Ra = Rd = “Euglycemic”

HYPERGLYCEMIA HYPOGLYCEMIA

Ra > Rd; Ra↑ or Rd↓ Ra < Rd; Ra↓ or Rd↑

Rd

Ra

50

mg/dL

Ra

Rd

50

mg/dL

Ra

Rd

200

mg/dL

Ra

Rd

200

mg/dL

Ra

Rd

100

mg/dL

11

Glucose Regulation Is Tightly Controlled

12

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

HYPERGLYCEMIA

Ominous Octet

13

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

DRUG?

Ominous Octet

HYPERGLYCEMIA

14

Muscle insulin resistance

Liver HGP (gluconeogenesis)

Pancreas insulin secretion

Fat cell “sick”

Adipocytes represent a storage depot for energy

(ie, fat). When the capacity of adipocytes to

store fat is exceed, there is an overflow of fat to:

HGP indicates hepatic glucose production.

Overflow Hypothesis

FFA

Gluconeogenesis

FFA

FFA

GlucoseOxidation

Insulin

Secretion

FFA indicates free fatty acid. 15

Lipotoxicity

Send discussion questions to

[email protected]

16

Relationship Between Insulin Sensitivity and

Intramyocellular Triglyceride Concentration in

Pima Indians With NGT

Skeletal Muscle–Associated Triglyceride

( mol/g wet weight of tissue)

0.2

0.4

0.6

0.8

06 8 102 4

r = -0.53

P <.0006

FFM indicates fat-free mass; NGT, normal glucose tolerance.

Reprinted with permission from Pan DA, Lillioja S, Kriketos AD, et al. Diabetes. 1997;46(6):983-988.

Insu

lin S

en

sitiv

ity

(Cla

mp

Lo

g1

0M

)

(mg/m

in·k

g F

FM

+ 1

7.7

)

17

Baseline

With

Insulin

Baseline

With

Insulin

0

25

50

75

100

125

Suppre

ssio

n o

f H

GP

(mg/m

2 ●

min

)

Low LiverFat (1.7%)

High LiverFat (10.5%)

a

FPI (pM)

Lo Fat 32±4Hi Fat 44±3b

LEAN MEN WITHOUT

DIABETES

aP <.05; bP <.02.

FPI indicates fasting plasma insulin; HGP, hepatic glucose production.

Seppälä-Lindroos A, Vehkavaara S, Häkkinen AM, et al. J Clin Endocrinol Metab. 2002;87(7):3023-3028.

Impact of Hepatic Fat Content on Ability to

Decrease Hepatic Glucose Production

18Adapted from Ryysy L, Häkkinen AM, Goto T, et al. Diabetes. 2000;49(5):749-758.

Fat mass (kg)

% S

up

pre

ss

ion

of

EG

P b

y I

ns

ulin

Liver fat (%)Liver fat (%)

Ins

ulin

Do

se

(U

/da

y)

Liv

er

fat

(%)

10 20 30

-100

-50

0

20 30 40

10

20

30

10 20 30

100

200

0

r = 0.72

P <.01

r = 0.76

P <.001

r = 0.73

P <.001

0 00

0

T2DM Patients Treated With Bedtime Insulin + Metformin

EGP indicates endogenous glucose production; T2DM, type 2 diabetes mellitus.

Liver Fat Content and Suppression of

Glucose Production From Liver

19

ADIPOCYTE

ASP & Adipsin

FFA

TNF

MIF

IL-6

Leptin

PAI-1

Resistin

Angioten-sinogen

Adiponectin

ASP indicates acylation-stimulating protein; FFA, free fatty acid; IL-6, interleukin 6; MIF, macrophage migration inhibitory factor; PAI-1,

plasminogen activator inhibitor-1; TNF , tumor necrosis factor-alpha.

―Sick,‖ Dysfunctional Fat Cell

20

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

Ominous Octet

DRUG?

HYPERGLYCEMIA

21

• Major source of net endogenous glucose production (kidney

maybe 10%-15% fasting)

• Accomplished by gluconeogenesis and glycogenolysis when

glucose is low and glycogen synthesis when glucose is high

• Can oxidize glucose for energy and convert it to fat which can

be incorporated into VLDL for transport

• In T2DM, there is increased gluconeogenesis

Liver and Kidney

T2DM indicates type 2 diabetes mellitus; VLDL, very low density lipoprotein.

Send discussion questions to

[email protected]

22

DECREASE INCREASE

0

Parasympathetic

Hyperglycemia

Insulin

FFA

Cortisol

Glucagon

Epinephrine

Growth Hormone

Sympathetic

FFA indicates free fatty acid.

Regulation of Hepatic Glucose Production

23

DECREASE INCREASE

0

Parasympathetic

Hyperglycemia

InsulinFFA

Cortisol

Glucagon

Epinephrine

Growth Hormone

Sympathetic

Regulation of Hepatic Glucose Production

FFA indicates free fatty acid.

24

DECREASE INCREASE

0

Parasympathetic

Hyperglycemia

Insulin

FFA

Cortisol

Glucagon

Epinephrine

Growth Hormone

Sympathetic

Regulation of Hepatic Glucose Production

FFA indicates free fatty acid.

25

Direct effect: 60%-70%

Indirect effect: 30%-40%

— FFA (adipocyte)

— Glucagon (alpha cell)

— Gluconeogenic precursors

Amino acids (muscle)

Glycerol (adipocyte)

Direct Versus Indirect Effect of Insulin on

Hepatic Glucose Production

FFA indicates free fatty acid.

26DeFronzo RA, Ferrannini E, Simonson DC. Metabolism. 1989;38(4):387-395.

Basal H

GP

(m

g/k

g ●

min

)

2.8

2.4

2.0

1.6

P <.001

CONTROL T2DM

FPG (mg/dL)

FPG indicates fasting plasma glucose; HGP, hepatic glucose production; T2DM, type 2 diabetes mellitus.

Basal Hepatic Glucose Production in T2DM:

Relationship With Fasting Plasma GlucoseB

asal H

GP

(mg

/kg

●m

in)

2.0

2.5

3.0

3.5

4.0

100 200 300

r = 0.85, P <.001

• Control

• T2DM

27

• Can convert glucose to glycogen (storage)

• Can convert glucose to pyruvate through glycolysis;

pyruvate is further metabolized to lactate, transaminated

to alanine, or channeled into the TCA cycle (energy)

• In the fasting state, can utilize FFA for fuel and mobilize

amino acids by proteolysis for transport to the liver for

gluconeogenesis

• Can break down glycogen (mobilization of stored

glucose)

FFA indicates free fatty acid; TCA, tricarboxylic acid.

Muscle

28Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835. Cusi K, Maezono K, Osman A, et al. J Clin Invest. 2000;105(3):311-320; Miyazaki Y, He H, Mandarino LJ,

DeFronzo RA. Diabetes. 2003;52(8):1943-1950.

InsulinReceptor

Plasma Membrane

ProteinSynthesis

LipidSynthesis

GlycogenSynthesis

+ Artery

p85Akt

PI-3-Kinase

p110

IRS-1

GlucoseGLUT4

GLUT4 indicates glucose transporter type 4; IRS-1, insulin receptor substrate-1; NOS, nitric oxide synthase; PI-3, phosphatidylinositol-3.

Insulin Signaling System in Humans

29

+ Artery

InsulinReceptor

Plasma Membrane

p85 p110Akt

InflammationAtherosclerosis

Shc

PI-3-Kinase

IRS-1

GLUT4

GLUT4 indicates glucose transporter type 4; IRS-1, insulin receptor substrate-1; MAP, mitogen-activated protein; NOS, nitric oxide synthase; PI-

3, phosphatidylinositol-3. Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835. Cusi K, Maezono K, Osman A, et al. J Clin Invest. 2000;105(3):311-320; Miyazaki Y, He H, Mandarino LJ,

DeFronzo RA. Diabetes. 2003;52(8):1943-1950.

Insulin Signaling System in Humans

30

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

Ominous Octet

DRUG? DRUG?

HYPERGLYCEMIA

31

Ins

uli

n S

ecre

tio

n

AIR

U/m

L)

IGT

NGT

NGTNGT NGT

DIA

500

400

300

200

100

0

Insulin Sensitivity

M-low (mg/kg EMBS per minute)

Progressors

Non-Progressors

1 2 3 4 5

Reprinted with permission from Weyer C, Bogardus C, Mott DM, Pratley RE. J Clin Invest. 1999;104(6):787-794.

Early Insulin Secretion Increases

With Decreasing Insulin Action

AIR indicates acute insulin secretory response; DIA, diabetes; EBMS, estimated metabolic body size; IGT, impaired glucose tolerance;

NGT, normal glucose tolerance.

32FPG indicates fasting plasma glucose; IFG, impaired fasting glucose; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus.

FP

G

(mg

/dL

-cell

Vo

lum

e (%

)

4

3

2

1

0

250

200

150

100

50

NGT

NGT

IFG

IFG

P <.01

P <.01

T2DM

T2DM

P <.001

P <.001

Adapted from Butler AE, Janson J, Bonner-Weir S, et al. Diabetes. 2003;52(1):102-110.

Beta Cell Volume Is Related to

Fasting Plasma Glucose Levels

33Gastaldelli A, Ferrannini E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47(1):31-39.

IGT

30

20

10

0

40∆

IN

SU

LIN

/ ∆

G

LU

CO

SE

÷IR

Lean

NGT

Obese

2-Hour PG

(mg/dL)

T2DM

CALCULATED

VIA OGTT

IGT indicates impaired glucose tolerance; IR, insulin resistance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PG, plasma

glucose; T2DM, type 2 diabetes mellitus.

Ability to Release Insulin in

Response to a Glucose Load

34

Med

ian

HB

A1c (

%)

Time (years)

Glibenclamide

Metformin

9

8

7

6

0

0 3 6 9 12 15

Conventional

HbA1c indicates glycosylated hemoglobin; Rx, prescription; SU, sulfonylurea; UKPDS, United Kingdom Prospective Diabetes Study.

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853;

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865.

UKPDS: Effect of SU & Metformin Rx on HbA1c

35

Insulin Resistance

Age

β CellFailure

Genetics

(TCF7L2)

Lipotoxicity

FFA

Glucose

Toxicity

Amyloid (IAPP)Deposition

Incretin

Effect

Etiology of Beta Cell Failure in T2DM

FFA indicates free fatty acid; IAPP, islet amyloid polypeptide; TCF7L2, transcription factor 7-like 2; T2DM, type 2 diabetes mellitis.

36

Time After Sustacal® Meal, min

0

5

10

15

20

-30 0 30 60 90 120 150 180

Pla

sm

a A

mylin

, pm

ol/L

Meal

T1DM (n = 190)

Insulin-using T2DM (n = 27)

Without diabetes (n = 12)

Pla

sm

a Insulin

, pm

ol/L

30

25

20

15

10

5

Time, 24-h

600

400

200

0

Meal Meal Meal

Amylin

Insulin

Pla

sm

a A

mylin

, pm

ol/L

Healthy male adults (n = 6)

7 AM Midnight5 PM12 Noon

Central satiety; decreases glucagon; slows gastric emptying

Reprinted with permission from Kruger DF, Gatcomb PM, Owen SK. Diabetes Educ. 1999;25(3):389-397.

Amylin Is Co-Secreted With Insulin

and Deficient in Diabetes

T1DM indicates type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

37

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

Ominous Octet

DRUG?

DRUG? HYPERGLYCEMIA

The Incretin Effect Is Reduced

in Patients With T2DM

• In diabetic patients vs. healthy subjects challenged with

an oral 50 g glucose load and IV glucose:

o Differences between responses to oral and IV glucose were

attributed to factors other than glucose itself (incretin effect)

o After oral glucose, immunoreactive insulin and connecting

peptide responses were delayed in diabetic vs. healthy subjects

o After IV glucose, insulin and connecting peptide responses were

greater in diabetic patients vs. healthy subjects (as

consequence of higher glycemic stimulus)

Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Diabetologia. 1986;29(1):46-52.

GLP-1 and GIP Responses in T2DM

• Postprandial GLP-1 levels are decreased in patients with

IGT and T2DM, compared to controls with normal

glucose tolerance

o Most pronounced GLP-1 decreases seen in T2DM

• Glucose-dependent insulinotrophic polypeptide (GIP)

levels are increased in T2DM, compared to controls with

normal glucose tolerance

Toft-Nielsen MB, Damholt MB, Madsbad S, et al. J Clin Endocrinol Metab. 2001;86(8):3717-3723.

Jones IR, Owens DR, Luzio S, Williams S, Hayes TM. Diabetologia. 1989;32(9):668-677.

40Flint A, Raben A, Astrup A, Holst JJ. J Clin Invest. 1998;101(3):515-520; Larsson H, Holst JJ, Ahrén B. Acta Physiol Scand. 1997;160(4):413-422;

Nauck MA, Wollschläger D, Werner J, et al. Diabetologia. 1996;39(12):1546-1553; Drucker DJ. Diabetes. 1998;47(2):159-169.

Stomach:Helps regulate gastric

emptying

Promotes satiety and

reduces appetite

Liver:

Glucagon reduces hepatic

glucose output

(glycogenolysis)β cells:

Enhances glucose-dependent

insulin secretion

α cells:Postprandial

glucagon secretion

GLP-1: Secreted upon the

ingestion of food

Exenatide: IV infusion

GLP-1 indicates glucagon-like peptide-1; IV, intravenous.

GLP-1 Modulates Numerous Functions in Humans

41

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

DecreasedIncretin EffectDecreased Insulin

Secretion

Increased

Hepatic

Glucose

Production

IncreasedGlucagonSecretion

Increased Lipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased Glucose

Uptake

Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):787-835.

Islet α cell

Ominous Octet

DRUG?

HYPERGLYCEMIA

42

SGLT1

SGLT-2

(180 L/day) (900 mg/L) = 162 g/day

10%

90%

Glucose

NOGLUCOSE

S1

S3

SGLT indicates sodium glucose cotransporter.

Renal Handling of Glucose

Send discussion questions to

[email protected]

43Adapted from Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Diabetes. 2005;54(12):3427-3434.

CON T2DM

AMG UPTAKE

0

500

1000

1500

2000

CP

M

a

SGLT-2 PROTEIN

0

1

2

3

4

5

CON T2DM

a

SGLT-2 mRNA

CON T2DM

0

2

4

6

No

rma

lize

d G

luc

os

e

Tra

ns

po

rte

r L

eve

lsa

Fo

ld In

cre

as

e

IN HUMAN RENAL PROXIMAL TUBULAR CELLS

aP <.05 - P <.01.

AMG indicates methyl-α-D-[U14C]-glucopyranoside; CON, control; CPM, counts per minute; mRNA, messenger ribonucleic acid; SGLT, sodium

glucose cotransporter; T2DM, type 2 diabetes mellitus.

Increased SGLT-2 Glucose Transporter mRNA

44

• Multiple drugs are likely necessary in type 2 diabetes mellitus to address

the underlying abnormalities

– Brain: amylinomimetics, GLP-1 agonists, dopamine agonists

– Fat: thiazolidinediones (TZDs)

– Liver and muscle: metformin and TZDs, but HGP can be reduced by “mass

action” through increased insulin (insulin, SU, etc)

– Glucagon: GLP-1 agonists, DPP-4 inhibitors, amylinomimetics

– Insulin: insulin, sulfonylureas, meglitinides, DPP-4 inhibitors, and GLP-1

agonists

– Incretins: GLP-1 agonists, DPP-4 inhibitors, alpha glucosidase inhibitors (?),

bile acid sequestrants (?)

– Renal glucose absorption: SGLT-2 inhibitors (not currently on the market)

DPP-4 indicates dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; HGP, hepatic glucose production; SGLT, sodium glucose cotransporter; SU,

sulfonylurea; TZD, thiazolidinedione.

Summary

45

• Glucose is tightly regulated in our bodies

• Regulation can be disrupted through many different pathways

• At least 8 different pathways or abnormalities have been identified

in diabetes

• None of the pathways have been proved to fully correct all of the

abnormalities associated with type 2 diabetes mellitus

• Affecting multiple pathways is likely advantageous

Summary

46

THANK YOU!

For any questions regarding this activity, contact:

[email protected]

Glucose Regulation in the Body:

New Understandings for Management