Biomedical Engineering Reference
In-Depth Information
increase in active GLP-1 and GIP following a meal. The effect of the inhibition
is maintained over a 24 h period, which allows it to be a once-daily oral
therapy.
71
DPP-4 inhibitors improve glycaemic control in patients with type 2
diabetes, irrespective of diabetes severity, body weight, or age.
72-76
DPP-4
inhibition improves insulin secretion rates, lowers the plasma glucagon con-
centration, and increases the ratio of plasma insulin to glucose.
77
These actions
improve glucose tolerance and insulin sensitivity. Gliptins also decrease fasting
plasma glucose and postprandial glucose levels.
78
Postprandial glucose levels
are improved more so than fasting plasma glucose levels because the action via
incretins is meal-dependent.
78
Currently available alternative drugs for type 2 diabetes include insulin
secretagogues such as sulfonylureas and insulin sensitizers such as metformin
and thiazolidinediones, which augment insulin in a glucose-independent man-
ner and thus increase the risk of hypoglycaemia and weight gain.
79
Given that
obesity is an important contributor to type 2 diabetes, the association of these
anti-diabetic drugs to weight gain is a major shortcoming. In contrast, DPP-4
inhibition promotes insulin secretion in a glucose-dependent manner, which is
unlikely to cause hypoglycemia or weight gain.
78
When compared to GLP-1 analogs, DPP-4 inhibitors result in a more phy-
siological activation of the insulin secretion system.
80
Additionally, DPP-4 is
orally active, whereas GLP-1 needs to be injected subcutaneously.
73
Moreover,
DPP-4 inhibitors could be safer than GLP-1 mimetics, as high GLP-1 analog
concentrations may have several adverse effects. Continuous activation of the
GLP-1 receptor by GLP-1 mimetics might have anorexic effects and cause
pancreatic b-cell overgrowth, although no such effect has been seen in clinical
trials.
81
5.2.5.3 Potential Benefits of DPP-4 Inhibitors in Metabolism
As well as improving glucose homeostasis, DPP-4 inhibitor treatment might
have additional beneficial metabolic effects (Figure 5.3). Impaired insulin
secretion due to insucient pancreatic b-cell function is a key feature of type
2 diabetes. Whereas conventional anti-diabetic drugs do not address the
progressive loss of b-cells in type 2 diabetes, DPP-4 inhibitors have been
shown to promote b-cell proliferation and islet neogenesis, and inhibit b-cell
apoptosis in preclinical studies.
82-85
In humans, DPP-4 inhibitors improve b-
cell function and the proinsulin-to-insulin ratio.
86-88
The effects on b-cell
function and proliferation may occur due to the elevated level of GLP-1
which has trophic effects on b-cell mass and function.
89
It is thought that
GLP-1 binding to its receptor upregulates pancreatic duodenal homeobox-1
(PDX-1), a transcription factor involved in pancreatic development and b-
cell maturation.
90
Hence, DPP-4 inhibitor therapy may improve pancreatic
islet health in type 2 diabetes and, thus, potentially limit disease progression.
Long-term studies in type 2 diabetic patients are required to demonstrate
this effect.
