THE ROLES OF ALPHA, BETA CELLS AND ISLET CELLS DYSFUNCTION IN T2DM

Agung Pranoto Diabetes and Nutrition Center Dr Soetomo Hospital, Airlangga University

Topics
Glucose normal Homeostasis Incretins, DPP-4 Inhibition & Islet Cell ALPHA, BETA CELLS (Islet Cells Pathofisiology) in T2DM Islet Enhancer Vildagliptin and DPP-4 Inhibition

Topics
Glucose normal Homeostasis Incretins, DPP-4 Inhibition & Islet Cell ALPHA, BETA CELLS (Islet Cells Pathofisiology) in T2DM Islet Enhancer Vildagliptin and DPP-4 Inhibition

Effects Upon Insulin Secretion by the Autonomic Nervous System, Gut Hormones, Amino Acid and Drugs
Adrenal medulla Sympathetic nerves Norepinephrine Parasympathetic nerves Ach PI PLC Galanin Somatostatin

AC GI G I cAMP
PKA + cAMP
GDH Metabolism Leucine

IP3 DAG

IP3R PKC Gs

Amino acids
Depolarization Arginine +

VIP

Gs
SUR

GLP I GIP Gut hormones (Incretins)

Sulfonylureas Diazodine

Weir et al, 2000

Figure 8. Dose-response relationships for effect of glucose to suppress glucagon and stimulate insulin release from the perfused rat pancreas. (Copyright 1974 by J Clin Invest.

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DIABETES Type 2 Diabetes

INCRETIN

Anti-incretin factors

Hypoinsulinemia

Figure 3. Hypothesis as to the mechanism responsible for the control of diabetes after gastric bypass.

Topics
Glucose normal Homeostasis Islet Cell Incretins, DPP-4 Inhibition & Islet Cell ALPHA, BETA CELLS (Islet Cells Pathofisiology) in T2DM Islet Enhancer Vildagliptin and DPP-4 Inhibition

Pancreatic Islet Dysfunction Leads to Hyperglycemia in T2DM

Fewer -Cells Insufficient Insulin + -Cells Hypertrophy Excessive Glucagon +

Glucose Uptake

Glucose

HGO

HGO=hepatic glucose output Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191198. 19

Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin/Glucagon Ratio)

400 mg/dL 300 200 100 0 150 U/mL 100 50 0 150 pg/mL NGT T2DM CHO meal NGT T2DM

Glucose

Insulin

125
100 75 -60 0 60 120 Time (min) 180 240

Glucagon
NGT T2DM

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus Adapted from Mller WA, et al. N Engl J Med. 1970; 283: 109115.

Insufficient Insulin and Elevated Glucagon in IGT ( Insulin/Glucagon Ratio)

250 mg/dL 200 150 100 50 600 pmol/L 400 200 0 45 pmol/L 40 35 30 25 -60 0 60 120 Time (min) 180 240 300 NGT IGT Glucose

Glucose

NGT IGT

Insulin

NGT IGT

Glucagon

IGT=impaired glucose tolerance; NGT=normal glucose tolerance Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 2229.

Suppression of Endogenous Glucose Production Is Impaired in T2DM

Meal
18 NGT (n=12) T2DM (n=18)

Endogenous Glucose (mol/min/kg)

14

10

2 30 15 0 30 60 90 120 150 180 210 240 270 300 Time (min)

NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus Adapted from Kelley D, et al. Metabolism. 1994; 43: 15491557.

Decreased Glucose Disposal and Increased HGP Contribute to Increased FPG in T2DM
2.8 2.4 Glucose 2.0 Clearance 1.6 (mL/kg min) 1.2 0.8 50 100 150 200 250 300

Diagnosis Impaired insulin-mediated glucose disposal

4.5 4.0 3.5 HGP 3.0 (mg/kg min) 2.5 2.0 1.5 1.0 50 100 150 200 250

Excessive glucagon-mediated glucose output

300

FPG (mg/dL)
FPG=fasting plasma glucose; HGP=hepatic glucose production; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Diabetes. 1988; 37: 667687.

GLP-1 Restores Insulin and Glucagon Responses in a Glucose-Sensitive Manner in Patients with T2DM
N=10
300

Glucose (mg/dL)
3.0

C-Peptide (nmol/L)
30

Glucagon (pmol/L)
GLP-1 infusion
25

GLP-1 infusion
250 2.5

GLP-1 infusion

200

2.0 * *

20 *

150

1.5

15 * *

*
* 100 * * 50 * * * 0.0 30 0 0.5 1.0

10 * * 5 * *

0 30 0

30 60 90 120 150 180 210 240 Time (Min)

30 60 90 120 150 180 210 240 Time (Min)

0 30

30 60 90 120 150 180 210 240 Time (Min)

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus *P <0.05 GLP-1(736 amide) infused at 1.2 pmol/kg/min for 240 minutes. Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741744.

GLP-1

Placebo
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Topics
Glucose normal Homeostasis Incretins, DPP-4 Inhibition & Islet Cell ALPHA, BETA CELLS (Islet Cells Pathofisiology) in T2DM DPP-4 Inhibition & Islet Enhancer Vildagliptin

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VILDAGLIPTIN

Blocking DPP-4 Can Improve Incretin Activity and Correct the Insulin:Glucagon Ratio in T2DM
Insulin
Further impaired islet function

T2DM
Incretin response diminished

Hyperglycemia

Glucagon

DPP-4 inhibitor Incretin activity prolonged

Insulin
Improved islet function

Improved glycemic control

Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573. 28

Vildagliptin: A Potent and Selective DPP-4 Inhibitor

H HO N

O
N

Highly selective DPP-4 inhibitor Has a high affinity for the human enzyme Reversible inhibition

X-ray crystallographic structure of vildagliptin (green) bound to the active site (yellow) of human DPP-4
DPP-4=dipeptidyl peptidase-4 29

Conclusion
Normal glucose homeostasis maintain by healthy alpha & beta islet cell Incretins, DPP-4 Inhibition & Islet Cell work synergistically to keep blood glucose concentrations normal

Pathomechanisms of T2DM are insulin resistance, Insufficient Insulin and elevated Glucagon
A new target treatment is pancreatic alpha cell dysfunction

VILDAGLIPTIN

UPCOMING EVENT
WORLD DIABETES DAY (14 Nov 2008)

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UPCOMING EVENT
WORLD DIABETES DAY (14 Nov 2008)

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TERIMA KASIH

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