Amylin: The Other ² Cell Hormone

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  • Amylin:The Other Cell Hormone

    John Buse, MD, PhDProfessor of Medicine

    Chief, Division of EndocrinologyUNC School of Medicine

    Chapel Hill, NC USA

  • Beaumont K, et al. Mol Pharm. 1993; 44:493-497Muff R, et al. Endocrinology. 1999; 140:2924-2927

    AmylinAmylin

    Receptor image Adapted from Christopoulos G, et al. Mol Pharmacol. 1999; 56: 235-242

    Peptide hormone co-localized and co-secreted with insulin 37 amino acid peptide related to calcitonin, CGRP, adrenomedullin Amylin gene - chromosome 12

    Neuroendocrine peptide Receptor identified Binding sites in CNS

    Area postremaDorsal raphaeNucleus accumbens

    C C

    N N

    Amylin Receptor

    RAMP1 CTR

    Amylin Binding Sites in the Brain

    Dorsal Raphe

    Nucleus Accumbens Area Postrema

  • Amylin Is Co-Secreted With InsulinAmylin Is Co-Secreted With Insulin

    Plas

    ma

    Insu

    lin (p

    M)

    25

    20

    15

    10

    57 am Midnight5 pm12 noon

    Time (24 h)

    600

    400

    200

    0

    Meal Meal Meal

    Plas

    ma

    Am

    ylin

    (pM

    )

    30

    InsulinAmylin

    Healthy adults; n = 6Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

  • Hepatic Glucose Output in Diabetes is Abnormally Increased After Meals

    Hepatic Glucose Output in Diabetes is Abnormally Increased After Meals

    Time (min)H

    epat

    ic G

    luco

    se O

    utpu

    t (m

    mol

    /min

    )

    -15 30 60 90 120 150 180

    2.0

    1.5

    1.0

    0.5

    Meal *

    * *

    Type 1 DiabetesSubjects Without Diabetes

    Time (min)

    Hep

    atic

    Glu

    cose

    Out

    put

    (m

    ol/k

    g/m

    in)

    5

    10

    15

    0 100 200 400300

    Meal

    Type 2 DiabetesSubjects Without Diabetes

    Type 2 Diabetes: P

  • Deficient Insulin and Hypersecreted GlucagonDeficient Insulin and Hypersecreted Glucagon

    Defects in diabetes:

    Deficient insulin release

    Glucagon not suppressed(postprandially)

    Hyperglycemia

    Mea

    l

    120

    60

    0

    Insulin(U/mL)

    100

    120

    140

    -60 0 60 120 180 240

    Time (min)

    Glucagon(pg/mL)

    360

    300

    240110

    80

    Glucose(mg/dL)

    Without Diabetes (n=14)Type 2 Diabetes (n=12)

    TYPE 2 DIABETESTYPE 2 DIABETES

    Data from Muller WA, et al. N Engl J Med 1970; 283:109-115

  • Plasma Glucose AUC0-30 min(mmol/L/min)

    Gastric-Emptying Rate Is an Important Determinant of Postprandial GlycemiaGastric-Emptying Rate Is an Important Determinant of Postprandial Glycemia

    % Emptied at 30 min

    260

    10 20 30 400

    240

    220

    200

    180

    160

    140

    Subjects without diabetes ; n = 16r = 0.58; P

  • Gastric Emptying Is Accelerated in DiabetesGastric Emptying Is Accelerated in Diabetes

    Type 1

    *

    Without DiabetesDiabetes

    0

    120

    180

    60

    0

    20

    40

    60

    80

    Type 2

    **

    Gas

    tric

    Hal

    f-Em

    ptyi

    ng T

    ime

    (min

    )

    Gas

    tric

    Hal

    f-Em

    ptyi

    ng T

    ime

    (min

    )

    Type 2: without diabetes, n = 9; type 2 diabetes, n = 9; *P

  • Amylin Is Deficient in DiabetesAmylin Is Deficient in Diabetes

    Time After Sustacal Meal (min)

    0

    5

    10

    15

    20

    -30 0 30 60 90 120 150 180

    Meal

    Late Stage Type 2

    Type 1

    Without DiabetesPl

    asm

    a A

    myl

    in (p

    M)

    Without diabetes; n = 27Late-stage type 2; n = 12Type 1; n = 190Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

  • Plasma Glucose

    Tissues

    GlucoseDisposal

    Rate ofglucose

    appearance

    Rate ofglucose

    disappearance

    Stomach

    BrainFoodIntake

    GastricEmptying

    Liver

    GLP-1

    Gut

    Multihormonal Regulation of GlucoseMultihormonal Regulation of Glucose

    PostprandialGlucagon

    Pancreas

    Insulin

    Insulin helps regulate glucose

    disappearance

    Amylin

    Amylin helps regulate glucose

    appearance

    APPEARANCE AND DISAPPEARANCEAPPEARANCE AND DISAPPEARANCE

    Model derived from animal studiesAdapted from Edelman S, et al. Diabetes Technol Ther 2002; 4:175-189

  • PramlintidePramlintide An analog of amylin that overcomes the tendency of human amylin to:

    Aggregate, form insoluble particles Adhere to surfaces

    Pharmacokinetic and pharmacodynamic properties similar to human amylin

    Human amylin Pramlintide (analog of amylin)

    AmideS S

    AY

    TNS

    GV N

    T

    T TT

    N

    AA

    A

    LI

    KS

    SC

    CQ

    RL N

    NNF

    G

    FL

    VH

    Amide

    PP P

    YT

    NS

    GV N

    T

    T TT

    N

    AA

    A

    LI

    KS

    SC

    CQ

    RL N

    NNF

    G

    FL

    VH

    Adapted from Young A, et al. Drug Dev Res 1996; 37:231-248Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87: 5036-5040

  • Pramlintide Reduces Postprandial GlucagonPramlintide Reduces Postprandial Glucagon

    Type 1 Diabetes

    Time (h)

    PlaceboPramlintide

    Placebo or 25 g/h pramlintide infusion-20

    0

    10

    20

    30

    -10

    InsulinSustacal

    0 2 3 4 51

    Type 2 Diabetes, Insulin treated

    Time (h)

    Plas

    ma

    Glu

    cago

    n (p

    g/m

    L)

    InsulinSustacal60

    40

    30

    50

    Placebo or 100 g/h pramlintide infusion

    0 1 2 3 4 5Pl

    asm

    a G

    luca

    gon

    (pg/

    mL)

    Type 2 diabetes, n = 12; AUC1-4 h: P = 0.005Type 1 diabetes, n = 9; AUC1-5 h: P

  • Effect of Pramlintide on Gastric Emptyingin Type 1 Diabetes

    Effect of Pramlintide on Gastric Emptyingin Type 1 Diabetes

    MeanHalf-Emptying

    Time (h)

    0

    1

    2

    3

    4~1-h delay*

    60 g

    *

    30 gPlacebo

    Insulin + PlaceboInsulin + PramlintideBreakfast

    Single SC pramlintide doses: n = 11, crossover; *P

  • Pramlintide Reduces Caloric Intakein Type 2 Diabetes

    Pramlintide Reduces Caloric Intakein Type 2 Diabetes

    0

    250

    500

    750

    1000

    1250

    Protein

    CHO

    Fat

    CHO

    Fat

    Protein

    -202 kcal(-23%)P

  • Pramlintide Clinical EffectsPramlintide Clinical Effects

    -2

    -1

    0

    1

    * **

    **

    **

    ****

    ****-4

    -2

    0

    2

    4

    6

    8

    -0.8

    -0.6

    -0.4

    -0.2

    0

    Insulin Use (%) A1C (%) Weight (kg)

    Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

    Placebo + Insulin120 g Pramlintide BID + Insulin

    TYPE 2 DIABETES COMBINED PIVOTALSTYPE 2 DIABETES COMBINED PIVOTALS

    ITT; Mean (SE); *P

  • Pramlintide Reduces Fasting andPostprandial Glucose

    Pramlintide Reduces Fasting andPostprandial Glucose

    Baseline6 Months

    120

    140

    160

    180

    200

    220

    Glu

    cose

    (mg/

    dL)

    pre-bf post-bf pre-lu post-lu pre-di post-di bedtime

    **

    *

    **

    * *

    TYPE 2 DIABETESTYPE 2 DIABETES

    N = 166; *P

  • Pramlintide Clinical EffectsPramlintide Clinical Effects

    -0.8

    -0.6

    -0.4

    -0.2

    0

    -4

    -2

    0

    2

    4

    6

    8

    -2

    -1

    0

    1

    ***

    ***

    ***

    **

    *

    ***

    *** ***

    Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

    Insulin Use (%) A1C (%) Weight (kg)

    Placebo + Insulin30 or 60 g Pramlintide TID or QID + Insulin

    TYPE 1 DIABETES COMBINED PIVOTALSTYPE 1 DIABETES COMBINED PIVOTALS

    ITT; Mean (SE); *P

  • Pramlintide Reduces Fasting andPostprandial Glucose

    Pramlintide Reduces Fasting andPostprandial Glucose

    120

    140

    160

    180

    pre-bf post-bf pre-lu post-lu pre-di post-di bedtime

    Glu

    cose

    (mg/

    dL)

    Baseline6 Months

    **

    TYPE 1 DIABETESTYPE 1 DIABETES

    N = 265; *P

  • Pramlintide Reduces Postprandial GlucosePramlintide Reduces Postprandial Glucose

    Pre-Breakfast Post-Breakfast

    100

    150

    200

    250

    Mean Glucose (mg/dL)

    Time (d)-7 30 60 90 1200 150 200170

    Time (d)-7 30 60 90 1200 150 200170

    100

    150

    200

    250

    Mean Glucose (mg/dL)

    PlaceboPramlintide

    PlaceboPramlintide

    TYPE 1 DIABETESTYPE 1 DIABETES

    Placebo, n = 147Pramlintide, n = 148

  • Study DesignStudy Design

    Pramlintide 120 g + Insulin Glargine

    Placebo + Insulin Glargine

    0 4 8 12 16

    Insulin Glargine Dose Titration (FPG target 70 and

  • Change in A1C From Baseline to Week 16Change in A1C From Baseline to Week 16

    MeanSE; ITT LOCF: Placebo N = 106; Pramlintide N = 105*p

  • Change in Glucose FluctuationsChange in Glucose Fluctuations

    100

    125

    150

    175

    200

    225

    250

    BaselineWeek16

    ******

    ***

    MeanSE; ITT observed**p

  • Change in Body Weight From Baseline to Week 16Change in Body Weight From Baseline to Week 16

    0 4 8 12 16-2.0

    -1.5

    -1.0

    -0.5

    0.0

    0.5

    1.0

    1.5

    Time (Weeks)

    *** ***

    *** ***

    ***

    -2.3 0. 4 kg

    MeanSE; ITT LOCF: Placebo N=106; Pramlintide N=105***p

  • Proportion of Patients Achieving