Page 56 - 51 the significance--29.2_opt

4. DPP-4 inhibitors in general and linagliptin in
particular as a new treatment option in T2DM

Professor Michael Nauck Dr Thomas Hach
Diabeteszentrum Bad Lauterberg TA Metabolism
Bad Lauterberg im Harz, Germany Boehringer Ingelheim Pharma GmbH & Co. KG
Ingelheim, Germany

The incretin effect

DPP-4 inhibition as a means of controlling blood sugar levels has at-
tracted considerable attention in recent decades. In order to under-
stand how DPP-4 inhibitors work, it is pertinent to briefly review the incre-
tin hormones and the physiological phenomenon known as the incretin
effect.

Insulin and glucagon play a central role in blood sugar homeostasis;
they are influenced by a group of gastrointestinal hormones – the in-
cretins. More than a century ago it was suggested that a hormone pro-
duced by the gastrointestinal tract stimulated secretory activity in the
pancreas. Building on these ideas it was later discovered that eating
1
promotes a much greater degree of insulin secretion compared with
simply infusing glucose into the circulation, thus bypassing the gut. This
1
phenomenon was termed the incretin (the crude intestinal extract be-
ing named secretin, with excretin stimulating the exocrine portion of
the pancreas, and incretin acting on the endocrine pancreas) effect
and it has since become clear that it involves several hormones (incre-
tin hormones) of which the most important are glucagon-like peptide-1
(GLP-1) and gastric inhibitory peptide (glucose-dependent insulino-
tropic peptide or GIP).
1
Both GLP-1 and GIP are similar to glucagon in terms of their amino
acid sequence. The former is secreted primarily by L-cells, which oc-
cur most abundantly in the ileum, colon and rectum, but also, to a
lesser degree, in the upper gastrointestinal (GI) tract while the latter is
secreted by K-cells in the duodenum/upper jejunum. The incretin hor-
mones, GLP-1 and GIP, are released throughout the day, with levels in-
creasing several-fold in response to a meal (Figure 1). They act on the
2
pancreas augmenting glucose-induced insulin secretion. GLP-1 also
suppresses glucagon secretion (GIP tends to stimulate glucagon se-
cretion). When blood glucose concentrations are normal or elevated,
3
GLP-1 and GIP stimulate insulin production and release from pancre-
atic β-cells thereby enhancing glucose uptake by insulin-dependent
tissues, effects that are complemented by the ability of GLP-1 to lower
glucagon secretion from the pancreatic α-cells (Figure 1). Decreased
2
glucagon levels, along with higher insulin levels, lead to reduced gluco-
neogenesis in the liver, thus lowering blood glucose levels in the fasting
and fed states (Figure 1). 2

56