Symposium
New therapeutics to enhance insulin secretion
Dennis Kim
San Diego, CA, USA
At the symposium, Dr. Jens J. Holst discussed the role of DPP-IV
inhibitors in enhancing the action of GLP-1 as a new therapeutic
modality in Type 2 diabetes or impaired glucose-tolerant individuals.
GLP-1
GLP-1 is a polypeptide produced and secreted mostly by intestinal
and pancreatic cells that exert beneficial influence on the body’s
glucose metabolism. Some of the physiological actions of GLP-1 include
potentiation of glucose and insulin secretion (which makes hypoglycemia
unlikely), increases all steps of insulin biosynthesis, up-regulates insulin gene expression and genes essential for beta-cell function, and
is mitotic for beta-cells. Moreover, and perhaps most importantly,
GLP-1 inhibits glucagon secretion. Other beneficial effects of GLP-1
include inhibition of gastrointestinal secretion/motility and also
moderation of appetite and overall food intake.
Given intravenously to experimental animals with glucose intolerance, GLP-1 has
been shown to be able to almost normalize postprandial glucose
level.
But…
GLP-1 is degraded almost immediately after its release (into GLP-1 9-36amide) by an enzyme called DPP-IV. Unfortunately, the breakdown
product of GLP-1 has been shown to have antagonistic activities against
GLP-1. In other words, the metabolite of GLP-1 is its own antagonist.
Subsequently, all the beneficial effects of GLP-1 are lost
immediately as a result of the DPP-IV action. Experimental rats deficient
in DPP-IV protein show that they have decreased propensity for
developing diabetes or impaired glucose tolerance after a prolonged diet
high in fat content, unlike their control counterparts.
DPP-IV inhibitor (logically)
The possible strategies to overcome these unfortunate biochemical
findings are several. However, a compound taken orally that inhibits the
actions of DDP-IV, and therefore GLP-1 degradation, appears most
promising. Several studies in experimental animals with and without
impaired glucose tolerance have shown that administration of a compound
called valine-pyrrolidide inhibits the actions of DPP-IV and increases the
subsequent levels of GLP-1. In turn, DPP-IV inhibition
completely protects both endogenous and exogenous GLP-1 from being
degraded, insulin secretion is enhanced, and glucose tolerance improved
particularly in glucose-intolerant animals (Figure 1). 
In summary…
It can be expected that in patients developing NIDDM, the usage of
such compounds that inhibit DDP-IV action, and in turn enhance GLP-1
action, can restore insulin deficiency, nomalize glucose level, remove
the stress on the beta-cell, lower body weight, improve insulin
sensitivity, and enhance beta-cell survival.
Figure: GLP-1 concentration measured over
time with GLP-1 infusion before and after valine-pyrrolidide (val-pyr)
administration.
And in conclusion…
DDP-IV inhibitors such as valine-pyrrolidide (still highly experimental)
may be helpful in the management of NIDDM. Because of the said proposed
mechanisms of action, DDP-IV inhibitors may also be effective for use in
patients who have impaired glucose tolerance since the transition to
overt NIDDM may be prevented.
