1. Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: How Do They Exert Their Metabolic Actions? Part 6

2. GLP-1 Regulates Central Feeding Behavior
Intracerebroventricular injection of GLP-1 causes a dose-response decrease in food intake in rats. As shown in the insert in the upper right, GLP-1 receptors are abundant in the paraventricuar nucleus of the hypothalamus and the central nucleus of the amygdala.
Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69-72.

3. Change in Body Weight Over 24 Weeks: Sitagliptin Monotherapy Studies
In a 24-week study, sitagliptin was shown to have no effect on body weight in patients with T2DM.
Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;2(12):

4. Sitagliptin + Pioglitazone Are Weight Neutral Compared to Pioglitazone Alone in T2DM
In a 24-week study, sitagliptin did not blunt the weight gain observed with pioglitazone treatment in patients with T2DM.
Rosenstock J, Brazg R, Andryuk PJ, et al; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):

5. Exenatide Continued to Reduce Weight in 3-Year Completers (n=217)
Exenatide produced progressive weight loss over a 3-year period.
Buse J, Macconell L, Stonehouse A, et al. Exenatide maintained glycemic control with associated weight reduction over three years in patients with type 2 diabetes. Presented at: ADA 67th Scientific Sessions; June 22-26, 2007; Chicago, IL. Abstract 0283-OR.

6. GLP-1 and Central Nervous System
Induces the differentiation of neuronal cells in culture, similar to nerve growth factor
Protects against neuronal death, via a mechanism involving increased cAMP
Protects against beta-amyloid–induced neurotoxicity (Alzheimer’s disease) and suppresses neurodegenerative cascades
GLP-1 analogues may have a role in the prevention of neurodegenerative disorders.

7. Actions of DPP-4 Inhibitors and GLP-1R Agonists in Regulating Glucose Homeostasis
Differences between the effect of DPP-4 inhibitors and GLP-1 receptor agonists (exenatide) are related to differences in the plasma GLP-1 levels achieved with the two therapies. DPP-4 inhibitors cause a physiologic rise in the plasma GLP-1 concentration (to pmol/L), whereas exenatide causes a pharmacologic rise in the plasma GLP-1 concentration (50-60 pmol/L). Satiety, weight loss, and delayed gastric emptying only are observed with pharmacologic levels of GLP-1, ie, as seen with exenatide.

8. Summary of Pharmacologic Incretin Actions on Different Target Tissues
Heart
Brain
Neuroprotection
Stomach
Appetite
Gastric
Emptying
Cardioprotection
Cardiac Output
GLP-1 _
Liver
Same as slide #4 – emphasize cardiac aspects.
Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):
GI Tract
Insulin Secretion
β-Cell Neogenesis
β-Cell Apoptosis
Glucagon Secretion
Glucose
Production +
Glucose
Uptake
Muscle
Drucker DJ, Cell Metab. 2006;3:

9. Cardiac Actions of GLP-1
↑ Cardiac output, ↓ LV end diastolic pressure, and ↑ myocardial glucose uptake in animal (rodent and dog) models of CHF and myocardial injury
↓ Infarct size in ischemic animal models
↑ LVEF and ↑ wall motion in humans with MI and EF <40%
GLP-1 (9-36)amide ↑ myocardial contractility (dp/dt) and glucose uptake in dogs with cardiomyopathy
GLP-1 and its metabolites may have clinically important effects to enhance cardiac performance.

10. Emerging Roles of Bioactive GLP-1 Metabolites
GLP-1 (7-36) amide and GIP (1-42) amide (left) and the metabolites of GLP-1 (9-36) amide (right) have multiple and diverse metabolic and cardiovascular effects. By blocking the generation of some of the metabolites of GLP-1 (7-36) amide, DPP-4 inhibitors may reduce the effectiveness of endogenously secreted GLP-1 on some metabolic/cardiovascular pathways.
Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care. 2007;30(6)

11. DPP-4 Degrades Multiple Peptide Substrates
DPP-4 degrades multiple peptides in the human body. The long-term effect(s) of inhibition of the degradation of these peptides remains to be determined.
Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care. 2007;30(6)

12. GLP-1R Agonists vs DPP-4 Inhibitors
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):

13. Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47(2):159-169.
GLP-1 vs DPP-4 Inhibitors: Understanding the Antidiabetic Actions of Incretin-Based Therapies
This slide highlights areas of similarity among GLP-1 receptor agonists and DPP-4 inhibitors (both enhance glucose-dependent insulin secretion and decrease inappropriate glucagon secretion), as well as areas of difference (only GLP-1 agonists slow gastric emptying, and act centrally to promote satiety and decrease feeding).
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101(3):
Larsson H, Holst JJ, Ahrén B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand. 1997;160(4):
Nauck MA, Wollschläger D, Werner J, et al. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia. 1996;39(12):
Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47(2):