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The Role of Alpha and Beta
The Role of Alpha and Beta
The Role of Alpha and Beta
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
Sulfonylureas Diazodine
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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13
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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
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
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.
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.
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10
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
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
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
0 30
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
25
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
Insulin
Improved islet function
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
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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