TY - JOUR

T1 - Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors

AU - Deacon, Carolyn F.

PY - 2020

Y1 - 2020

N2 - Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and postrelease degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassaybased methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.

AB - Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and postrelease degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassaybased methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.

KW - Dipeptidyl peptidase-4

KW - Glucose-dependent insulinotropic polypeptide

KW - Incretin

KW - Peptide degradation

KW - Therapy

KW - Type 2 diabetes

KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE

KW - GLUCAGON-LIKE PEPTIDE-1

KW - IV-RESISTANT

KW - NEUTRAL ENDOPEPTIDASE-24.11

KW - RECEPTOR EXPRESSION

KW - INCRETIN HORMONES

KW - 7-36 AMIDE

KW - IN-VITRO

KW - SECRETION

KW - DEGRADATION

U2 - 10.1016/j.peptides.2019.170196

DO - 10.1016/j.peptides.2019.170196

M3 - Review

C2 - 31706956

VL - 125

JO - Peptides

JF - Peptides

SN - 0196-9781

M1 - 170196

ER -