Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance

Figures & data

Figure 1 Graphical representation of the concentration and activity of DPP-4 in different organs/tissues/cells.

Figure 2 Molecular structure of DPP-4.

Table 1 Various Target Peptide of DPP-4

Peptide	Function	Reference
GIP	Glucose metabolism	[31–34]
Glucagon
PACAP-38
GLP-1
Peptide YY	Appetite regulation	[35]
IGF-1	Growth	[36,37]
GHRH
GLP-2	Gut Motility	[35,38–40]
VIP
NPY
GRP
CCL11/eotaxin	Chemokine	[41–47]
CXCL9/MIg
CCL22/MDC
CCL5/RANTES
CXCL10/IP10
CXL12/SDF-1
CXCL11/I-TAC
Prolactin	Reproduction	[36,37,48]
hCGα
LHα
Enkephalin	Pain regulation	[49–51]
Endomorphins
Substance P
Thyotrophin α	Homeostasis	[52]
Vasostatin-I	Endothelial cell growth inhibition	[53]

Figure 3 Physiological properties of DPP-4 in various regions.

Figure 4 Role of Incretins and DPP-4 in glucose regulation.

Figure 5 Schematic representation of HCV infected hepatocytes releases IP-10 responsible for an immune response towards HCV infection but DPP-4 level elevated due to CD8+ cells attacked by HCV. Increased DPP-4 converted the IP-10 into an inactive form which suppresses the immune response and on the other hand DPP-4 results in glucose intolerance by degrading incretins. Interferon and DPP-4 inhibitors are found to be significant in both HCV resulting conditions.

Figure 6 Non-alcoholic fatty liver disease results in an increased level of DPP-4 expression leads to hepatic insulin sensitivity and liver steatosis but sitagliptin and omarigliptin improve the conditions.

Figure 7 Liver diseases cause an increase in DPP-4, which causes glucose intolerance and DPP-4 inhibitors lead to relief in glucose intolerance as well as in liver conditions.

Table 2 Various Mechanisms of Action and Management of Some DPP-4-Associated Liver Diseases

Disease	Area of Concern	Mechanism of Action	Management/Reduce the Risk of Concern Disease	Reference
Hepatitis C	CD8+ T-cells	HCV attacks CD8+ T-cells, hence HCV-infected T-cells could be blamed for the elevated blood DPP-4 activation and DPP-4 inactivate of the incretins which lead to hyperglycemia.	Interferon therapy for HCV and Sitagliptin	[80,81]
Non-alcoholic fatty liver	Hepatoma cells (HepG2)	Elevated blood glucose is stimulated by DPP-4 expression in hepatoma cells (HepG2), and the amount of liver DPP-4 mRNA activity in the livers. Hepatic DPP-4 expression and serum DPP-4 activity are linked to hepatic steatosis and fatty liver grading. DPP-4 amount elevation causes glucose intolerance	Sitagliptin	[103,130]
Hepatocellular carcinoma	Carcinomal hepatocyte	Increased DPP-4 expression is also found in liver tissues and serum from rats and humans with hepatocellular carcinoma (HCC). DPP-4 inhibition suppresses tyrosine kinase in human hepatoma cells, resulting in anti-apoptotic effects. Recently, a patient with HCV-related chronic hepatitis experienced remarkable HCC reduction following four weeks of treatment with a DPP-4 inhibitor.	DPP-4 inhibitors like Sitagliptin, saxagliptin, linagliptin, and alogliptin.	[165,171,172]
Hepatic regeneration and stem cell	Liver stem cells	CXCL12/SDF-1 is a chemokine that promotes the homing of hematopoietic stem cells (HSCs) and is critical for hepatic regeneration. CXCL12/SDF-1 is a DPP-4 target peptide, and inhibiting cell-surface DPP-4 activity promotes CXCL12/SDF-1. As a result, inhibiting DPP-4 might be a good way to improve the efficacy and success of HSC/hematopoietic progenitor cell transplantation. DPP-4 suppression also increases the number of progenitor cells, and DPP-4 inhibition can stabilize endogenous CXCL12/SDF-1 which also helps in the reduction of hyperglycemia.	DPP-4 inhibitors	[155,157]

Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor-associated angioedema. Hypertension. 2008;51(1):141–147. doi:10.1161/HYPERTENSIONAHA.107.096552

 Web of Science ®Google Scholar

Mentlein R. Dipeptidyl-peptidase IV (CD26) -role in the inactivation of regulatory peptides. Regul Pept. 1999;85:9–24. doi:10.1016/S0167-0115(99)00089-0

 PubMed Web of Science ®Google Scholar

Liu X, Murali SG, Holst JJ, Ney DM. Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats. Am J Physiol. 2008;295(6):1794–1802. doi:10.1152/ajpregu.90616.2008

 Web of Science ®Google Scholar

Faidley TD, Leiting B, Pryor KD, Lyons K, Hickey GJ, Thompson DR. Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs. Exp Biol Med. 2006;231:1373–1378. doi:10.1177/153537020623100811

 Web of Science ®Google Scholar

Tian L, Gao J, Hao J, et al. Reversal of new-onset diabetes through modulating inflammation and stimulating β-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor. Endocrinology. 2010;151(7):3049–3060. doi:10.1210/en.2010-0068

 PubMed Web of Science ®Google Scholar

Zhang XY, De Meester I, Lambeir AM, et al. Study of the enzymatic degradation of vasostatin I and II and their precursor chromogranin A by dipeptidyl peptidase IV using high-performance liquid chromatography/electrospray mass spectrometry. J Mass Spectrom. 1999;34(4):255–263. doi:10.1002/(SICI)1096-9888(199904)34:4<255::AID-JMS752>3.0.CO;2-7

 Web of Science ®Google Scholar

Dimitropoulou D, Karakantza M, Tsamandas AC, Mouzaki A, Theodorou G, Gogos CA. T-lymphocyte subsets in peripheral blood and liver tissue of patients with chronic hepatitis B and C. In vivo. 2011;25(5):833–840.

 Web of Science ®Google Scholar

Rahman W, Huang P, Belov L, et al. Analysis of human liver disease using a cluster of differentiation (CD) antibody microarray. Liver Int. 2012;32(10):1527–1534. doi:10.1111/j.1478-3231.2012.02854.x

 Web of Science ®Google Scholar

Miyazaki M, Kato M, Tanaka K, et al. Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism. Mol Med Rep. 2012;5(3):729–733. doi:10.3892/mmr.2011.707

 PubMed Web of Science ®Google Scholar

Balaban YH, Korkusuz P, Simsek H, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007;6(4):242–250. doi:10.1016/s1665-2681(19)31905-2

 PubMed Web of Science ®Google Scholar

Nishina S, Yamauchi A, Kawaguchi T, et al. Dipeptidyl peptidase 4 inhibitors reduce hepatocellular carcinoma by activating lymphocyte chemotaxis in mice. Cell Mol Gastroenterol Hepatol. 2019;7(1):115–134. doi:10.1016/j.jcmgh.2018.08.008

 PubMed Web of Science ®Google Scholar

Stecca BA, Nardo B, Chieco P, Mazziotti A, Bolondi L, Cavallari A. Aberrant dipeptidyl peptidase IV (DPP IV/CD26) expression in human hepatocellular carcinoma. J Hepatol. 1997;27(2):337–345. doi:10.1016/S0168-8278(97)80180-8

 Web of Science ®Google Scholar

Kawakubo M, Tanaka M, Ochi K, et al. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis–associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci Rep. 2020;10(1):1–11. doi:10.1038/s41598-020-57935-6

 Web of Science ®Google Scholar

Mavier P, Martin N, Couchie D, Préaux AM, Laperche Y, Zafrani ES. Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat. Am J Pathol. 2004;165(6):1969–1977. doi:10.1016/S0002-9440(10)63248-8

 Web of Science ®Google Scholar

Campbell TB, Broxmeyer HE. CD26 inhibition and hematopoiesis: a novel approach to enhance transplantation. Front Biosci. 2008;13:1795–1805. doi:10.2741/2800

 PubMed Web of Science ®Google Scholar