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Extrapancreatic contribution to glucose regulation by dipeptidyl peptidase 4 inhibition

Omar, Bilal A.; Ahrén, Bo

Cardiovascular Endocrinology & Metabolism: September 2016 - Volume 5 - Issue 3 - p 82–85
doi: 10.1097/XCE.0000000000000088
Review Articles
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Dipeptidyl peptidase 4 (DPP-4) inhibitors are now being clinically utilized as glucose-lowering medications for the treatment of type 2 diabetes. Their widespread use and effective glucose-lowering properties have led to great interest in the mechanism of action of this class of drug. Although it has been well accepted that DPP-4 inhibitors lower glucose in part by increasing postprandial insulin secretion and suppressing fasting and postprandial hyperglucagonemia, recent studies have suggested that DPP-4 inhibition has other metabolically beneficial properties that are extrapancreatic in nature. This review explores the changes in DPP-4 expression and activity in metabolic disease states and discusses the metabolic consequences of DPP-4 inhibition on a systemic and tissue-specific basis. It concludes that there is considerable scientific evidence and a growing body of clinical evidence to suggest that DPP-4 inhibition would be beneficial in a number of metabolic disorders in addition to type 2 diabetes.

Department of Clinical Sciences, Biomedical Center B-C-11, Faculty of Medicine, Lund University, Lund, Sweden

Correspondence to Bo Ahrén, MD, PhD, Department of Clinical Sciences, Lund University, Biomedical Center B11, Lund, 22184 Sweden Tel: +46 46 222 0758; fax +46 46 222 4022; e-mail: bo.ahren@med.lu.se

Received April 21, 2016

Accepted June 23, 2016

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Overview

Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering therapy in type 2 diabetes 1,2. DPP-4, also known as CD26, is a serine protease that metabolizes a variety of peptides by cleaving at the β amino acid, recognizing an Xaa-Pro or an Xaa-Ala motif, from the N-terminus 3. DPP-4 is best known for its metabolism of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide 4. DPP-4 is also well known for its role in the cleavage of neuropeptides, chemokines, and cytokines such as NPY, IP-10, SDF-1, RANTES, and IL-8 3. A number of studies have reported increased plasma DPP-4 activity in obese type 2 diabetic patients 5 as well as obese nondiabetic patients 6. Recent studies have even shown that increases in circulating DPP-4 activity are predictive of future hyperglycemia in certain patient populations 7. Despite these increases in DPP-4 activity, there has not been a consistent, reproducible demonstration of decreased circulating intact GLP-1 and glucose dependent insulinotropic polypeptide in these same patient populations. These and others observations have led some to question the physiological importance of plasma DPP-4 activity 8,9. We, and others, therefore propose that DPP-4 activity in different tissue compartments is potentially more important than plasma DPP-4 activity to the metabolic effects of DPP-4 inhibition. In this review, we will examine the prevailing evidence for the contribution of DPP-4, both systemically and in individual tissues, toward the most key aspects of diabetes pathophysiology.

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Systemic insulin resistance

The earliest pathophysiological defect in the development of type 2 diabetes is systemic insulin resistance 10. Although the method of action for the glucose-lowering action of DPP-4 inhibitors is believed to be mediated primarily by improved insulin secretion and reduced fasting and postprandial glucagon 11, improvement in insulin sensitivity with DPP-4 inhibitor use has also been shown 12. This appears to be independent of weight loss as DPP-4 inhibitors have been repeatedly shown to be weight neutral 13.

Studies have reported that DPP-4 inhibition results in decreased systemic markers of inflammation in humans and in tissue markers of inflammation in animals possibly by blunting the daily fluctuations in blood glucose 14,15. This is of clinical relevance as inflammation originating from the adipose tissue is one of the early events that lead to insulin resistance in multiple tissues such as liver, muscle, and the adipose tissue itself 16.

A relation between DPP-4 and obesity is also evident from findings that circulating DPP-4 activity correlates to measures of adiposity 17. There appears, in fact, to be dynamic regulation of plasma DPP-4 in obese patients, as exercise has been shown to decrease circulating DPP-4 18. This decrease in circulating DPP-4 was associated with an increase in whole-body insulin sensitivity as determined by euglycemic clamp and HOMA-IR 18. Similar results were found in obese children, with respect to DPP-4 activity and insulin sensitivity, after diet-induced weight loss 19. Similarly, plasma DPP-4 activity is decreased in obese patients after gastric bypass surgery, but this decrease was found not to be correlated to the postoperative increase in plasma incretin hormones observed after surgery 20. Thus, it was established that there was a clear correlation between obesity and DPP-4 activity.

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Adipose tissue and DPP-4

Later studies would show that adipose tissue, specifically adipocytes, are a major source of circulating DPP-4 17. DPP-4 secretion from adipose tissue is correlated positively to obesity, metabolic syndrome, and circulating inflammatory markers such as TNF-α 17. Later in-vitro studies would show that TNF-α induces DPP-4 release from adipocytes at both normal and hyperglycemic glucose concentrations 21. It thus appears that obesity-associated adipose tissue inflammation is related to adipose tissue DPP-4 expression and activity. However, it is not completely clear from these studies whether DPP-4 is causing adipose tissue inflammation or is a consequence of it, and therefore, this mechanism may contribute toward the improved insulin sensitivity during DPP-4 inhibition.

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Skeletal muscle and DPP-4

Although the expression of DPP-4 by smooth muscle cells has been established 22,23, there is a dearth of evidence suggesting that DPP-4 is expressed in, or directly affects, skeletal muscle glucose metabolism or insulin sensitivity in skeletal muscle. DPP-4 has been shown, in one study, to be secreted from primary human myotubes 24; however, in-vivo data are lacking. Similarly, a considerable amount of preclinical research has been carried out into the cardioprotective effects of DPP-4 inhibitors; however, there is little evidence to suggest that DPP-4 is expressed by the cardiomyocytes themselves.

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Liver and DPP-4

A number of studies have investigated DPP-4 as a biomarker of liver disease in different populations 25,26; however, the specific interplay between DPP-4 and liver insulin resistance is more difficult to ascertain. Similar to adipose tissue, the liver has been shown to be a major contributor toward serum DPP-4 activity 27. A significant positive correlation between fasting serum DPP-4 activity and insulin resistance, as determined by HOMA2-IR, has been identified 27. As HOMA-IR is predominantly a measure of liver insulin resistance, it is likely that there is a strong correlation between serum DPP-activity and liver insulin resistance. The level of insulin resistance in the patients of this study is likely underestimated as an appreciable number of the patients in the study were taking metformin, which decreases fasting glucose output from the liver, thus lowering the HOMA2-IR score. In relation to the liver being a source of circulating DPP-4 activity, DPP-4 inhibitors have repeatedly been shown to alleviate complications of fatty liver disease in preclinical models of diabetes and insulin resistance 28–30. In fact, trials of DPP-4 inhibitors in the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in humans are ongoing 31.

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DPP-4 and renal function (kidney)

The kidneys have the highest expression of DPP-4 of any tissue in rodents and humans 3. Although there are no data currently available as to the effect of diabetes or glucose intolerance on kidney DPP-4 activity in humans, kidney DPP-4 activity is increased in rat models of diabetes and hypertension 32,33. Inhibition of DPP-4 activity in these models has been shown to alleviate kidney damage caused by diabetes and hypertension 32,34. There are multiple potential mechanisms that link DPP-4 expression and activity to renal dysfunction 35,36. Inflammation is a mechanism that has been shown to induce DPP-4 in multiple tissues and reduction of tissue inflammation is observed after chronic DPP-4 inhibition in concert with an improvement in renal function. Another mechanism connecting DPP-4 to renal dysfunction is through promotion of kidney fibrosis. The primary mediator of kidney fibrosis development is transforming growth factor beta (TGF-β) 34. DPP-4 plays an integral role in the dimerization of the TGF-β receptor, a necessary step for the mediation of TGF-β downstream signaling and fibrosis progression 37. Inhibition of DPP-4 by siRNA or DPP-4 inhibitors effectively blocks this process, reducing the appearance of fibrotic markers 37. Fibrosis in the kidney leads to other kidney dysfunctions that are manifested by microalbuminuria and macroalbuminuria. Studies in both rodents and humans have shown that DPP-4 inhibition significantly reduces albuminuria after long-term treatment 38,39.

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Pancreatic islets and DPP-4

In terms of the endocrine pancreas, there is considerable evidence that DPP-4 inhibitors prevent inflammation within the islet and that this can be a potential mechanism for the glucose-lowering effect of the drug class 9. Studies carried out within our research group have reported that DPP-4 is present within pancreatic islets and predominantly expressed in human alpha cells 40. Importantly, DPP-4 activity was found to be decreased in the islets of type 2 diabetic humans compared with nondiabetic control participants 40. DPP-4 protein expression is also decreased in type 2 diabetic islets. Augstein et al. 41 have reported that islet DPP-4 is also expressed primarily in the alpha cells of the residual islets of type 1 diabetic donors. The expression of DPP-4 in the islet and the decrease in the expression and activity of DPP-4 in diabetes suggest that DPP-4 is under physiological regulation. Factors that potentially influence the expression and activity of DPP-4 in human and rodent islets have been investigated; however, none of the factors examined (glucose, insulin, and glucagon) proved to influence DPP-4 activity ex-vivo 42. The regulated expression and activity of DPP-4 within the islet suggests that inhibition of DPP-4 in the islet could directly contribute toward improvements in β-cell function. This hypothesis was first examined by Shah et al. 43, who showed that linagliptin reduces the expression of inflammatory markers and preserves the local production of GLP-1 by alpha cells, resulting in improved β-cell function and islet survival.

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Conclusion and future perspectives

Over the last few years, a clearer picture of how DPP-4 inhibitors mediate their glucose-lowering effect has been revealed. With it has come a new understanding that additional mechanisms other than regulation of insulin and glucagon secretion occur. The expression and activity of DPP-4 in other tissues, and the metabolic consequences of their inhibition in these tissues, suggest that extrapancreatic tissues are significant contributors toward the metabolic effects of DPP-4 inhibitors.

With the increased understanding of the role of DPP-4 activity in tissue compartments there is the promise of applying DPP-4 inhibitors to the treatment of a number of diseases and disorders other than diabetes. There is a growing body of evidence that DPP-4 inhibitors can potentially be beneficial in diseases such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cardiovascular disease. Although there is not a large amount of human trial data to show the benefit of DPP-4 inhibitors in liver disorders, cardiovascular outcome trials have been carried out for many of the DPP-4 inhibitors currently used in clinical practice. These studies show that in patients with established cardiovascular disease, DPP-4 inhibitor use neither improves nor impairs the rate of cardiovascular events 44. However, all of these studies have been carried out in placebo-controlled trials of patients who have already had a cardiovascular event. Experimental trials of DPP-4 inhibitors against active comparators in patients who have never had a cardiovascular event, but are at risk for one, will be needed to definitively determine whether DPP-4 inhibitors can be effective in preventing future cardiovascular disease.

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Acknowledgements

This work was supported by grants from the Swedish Research Council, The Lund University Medical Faculty, and Region Skåne. This work has not been presented elsewhere.

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Conflicts of interest

B.A. has consulted for Merck, Novartis, Boehringer Ingelheim and Takeda, and has received lecture fees from Novartis and Merck, all of which are companies that manufacture DPP-4 inhibitors. B.O. is currently employed by Medimmune LLC, a subsidiary of AstraZeneca, that manufactures DPP-4 inhibitors.

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References

1. Ahrén B, Foley JE. Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism. Diabetologia 2016; 59:907–917.
2. Ahren B. Inhibition of dipeptidyl peptidase-4 (DPP-4): a target to treat type 2 diabetes. Curr Enzyme Inhib 2011; 7:205–217.
3. Mentlein R. Dipeptidyl-peptidase IV (CD26 – role in the inactivation of regulatory peptides. Regul Pept 1999; 85:9–24.
4. Ahrén B. The future of incretin-based therapy: novel avenues – novel targets. Diabetes Obes Metab 2011; 13 (Suppl 1):158–166.
5. Ryskjaer J, Deacon CF, Carr RD, Krarup T, Madsbad S, Holst J, Vilsbøll T. Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake. Eur J Endocrinol 2006; 155:485–493.
6. Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, et al.. Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 2013; 36:4083–4090.
7. Zheng T, Baskota A, Gao Y, Chen T, Tian H, Yang F. Increased plasma DPP4 activities predict new-onset hyperglycemia in Chinese over a four-year period: possible associations with inflammation. Metabolism 2015; 64:498–505.
8. Waget A, Cabou C, Masseboeuf M, Cattan P, Armanet M, Karaca M, et al.. Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology 2011; 152:3018–3029.
9. Omar B, Ahren B. Pleiotropic mechanisms for the glucose-lowering actions of DPP-4 inhibitors. Diabetes 2014; 63:2196–2202.
10. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention. Am J Med 1998; 105 (1A):20S–26S.
11. Ahrén B, Schweizer A, Dejager S, Villhauer EB, Dunning BE, Foley JE. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes Metab 2011; 13:775–783.
12. Utzschneider KM, Tong J, Montgomery B, Udayasankar J, Gerchman F, Marcovina SM, et al.. The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose. Diabetes Care 2008; 31:108–113.
13. de Mello AH, Prá M, Cardoso LC, de Bona Schraiber R, Rezin GT. Incretin-based therapies for obesity treatment. Metabolism 2015; 64:967–981.
14. Rizzo MR, Barbieri M, Marfella R, Paolisso G. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care 2012; 35:2076–2082.
15. Omar BA, Vikman J, Winzell MS, Voss U, Ekblad E, Foley JE, Ahrén B. Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model. Diabetologia 2013; 56:1752–1760.
16. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148:852–871.
17. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al.. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60:1917–1925.
18. Malin SK, Huang H, Mulya A, Kashyap SR, Kirwan JP. Lower dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome. Peptides 2013; 47:142–147.
19. Reinehr T, Roth CL, Enriori PJ, Masur K. Changes of dipeptidyl peptidase IV (DPP-IV) in obese children with weight loss: relationships to peptide YY, pancreatic peptide, and insulin sensitivity. J Pediatr Endocrinol Metab 2010; 23 (1–2):101–108.
20. Alam ML, Van der Schueren BJ, Ahren B, Wang GC, Swerdlow NJ, Arias S, et al.. Gastric bypass surgery, but not caloric restriction, decreases dipeptidyl peptidase-4 activity in obese patients with type 2 diabetes. Diabetes Obes Metab 2011; 13:378–381.
21. Das SS, Hayashi H, Sato T, Yamada R, Hiratsuka M, Hirasawa N. Regulation of dipeptidyl peptidase 4 production in adipocytes by glucose. Diabetes Metab Syndr Obes 2014; 7:185–194.
22. Palmieri FE, Ward PE. Dipeptidyl(amino)peptidase IV and post proline cleaving enzyme in cultured endothelial and smooth muscle cells. Adv Exp Med Biol 1989; 247A:305–311.
23. Röhrborn D, Eckel J, Sell H. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett 2014; 588:3870–3877.
24. Raschke S, Eckardt K, Bjørklund Holven K, Jensen J, Eckel J. Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS One 2013; 8:e62008.
25. Firneisz G, Somogyi A. Serum level of soluble CD26/dieptidyl peptidase-4 (DPP-4) activity correlates with other liver disease biomarkers both in Asian and European patients. Transl Res 2012; 160:95–96.
26. Gámán G, Sárváry E, Gelley F, Doros A, Görög D, Fehérvári I, et al.. New-onset diabetes mellitus and the analysis of dipeptidyl-peptidase-4 after liver transplantation. Transplant Proc 2014; 46:2177–2180.
27. Firneisz G, Varga T, Lengyel G, Fehér J, Ghyczy D, Wichmann B, et al.. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One 2010; 5:e12226.
28. Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, et al.. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes 2011; 60:1246–1257.
29. Kern M, Klöting N, Niessen HG, Thomas L, Stiller D, Mark M, et al.. Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS One 2012; 7:e38744.
30. Aroor AR, Habibi J, Ford DA, Nistala R, Lastra G, Manrique C, et al.. Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Diabetes 2015; 64:1988–2001.
31. Blaslov K, Bulum T, Zibar K, Duvnjak L. Incretin based therapies: a novel treatment approach for non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20:7356–7365.
32. Kodera R, Shikata K, Takatsuka T, Oda K, Miyamoto S, Kajitani N, et al.. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes. Biochem Biophys Res Commun 2014; 443:828–833.
33. Sakai M, Uchii M, Myojo K, Kitayama T, Kunori S. Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol 2015; 761:109–115.
34. Wang W, Koka V, Lan HY. Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology (Carlton) 2005; 10:48–56.
35. Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, et al.. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014; 63:2120–2131.
36. Lee DS, Lee ES, Alam MM, Jang JH, Lee HS, Oh H, et al.. Soluble DPP-4 up-regulates toll-like receptors and augments inflammatory reactions, which are ameliorated by vildagliptin or mannose-6-phosphate. Metabolism 2016; 65:89–101.
37. Shi S, Srivastava SP, Kanasaki M, He J, Kitada M, Nagai T, et al.. Interactions of DPP-4 and integrin β1 influences endothelial-to-mesenchymal transition. Kidney Int 2015; 88:479–489.
38. Mega C, de Lemos ET, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, et al.. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res 2011; 2011:162092.
39. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care 2013; 36:3460–3468.
40. Omar B, Liehua L, Yamada Y, Seino Y, Marchetti P, Ahren B. Dipeptidyl Peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from type 2 diabetic individuals. Diabetologia 2014; 57:1876–1883.
41. Augstein P, Naselli G, Loudovaris T, Hawthorne WJ, Campbell P, Bandala-Sanchez E, et al.. Localization of dipeptidyl peptidase-4 (CD26) to human pancreatic ducts and islet alpha cells. Diabetes Res Clin Pract 2015; 110:291–300.
42. Liu L, Omar B, Marchetti P, Ahrén B. Dipeptidyl peptidase-4 (DPP-4): localization and activity in human and rodent islets. Biochem Biophys Res Commun 2014; 453:398–404.
43. Shah P, Ardestani A, Dharmadhikari G, Laue S, Schumann DM, Kerr-Conte J, et al.. The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization. J Clin Endocrinol Metab 2013; 98:E1163–E1172.
44. Abbas AS, Dehbi HM, Ray KK. Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. Diabetes Obes Metab 2016; 18:295–299.
Keywords:

dipeptidyl peptidase-4; glucose; insulin; insulin sensitivity; liver

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