Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents
Research output: Contribution to journal › Journal article › peer-review
Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30)NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TAG uptake. So far, there are no studies with a GIPR antagonist in patients with type 2 diabetes (T2D), but because the elevations in fasting plasma glucagon and paradoxical postprandial glucagon excursions, seen in patients with T2D, are aggravated by GIP, a GIPR antagonist could partly alleviate this and possibly improve the fasting and postprandial glycemia. Since the majority of patients with T2D are overweight, inhibition of GIP-induced fat deposition may be beneficial as well. Here we summarize the studies of GIPR antagonists and discuss the therapeutic potential of the GIP system in humans.
|Publication status||Published - Feb 2018|
- Journal Article