1. Incretin Physiology in Type 2 Diabetes Mellitus
Part 2

2. GLP-1 & GIP Secretion in Type 2 Diabetes Mellitus

3. Postprandial GLP-1 Levels Are Decreased in Patients With IGT and Type 2 Diabetes
During a meal tolerance test, GLP-1 levels are reduced in participants with IGT and further decreased in participants with T2DM.
Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86(8):

4. Glucose-Dependent Insulinotropic Polypeptide (GIP) Response During OGTT
In contrast to GLP-1 levels, plasma GIP is increased in patients with T2DM during an OGTT, while the plasma insulin response is diminished. This suggests resistance to the stimulator effect of GIP on insulin secretion and, in fact, this has been demon-strated by Holst et al. (Holst citation is included below for reference. Data does not appear on this slide.)
Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32(9):
Holst JJ, et al. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:

5. What Is DPP-4?
A serine protease widely distributed throughout the body
Cleaves N-terminal amino acids of a number of biologically active peptides, including the incretins GLP-1 and gastric inhibitory peptide (GIP), resulting in inactivation
Its effects on GLP-1 and GIP have been shown to affect incretin activity
Inactivates GLP-1 >50% in ~1 to 2 minutes
Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.

6. DPP-4
Rasmussen HB, Branner S, Wiberg FC, et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol. 2003;10(1):19-25

7. DPP-4 Action/Inhibition
DPP-4 is present ubiquitously in plasma and on cell membranes and rapidly cleaves two amino acids off of GIP and GLP-1, rendering them inactive. Inhibition of DPP-4 activity blocks the degradation of GLP-1 and GIP, and prolongs their half-life in the plasma.

8. Overview Discuss normal GLP-1 physiology
Examine the actions of DPP-4 inhibitors and GLP-1R agonists
Review the tissue-specific differences in the mechanisms of action of GLP-1 analogs, DPP-4 inhibitors, and GLP-1R agonists
Self-explanatory

9. Inhibition of DPP-4 Increases Active GLP-1
The half-life of GLP-1 is very short, 1 to 2 minutes, but can be prolonged markedly with a DPP-4 inhibitor.
Adapted from Rothenberg P, Kalbag J, Smith M, et al. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans. Diabetes. 2000;49(suppl 1):A39.

10. Normalization of Diurnal Plasma Glucose Concentrations by Continuous IV GLP-1
Rachman et al demonstrated that continuous infusion of GLP-1 maintained a constant level of hormone in plasma-augmented insulin secretion, inhibited glucagon secretion, and normalized fasting and postprandial glucose levels in study participants with type 2 diabetes mellitus (T2DM).
Rachman J, Barrow BA, Levy JC, et al. Diabetologia. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. 1997;40(2):

11. Levels of Intact GLP-1 (7-36 amide) Postmeal Are Increased Within the Normal Range After Vildagliptin
DPP-4 inhibition with vildagliptin raises the GLP-1 levels of participants with T2DM into the normal range (10-12 pmol/L), but these GLP-1 levels are much lower than those observed following a subcutaneous injection of exenatide or GLP-1.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):