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Diabetes Management DPP-4 Inhibitors
Figure 1: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Enhance Incretin Levels Through Inhibition of DPP-4
Ingestion of food
Glucose-dependentPancreas
b2up insulin from beta cells
Beta cells
b2up Peripheral
(GLP-1 and GIP)
Alpha cells
glucose
uptake
Release of
GI tract
active incretins
GLP-1 and GIP*
DPP-4 enzyme
b2down Blood glucose
XDPP-4 inhibitor in fasting and
post-prandial states
Glucose-
dependent
glucagon from
Inactive GLP-1 Inactive GIP
alpha cells (GLP-1)
b2down Hepatic
glucose
production
DPP-4= dipeptidyl peptidase-4; GI = gastrointestinal; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide 1. *Incretin hormones GLP-1 and GIP are released by the
intestine throughout the day, and their levels increase in response to a meal. In persons with type 2 diabetes, incretin response to caloric intake is severely impaired or diminished.
Dipeptidyl Peptidase-4 Inhibitors Inhibitors may also differ in their selectivity for DPP-4 over other
Intact, biologically active GLP-1 represents only 10–20% of total related enzymes, such as DPP-8 and DPP-9.
22,23
The exact functions of
plasma GLP-1.
14
GLP-1 and GIP are renally cleared and rapidly these enzymes are unknown and the clinical significance of their
inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), a widely inhibition in human subjects, if any, is unclear. Another potential
expressed serine protease.
15
concern is the specificity of agents for the catalytic activity of DPP-4
over other functions of the DPP-4/CD26 molecule.
23
CD26 is a cell-
DPP-4 inhibitors are reversible competitive inhibitors of DPP-4 (see surface molecule on immune cells and is an important co-stimulatory
Figure 1). Currently available DPP-4 inhibitors appear similar in their molecule in immune activation. Thus, close surveillance of these
ability to inhibit DPP-4 activity and give rise to comparable increases in agents must continue for potential effects on the immune system,
intact hormone concentrations. Levels of GLP-1 achieved are generally although there have been no real concerns to date. Finally, there may
sufficient to cause increased insulin secretion and decreased glucagon also be compound-specific properties unrelated to DPP-4 inhibition
production, although not sufficient to induce the decreased appetite that could result in unwanted side effects from a particular agent.
and food intake or the subsequent weight loss typically seen with
GLP-1 analogs.
21
By contrast, these orally administered DPP-4 inhibitors Implications for Type 2 Diabetes
are generally considered weight-neutral and are less commonly In animal models, GLP-1 has been shown to expand beta-cell mass by
associated with the gastrointestinal side effects of the GLP-1 analogs stimulating beta-cell proliferation and inhibiting beta-cell apoptosis.
15,24–27
such as nausea, vomiting, or diarrhea. Similarly, GLP-1 added to freshly isolated human islets improves
glucose responsiveness and protects against apoptotic beta-cell
A potential long-term concern with this class of agents is the death.
28
In a rodent model of type 2 diabetes, administration of a
unknown consequences of affecting DPP-4 activity on substrates DPP-4 inhibitor increased pancreatic beta-cell mass and improved
other than GLP-1 and GIP. glucose-stimulated insulin secretion in isolated islets.
29
Thus, incretin-
based therapies may address the issue of beta-cell failure, a key
There may be other important compound-related differences that mechanism underlying disease progression in type 2 diabetes.
ultimately differentiate between the DPP-4 inhibitors. For example,
these agents vary in their routes of metabolism and elimination.
22
While preliminary results are encouraging, it is important to recognize
Sitagliptin does not undergo appreciable metabolism and is primarily that the significance of these findings to human subjects remains to be
excreted unchanged by the kidney. By contrast, saxagliptin is established. Recent studies also suggest GLP-1 may have protective
hepatically metabolized to an active metabolite via CYP450 3A4/5; effects on the cardiovascular system.
30–33
These observations are
both parent compound and metabolite are renally excreted. particularly interesting given the high rates of cardiovascular disease
Vildagliptin is hydrolyzed, to a large extent, by the liver to an inactive among patients with diabetes; however, a detailed discussion of this
compound that is excreted in the urine. topic is beyond the scope of the current review.
64 US ENDOCRINOLOGY
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