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Horm Metab Res 2014; 46(11): 814-818
DOI: 10.1055/s-0034-1382015
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

The Dipeptidyl Peptidase-4 Inhibitor Vildagliptin has the Capacity to Repair β-Cell Dysfunction and Insulin Resistance

A. Horie
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
,
Y. Tokuyama
2   Kashiwado Hospital, Chiba, Japan
,
T. Ishizuka
3   Sato Clinic, Chiba, Japan
,
Y. Suzuki
4   Asahi General Hospital, Asahi, Japan
,
K. Marumo
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
,
K. Oshikiri
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
,
K. Ide
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
,
M. Sunaga
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
,
A. Kanatsuka
1   The Diabetes Center, Chiba Central Medical Center, Chiba, Japan
› Author Affiliations
Further Information

Publication History

received 15 February 2014

accepted 15 May 2014

Publication Date:
30 June 2014 (online)

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Abstract

The aim of the present study was to determine whether the dipeptidyl peptidase (DPP)-4 inhibitor could repair pancreatic β-cell dysfunction and insulin resistance. Ten subjects with type 2 diabetes who had never received DPP-4 inhibitor treatment were enrolled in the study. Just before and 3 months after twice-daily administration of vildagliptin (50 mg tablets), insulin secretion and insulin sensitivity were estimated using 2-compartment model analysis of C-peptide kinetics and insulin-modified minimal model parameters, respectively. The first-phase insulin secretion (CS1) was determined as the sum of the C-peptide secretion rate (CSR) from 0 to 5 min (normal range 6.8–18.5 ng/ml/min). The whole-body insulin sensitivity index (SI) was calculated using a minimal model software program (normal range 2.6–7.6×10−4/min/μU/ml). After vildagliptin treatment, reductions in mean (± SE) HbA1c were noted (43.28±1.53 vs. 40.98±1.77 mmol/mol; p=0.019). Vildagliptin treatment increased the area under the curve for the C peptide reactivity (CPR) (AUCCPR; 26.66±5.15 vs. 33.02±6.12 ng/ml · 20 min; p=0.003) and CS1 (0.80±0.20 vs. 1.35±0.38 ng/ml/min; p=0.037) in response to an intravenous glucose load. ­Vildagliptin treatment significantly increased SI (0.46±0.27 vs. 1.21±0.48×10−4/min/μU/ml; p=0.037). The long-term administration of vildagliptin improved CS1 and Si suggesting that this drug has the capacity to repair impairments in pancreatic β-cell function and insulin resistance in type 2 diabetes.

Key words

type 2 diabetes mellitus - glucagon-like peptide-1 - first-phase insulin secretion - insulin-modified minimal model - insulin sensitivity
 

  • References

  • 1 Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagons like polypeptide 1 in vitro and in vivo by dipeptidyl peptidadase IV. Endocrinology 1995; 136: 3585-3596
    CrossrefPubMedGoogle Scholar
  • 2 MacDonald PE, EL-Kholy W, Riedel MJ. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002; 51 (Suppl. 03) S434-S442
    CrossrefPubMedGoogle Scholar
  • 3 Nauck MA, El-Ouaghlidi A. The therapeutic actions of DPP-IV inhibition are not mediated by glucagons-like peptide-1. Diabetologia 2005; 48: 608-611
    CrossrefPubMedGoogle Scholar
  • 4 Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors. Diabetologia 2005; 48: 612-615
    CrossrefPubMedGoogle Scholar
  • 5 Antoine M, Husam G, Mehul V, Kelly G, Sanan A, Ajay C, Sandeep D, Paresh D. Sitagliptin exerts an antiinflammatory action. J Clin Endocrinol Metab 2012; 97: 3333-3341
    CrossrefPubMedGoogle Scholar
  • 6 Junichi M, Seigo S, Eiichi A, Satomi I, Hirofumi K, Keisuke O, Hirofumi M, Koichiro F, Eiichiro Y, Koichi K, Seiji H, Hideaki J, Hisao O. Dipeptydyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 2013; 77: 1337-1344
    CrossrefPubMedGoogle Scholar
  • 7 Campos RV, Lee YC, Drucker DJ. Divergent tissue-specific and developmental expression of receptors for glucagons and glucagons-like peptide-1 in the mouse. Endocrinology 1994; 134: 2156-2164
    CrossrefPubMedGoogle Scholar
  • 8 Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagons-like peptide-1 receptor. Endocrinology 1996; 137: 2968-2978
    CrossrefPubMedGoogle Scholar
  • 9 Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci 2005; 108: 277-292
    CrossrefPubMedGoogle Scholar
  • 10 Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O’Hare JP, Charlsson L, Kumar S, McTernan PG. DPP-IV inhibition enhances the antilypolytic action of NPY in human adipose tissue. Diabetes Obes Metab 2009; 11: 285-292
    CrossrefPubMedGoogle Scholar
  • 11 Faber OK, Hagen C, Binder C, Markussen J, Naithani VK, Blix PM, Kuzuya H, Horwitz DL, Rubenstein AH, Rossing N. Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest 1978; 62: 197-203
    CrossrefPubMedGoogle Scholar
  • 12 Kanatsuka A, Makino H, Sakurada M, Hashimoto N, Iwaoka H, Yamaguchi T, Taira M, Yoshida S, Yoshida A. First-phase insulin response to glucose in nonobese or obese subjects with glucose intolerance: Analysis by C-peptide secretion rate. Metabolism 1988; 37: 878-884
    CrossrefPubMedGoogle Scholar
  • 13 Kanatsuka A, Tokuyama Y, Nozaki O, Matsui K, Egashira T. Beta-Cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4. Metabolism 2002; 51: 1161-1165
    CrossrefPubMedGoogle Scholar
  • 14 Tokuyama Y, Sakurai K, Yagui K, Hashimoto N, Saito Y, Kanatsuka A. Pathophysiologic phenotypes of Japanese subjects with varying degrees of glucose tolerance: using the combination of C-peptide secretion rate and minimal model analysis. Metabolism 2001; 50: 812-818
    CrossrefPubMedGoogle Scholar
  • 15 Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide1 receptor gene in Japanese population. Diabetes Res Clin Pract 2004; 66: 63-69
    CrossrefPubMedGoogle Scholar
  • 16 Yoshida Y, Hashimoto N, Tokuyama Y, Kitagawa H, Takahashi K, Yagui K, Kanatsuka A, Bujo H, Higurashi M, Miyazawa S, Yoshida S, Saito Y. Efects of weight loss in obese subjects with normal fasting plasma glucose of impaired glucose tolerance on insulin release and insulin resistance according to minimal model analysis. Metabolism 2004; 53: 1095-1100
    CrossrefPubMedGoogle Scholar
  • 17 Ferrannini DT, Mari A. How to measure insulin sensitivity. J Hypertens 1998; 16: 895-906
    Google Scholar
  • 18 Bergman RN, Ider YZ, Bowden CR, Cobell C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667-E677
    PubMedGoogle Scholar
  • 19 The Guideline for Epidemiology Study in Japan. The Ministry of Health, Labor and Welfare. June 30, 2003 (Japanese)
    PubMed
  • 20 Eaton RP, Allen RC, Schade DS, Erickson KM, Standefer J. Prehepatic insulin production in man: Kinetic analysis using peripheral connecting peptide behavior. J Clin Endocrinol Metab 1980; 51: 520-528
    CrossrefPubMedGoogle Scholar
  • 21 Cerasi E, Luft R, Efndic S. Decreased sensitivity of the pancreatic beta cell to glucose in prediabetic and diabetic patients. Diabetes 1972; 21: 224-234
    CrossrefPubMedGoogle Scholar
  • 22 Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 1992; 41: 368-377
    CrossrefPubMedGoogle Scholar
  • 23 Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, Porte Jr D. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 1976; 42: 222-229
    CrossrefPubMedGoogle Scholar
  • 24 Field JB. Extraction of insulin by liver. Am J Physiol 1979; 237: E185-E191
    PubMedGoogle Scholar
  • 25 Kristina MT, Jenny T, Brenda M, Jayalakshmi U, Fernando G, Santica MM, Catherine EW, Monica AL, James EF, Jens JH, Carolyn FD, Steven EK. The dipeptidyl peptidase-4 inhibitor vildagliptin improves β-cell function and insulin sensitivity in subjects with impaired fasting glucose. Diabetes Care 2008; 31: 108-113
    CrossrefPubMedGoogle Scholar
  • 26 Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M, Zhang C, Tamamoto A, Satoh T, Miyazaki J, Seino S. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. PNAS 2007; 104: 19333-19338
    CrossrefPubMedGoogle Scholar
  • 27 Zhang C, Katoh M, Shibasaki T, Minami K, Sunaga Y, Takahashi H, Yokoi N, Iwasaki M, Miki T, Seino S. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science 2009; 325: 607-610
    CrossrefPubMedGoogle Scholar
  • 28 Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagons-like peptide-1 receptor agonist, exendin-4. Diabetes 2010; 59: 1030-1037
    CrossrefPubMedGoogle Scholar
  • 29 Zubair S, Thomas K, Jeffrey D, Sonja H, Stefan L, Margriet O, Kristin E, Jean MK, Mikael R, Stefan M, Franz-George H, Johannes R, Peter A, Henrike S, Juergen E. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011; 124: 2338-2349
    CrossrefPubMedGoogle Scholar
  • 30 Daniela L, Susanne F, Nina W. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60: 1917-1925
    CrossrefPubMedGoogle Scholar
  • 31 Giuseppe D, Anna C, Ivano F, Fabrizio Q, Elena F, Lucio B, Aldo B, Davide R, Arrigo C, Pamela M. Effects of a combination of sitagliptin plus metformin vs. metformin monotherapy on glycemic control, β-cell function and insulin resistance in type 2 diabetes patients. Diabetes Res Clin Pract 2012; 98: 51-60
    CrossrefPubMedGoogle Scholar
  • 32 Giuseppe D, Arrigo C, Ivano F, Fabrizio Q, Anna C, Mario P, Angela D, Elena F, Pamela M. A Randomized, double-blind, comparative therapy evaluating sitagliptin versus glibenclamide in type 2 diabetes patients already treated with pioglitazone and metformin: A 3-Year Study. Diabetes Technol Ther 2013; 15: 214-222
    CrossrefPubMedGoogle Scholar
  • 33 Bo A, Giovanni P, James EF, Anja S. Improved meal-related β-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005; 28: 1936-1940
    CrossrefPubMedGoogle Scholar