From the Guidelines
Dipeptidyl Peptidase-4 (DPP-4) is a cell-surface enzyme that deactivates several peptides, including glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1).
Function of DPP-4
- DPP-4 inhibitors increase the endogenous level of GLP-1 by reducing the deactivation of GLP-1 in vivo through inhibition of DPP-4 1
- The enzyme plays a crucial role in glucose regulation by deactivating peptides that enhance insulin secretion and inhibit glucagon secretion in a glucose-dependent manner 1
- DPP-4 is involved in the regulation of insulin and glucagon secretion, and its inhibition has a moderate glucose-lowering efficacy 1
Clinical Implications
- DPP-4 inhibitors are well tolerated, have a neutral effect on weight, and have minimal risk of hypoglycemia when used as monotherapy 1
- The use of DPP-4 inhibitors alone does not increase the risk of hypoglycaemia and includes a neutral or mild effect on weight gain 1
- DPP-4 inhibitors have been shown to be effective in reducing HbA1c levels in patients with type 2 diabetes, with a reduction of 0.4% to 0.9% 1
From the Research
Function of Dipeptidyl Peptidase-4 (DPP-4)
- DPP-4 is a multi-functional protein that exhibits catalytic activity, functions as a binding protein, and acts as a ligand for various extracellular molecules 2.
- It is an integral membrane protein expressed on cells throughout the body and also circulates as a soluble protein in the plasma 2.
- DPP-4 plays a crucial role in glucose homeostasis by cleaving the incretin hormone glucagon-like peptide-1 (GLP-1), which is essential for maintaining normal glucose levels 2, 3.
- The enzyme also influences metabolic control by proteolytically affecting other regulatory peptides and potentially modulating insulin sensitivity through non-enzymatic interactions with membrane proteins 2.
- DPP-4 has been implicated in the pathogenesis of type 2 diabetes, obesity, and non-alcoholic fatty liver disease, with its expression and activity altered in these conditions 3, 4.
Mechanism of Action
- DPP-4 inhibitors work by preventing the degradation of incretins, such as GLP-1 and glucose-dependent insulinotropic peptide (GIP), thereby increasing their levels and enhancing insulin secretion 5, 6.
- This mechanism of action is distinct from other anti-diabetic drugs and offers a physiological approach to controlling hyperglycemia 5.
- DPP-4 inhibitors have been shown to stimulate insulin secretion from beta-cells, decrease glucagon secretion from pancreatic alpha-cells, and reduce glucose production by the liver 5.
Role in Disease Pathogenesis
- Altered expression and activity of DPP-4 have been associated with increasing body mass index and hyperglycemia, suggesting a link between DPP-4 and the development of type 2 diabetes and obesity 2, 4.
- DPP-4 may also play a role in modulating beta-cell function and influencing the progression of metabolic disease through its effects on inflammation and insulin resistance 2, 3.