Abstract
Objectives
Dipeptidyl peptidase-4 inhibition and gastric inhibitory polypeptide (GIP) receptor antagonism have therapeutic effects in type 2 diabetes mellitus. We assessed the effects of sitagliptin and Pro3(GIP) in a mouse model of diabetes.
Methods
Diabetes was induced in C57BL/6J mice by a high-fat diet and intraperitoneal injection of streptozocin. Blood glucose was assessed weekly. Six weeks later, serum triglycerides, total cholesterol and glucose tolerance were assessed and pancreatic and adipose tissues were collected.
Results
Combination therapy with sitagliptin and Pro3(GIP) resulted in significantly greater reductions of blood glucose and triglycerides than either monotherapy. Combination therapy also improved insulin sensitivity and glucose tolerance. β-cell mass and insulin-positive cell percentage in the pancreas was higher in mice receiving combination therapy compared with either monotherapy. Crown-like structures, inflammatory markers in adipose tissue, and serum leptin concentrations were decreased in mice receiving combination therapy compared with either monotherapy.
Conclusions
Combination therapy with Pro3(GIP) and sitagliptin improved metabolic abnormalities in diabetic mice. Changes in serum leptins and reduced inflammatory cell infiltration in adipose tissue might account for the observed effects.
Keywords: Sitagliptin, Pro3(GIP), mouse model, diabetes, combination therapy, leptin
Introduction
Dipeptidyl peptidase-4 (DPP4) is a transmembrane glycoprotein expressed by many types of epithelial cells that can break down endogenous glucagon-like peptide 1 (GLP1) and glucose-dependent insulin tropic polypeptide (GIP).1 DPP4 inhibitors are a class of anti-diabetes agents that suppress degradation of GLP1 and GIP. Sitagliptin is the first commercialized DPP4 inhibitor and remains the most widely used. Sitagliptin lowers glucose and glycosylated hemoglobin levels,2,3 thereby improving β-cell function by reducing the fasting proinsulin-to-insulin ratio, fasting insulin secretion, and the insulinogenic index.4 A meta-analysis showed that sitagliptin significantly decreased serum triglycerides (TGs) and increased high-density lipoprotein cholesterol levels.5 Sitagliptin was also reported to lower total cholesterol (TC) and non-high-density lipoprotein cholesterol, although it remains unclear whether improvements in serum lipids are caused directly by sitagliptin or indirectly via improved glucose control.6 There is evidence demonstrating that sitagliptin reduces inflammation in adipose tissue7–9 as shown by decreased levels of interleukin (IL)-6, IL-12, IL-18, tumor necrosis factor (TNF)-α, secretory phospholipase A2, and cell adhesion molecules. In addition, sitagliptin exerts anti-inflammatory activity in the adipose tissue of obese mice by decreasing expression of adipocyte inflammatory factors.10
GIP is a nutrient-dependent insulinotropic hormone released by jejunal mucosal K cells that possesses metabolic activity in type 2 diabetes and obesity.1 GIP is an incretin that stimulates insulin release to improve diabetes control. Fasting levels of GIP are high in type 2 diabetes mellitus, and are considered a risk factor for this disease.11 In previous studies, GIP was demonstrated to increase the absorption of peptides, amino acids and blood glucose by activating peptide transporter-1 in the apical membranes of intestinal mucosal cells.12 GIP-induced obesity and insulin resistance are attributed to excessive absorption of nutrients. Furthermore, GIP single nucleotide polymorphisms have been linked to elevated visceral fat, plasma TGs, and hemoglobin A1c levels in Japanese adults.13 Shibue et al.14 reported that GIP contributes to diet-induced obesity by promoting fatty acid binding protein 5 activity. Additionally, GIP may promote inflammatory cell infiltration into adipose tissue and impair insulin sensitivity via the hypoxia-inducible factor-1ɑ pathway.15 Previous studies have indicated that human Pro3(GIP) is a GIP receptor antagonist in obese diabetic mice.15 Daily administration of Pro3(GIP) can improve glucose homeostasis, insulin resistance and blood parameters in mouse models of diet-induced diabetes.15 However, the effectiveness of Pro3(GIP) in mouse models of diabetes remains controversial because it is regarded as a partial agonist.15 Discrepancies among studies may relate to differences in cell types or species.
Despite differences in the modes of action of sitagliptin and Pro3(GIP), Pro3(GIP) inhibits and offsets defective glucoregulation following augmentation of endogenous GIP by sitagliptin.3 This effect results from insulin sensitization following degradation of lipid profile-induced Pro3(GIP). However, the effects of combination therapy with sitagliptin and Pro3(GIP) in models of type 2 diabetes remain unclear. Therefore, this study was designed to assess the metabolic effects of administering sitagliptin and Pro3(GIP) alone or in combination in a mouse model of streptozocin-induced diabetes.
Material and methods
Protocols for animal experiments were approved by the Animal Care Committee of Xi’an Jiaotong University. Male C57BL/6J mice were purchased from the Animal Care Committee of Xi’an Jiaotong University at 6 to 7 weeks of age. Mice were housed in nonspecific pathogen-free rooms at 22 ± 2°C under a 12-hour/12-hour light/dark cycle with free access to food and water. The mice were fed either a high-fat diet consisting of 45% fat, 20% protein, and 35% carbohydrates or a standard rodent diet consisting of 10% fat, 30% protein, and 60% carbohydrate for 4 weeks. Mice were then injected intraperitoneally with streptozocin (40 mg/kg) dissolved in sodium citrate buffer (pH 4.5) or a similar volume of citrate buffer alone once a day for 3 days. Mice with blood glucose levels ≥ 16.9 mmol/L were considered diabetic.
Experimental procedures
Sixty mice were randomly allocated in equal numbers to the following groups: normal control, diabetes model, diabetes model + sitagliptin, diabetes model + Pro3(GIP), or diabetes model + sitagliptin + Pro3(GIP). Pro3(GIP) (25 nmol/kg) or a 0.9% saline vehicle were administered intraperitoneally once daily. Sitagliptin (10 mg/kg) or a 0.5% sodium carboxymethyl cellulose vehicle were administered once daily by gavage for 6 weeks.16 In the control and diabetes model group, 0.9% saline and 0.5% sodium carboxymethyl cellulose were administered according to the same protocol. Animals had free access to food and water. Blood glucose levels were recorded weekly. Handlers weighed the total mass of all feed placed in each cage as well as leftovers at regular intervals to calculate daily food consumption. All experiments began at 10:00 AM. After the final administration, mice were anesthetized with 100 mg/kg ketamine and 16 mg/kg xylazine. Pancreatic tissue was collected and subcutaneous adipose tissue, perirenal adipose tissue, and epididymal adipose tissue were stripped and weighed. Blood samples were collected from the tail vein. The mice were sacrificed by cervical dislocation.
Pro 3 (GIP) and sitagliptin
Pro3(GIP) was synthesized on an Applied Biosystems (Foster City, CA, USA) Model 432 automated peptide synthesizer. GIP was dried in vacuo and purified by reverse-phase high pressure liquid chromatography using a Millennium 2010 chromatography system version 2.1.5 (Waters, Milford, MA, USA). Sitagliptin was purchased from Sigma-Aldrich (St. Louis, MO, USA).
Metabolic assays
After 6 weeks of treatment, plasma TG and TC levels were determined using a lipid profile automatic analyzer (Boehringer Mannheim, Mannheim, Germany). An intravenous glucose tolerance test (IVGTT) was performed at the same time. Mice fasted for 18 hours and were then injected intraperitoneally with glucose (18 mmol/kg). Blood samples were taken via the tail vein 0, 30, 60, and 120 minutes after glucose administration. Plasma glucose was measured using a glucometer. Serum insulin and leptin levels were measured using enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN, USA) following the manufacturer’s instructions.
Adipose tissue inflammation
Abdominal adipose tissues were isolated from sacrificed mice, fixed in 10% formalin overnight, and embedded in paraffin. Tissues were sectioned (thickness 20 µm) and stained with hematoxylin and eosin for observation of inflammatory cells. The number of crown-like structures (CLSs) in each field of 100 adipocytes was recorded as previously described.17 Tissue sections were observed and photographed using a BZ-9000 microscope (Keyence, Shanghai, China).
Histological evaluation
Pancreatic tissues were fixed in 10% formalin and embedded in paraffin. Sections were cut (thickness 5 µm) and stained with anti-insulin antibody. Images were captured with a BX-51 microscope (Olympus, Tokyo, Japan). The percentage of β-cells in each pancreas tissue sample was determined using ImagePro plus software (Media Cybernetics, Rockville, MD, USA).
Statistical analysis
Data were expressed as means ± standard deviations. Differences among multiple groups were assessed using analysis of variance followed by the Student–Newman–Keuls post hoc test. Values of P < 0.05 were considered statistically significant. Statistical analysis was conducted using SPSS 22.0 software (IBM, Armonk, NY, USA).
Results
Plasma glucose changes
Plasma glucose levels in diabetic mice treated for 1 to 4 weeks with sitagliptin or Pro3(GIP), alone or combination, were similar and lower than those of untreated diabetic mice (Table 1). After 5 weeks of treatment, plasma glucose was lower in the combination therapy group than in the sitagliptin and Pro3(GIP) groups; however, only the difference between the combination therapy and sitagliptin groups reached statistical significance (P < 0.05). After 6 weeks of treatment, plasma glucose levels in the combination therapy group were significantly lower than those in both the sitagliptin and Pro3(GIP) groups.
Table 1.
Plasma glucose levels in normal mice, untreated diabetic mice and sitagliptin/Pro3(GIP)-treated diabetic mice.
| Weeks of treatment | Number of mice |
Plasma glucose (mmol/L) |
||||
|---|---|---|---|---|---|---|
| Normal | Diabetes (untreated) | Diabetes (sitagliptin) | Diabetes (combination therapy) | Diabetes (Pro3(GIP)) | ||
| 0 | 9 | 8.53 ± 1.03**, ## | 22.23 ± 1.61 | 22.80 ± 1.02 | 22.61 ± 1.55 | 22.18 ± 1.73 |
| 1 | 9 | 8.60 ± 0.88**, ## | 23.53 ± 0.94* | 20.68 ± 0.89# | 20.40 ± 1.48# | 18.86 ± 1.39# |
| 2 | 9 | 8.60 ± 0.84**, ## | 24.58 ± 1.02* | 21.70 ± 1.77# | 20.70 ± 1.59# | 19.42 ± 1.36# |
| 3 | 9 | 8.60 ± 0.85**, ## | 25.63 ± 1.18** | 20.70 ± 1.39## | 18.23 ± 1.40## | 19.08 ± 0.96## |
| 4 | 9 | 8.65 ± 0.79**, ## | 28.9 ± 1.56** | 20.16 ± 1.33## | 17.07 ± 1.67## | 18.45 ± 1.19## |
| 5 | 9 | 8.57 ± 0.87**, ## | 29.06 ± 1.27** | 19.08 ± 1.00*## | 15.24 ± 1.22## | 17.83 ± 1.26## |
| 6 | 9 | 8.72 ± 0.88**, ## | 29.35 ± 1.36** | 18.10 ± 1.90**, ## | 13.11 ± 0.96## | 17.06 ± 1.15*## |
Values represent means ± standard deviations. *P < 0.05 and ** P < 0.01 vs. combination therapy. #P < 0.05 and ##P < 0.01 vs. untreated diabetic mice.
Lipid profiles
As shown in Table 2, there were no significant differences in body weight, food intake, or fat weight among the different groups. After 6 weeks of treatment, TG levels in diabetic mice treated with either sitagliptin or Pro3(GIP) were higher than those of normal mice (P < 0.01, Table 3). Mice treated with either sitagliptin, Pro3(GIP), or the combination thereof had significantly lower TG levels compared with untreated diabetic mice. However, only combination therapy decreased the mean concentration of TGs to a normal level (P < 0.01, Table 3). Changes in TC levels following treatment with sitagliptin and Pro3(GIP), alone or in combination, were not significant compared with diabetic or control mice (Table 3).
Table 2.
Food intake and adipose tissue weight in normal mice, untreated diabetic mice and sitagliptin/Pro3(GIP)-treated diabetic mice.
| Group | Body weight | Food intake (g/day) |
Perirenal fat (g) |
Epididymal fat (g) |
Subcutaneous fat (g) |
White fat (g) |
|---|---|---|---|---|---|---|
| Normal | 30 ± 1.77 | 3.55 ± 0.08 | 0.21 ± 0.05 | 0.47 ± 0.12 | 0.12 ± 0.03 | 0.76 ± 0.07 |
| Diabetes (untreated) | 32.80 ± 1.23 | 3.82 ± 0.25 | 0.29 ± 0.19 | 0.58 ± 0.38 | 0.15 ± 0.12 | 1.01 ± 0.14 |
| Diabetes (sitagliptin) | 29.50 ± 2.39 | 3.70 ± 0.31 | 0.25 ± 0.04 | 0.47 ± 0.21 | 0.13 ± 0.09 | 0.78 ± 0.12 |
| Diabetes (Pro3(GIP)) | 28.96 ± 1.13 | 3.64 ± 0.44 | 0.23 ± 0.09 | 0.49 ± 0.07 | 0.12 ± 0.05 | 0.69 ± 0.16 |
| Diabetes (combination therapy) |
29.90 ± 2.77 | 3.61 ± 028 | 0.27 ± 0.08 | 0.51 ± 0.10 | 0.13 ± 0.08 | 0.74 ± 0.27 |
Values represent means ± standard deviations. #P < 0.05 vs. untreated diabetic mice.
Table 3.
Triglyceride and cholesterol levels in normal mice, untreated diabetic mice and sitagliptin/Pro3(GIP)-treated diabetic mice.
| Group | Number of mice | Triglycerides (mmol/L) | Cholesterol (mmol/L) |
|---|---|---|---|
| Normal | 9 | 1.12 ± 0.30**, ## | 2.60 ± 0.33 |
| Diabetes (untreated) | 7 | 1.55 ± 0.23** | 2.82 ± 0.48 |
| Diabetes (sitagliptin) | 6 | 1.37 ± 0.40* | 2.81 ± 0.21 |
| Diabetes (combination therapy) | 6 | 0.88 ± 0.20## | 2.48 ± 0.37 |
| Diabetes (Pro3(GIP)) | 6 | 1.27 ± 0.09* | 2.80 ± 0.26 |
Values represent means ± standard deviations. *P < 0.05 and **P < 0.01 vs. combination therapy. ##P < 0.01 vs. untreated diabetic mice.
IVGTT
IVGTTs were performed to evaluate insulin sensitivity and glucose metabolism. Glucose tolerance in untreated diabetic mice and diabetic mice receiving sitagliptin, Pro3(GIP), or combination therapy was similar (Figure 1a). The area under the curve from 0 to 120 minutes in the combination therapy group was smaller compared with the sitagliptin monotherapy and Pro3(GIP) monotherapy groups (Figure 1b). There was a consistently significant decrease in the insulin values of diabetic mice treated with sitagliptin or combination therapy compared with untreated diabetic mice. Moreover, decreases in insulin values were greater when sitagliptin and Pro3(GIP) were combined (Figure 1c). Combined administration of sitagliptin and Pro3(GIP) resulted in better improvements of glucose tolerance and insulin resistance compared with either agent alone.
Figure 1.
Effects of sitagliptin and Pro3(GIP), alone or in combination, on glucose tolerance. a: Serum glucose concentrations. b: Area under the curve from 0 to 120 minutes in intravenous glucose tolerance tests. c: Fasting insulin concentrations. Values represent means of five to seven mice and error bars indicate standard errors of the means. *P < 0.05 vs. combination therapy, **P < 0.01 vs. combination therapy.
Adipose tissue morphometry and inflammation
Adipose tissue inflammation is characterized by formation of CLSs. Significantly fewer CLSs were observed in the adipose tissues of mice treated with sitagliptin, Pro3(GIP), or the combination thereof relative to untreated diabetic mice (Figure 2a). Inflammatory cell infiltration was also less extensive in the combination therapy group than in the untreated diabetic mice (Figure 2b). However, the amount of subcutaneous adipose tissues was unchanged after treatment with Pro3(GIP) or sitagliptin, alone or in combination (data not shown).
Figure 2.
Combination therapy with sitagliptin and Pro3(GIP) resulted in decreased inflammation infiltration into subcutaneous adipose. a: Number of crown-like structures (CLSs, normalized to 100 adipocytes). b: Markers of inflammation infiltration in crown-like structures. *P < 0.05 vs. combination therapy, **P < 0.01 vs. combination therapy.
Pancreatic β-cell mass
The effects of sitagliptin and Pro3(GIP) therapy on insulin release were evaluated via assessment of β-cell mass and islet function. The proportion of islet cells and β-cell mass were both reduced in untreated diabetic mice compared with normal mice (Figure 3a). Following sitagliptin or Pro3(GIP) treatment, islet cell area, β-cell mass, and insulin release were significantly increased compared with untreated diabetic mice. Furthermore, combination therapy was more effective than either onotherapy in improving islet cell area, β-cell mass, and insulin release. The percentages of insulin-positive areas within the pancreas were greater in all three treatment groups compared with those of untreated diabetic mice, but smaller than those of normal mice (Figure 3b). The largest responses were observed in diabetic mice treated with both sitagliptin and Pro3(GIP).
Figure 3.
Sitagliptin and Pro3(GIP) increased β-cell mass in diabetic mice. a: β-cells are indicated by brown areas of positive insulin staining. b: Insulin-positive percentage of the total area of pancreas tissue. Error bars show standard deviations. #P < 0.05 and ##P < 0.01 vs. untreated diabetic mice; *P < 0.05 and **P < 0.01 vs. combination therapy.
Serum adipocytokine levels
The effects of sitagliptin and Pro3(GIP) in adipose tissue were investigated by quantitating secretion of the adipocytokines leptin and adiponectin. Serum leptin was 1.8-fold higher in diabetic mice compared with normal mice (Figure 4). Mice treated with sitagliptin and Pro3(GIP), alone or in combination, had reduced leptin secretion compared with untreated diabetic mice. However, the effect of combination therapy was smaller than either sitagliptin or Pro3(GIP) alone. Serum adiponectin was significantly lower in diabetic mice compared with normal mice. No significant differences in serum adiponectin levels were observed in untreated diabetic mice or diabetic mice in any treatment group (data not shown).
Figure 4.
Levels of plasma leptin in normal mice, untreated diabetic mice, and sitagliptin- and/or Pro3(GIP)-treated diabetic mice. Values represent means of five to seven mice and error bars indicate standard errors of the means. *P < 0.05 and **P < 0.01 vs. combination therapy; #P < 0.05 and ##P < 0.01 vs. untreated diabetic mice
Discussion
In the present study, a mouse model of type 2 diabetes was established by feeding a high-fat diet and streptozocin injection. A previous study showed that a high-fat diet, in conjunction with streptozocin injection, could induce hyperglycemia, insulin resistance, hyperlipidemia, and obesity.218 We found that sitagliptin or Pro3(GIP) treatment significantly reduced blood glucose and increased insulin levels as well as the percentage of insulin-positive areas in the pancreas. These results were consistent with previous studies.19,20 Surprisingly, combination therapy with Pro3(GIP) and sitagliptin showed synergy in decreasing plasma glucose, insulin resistance, and adipose tissue inflammation in a mouse model of type 2 diabetes.21 Additionally, analysis of IVGTT area under the curve indicated that plasma glucose was more significantly reduced 5 and 6 weeks after combination therapy with sitagliptin and Pro3(GIP) compared with either monotherapy. Furthermore, increased β-cell mass and insulin-positive areas were observed in the pancreas, suggesting that combination therapy increased insulin sensitivity to achieve a hypoglycemic effect. The beneficial effects of combination therapy depended upon the combined functions of sitagliptin and Pro3(GIP) on the response of adipose tissue to insulin secretion.10,22,23
DPP4 secreted by adipose tissue impairs insulin signaling in adipose cells, leading to insulin resistance. Sitagliptin has been shown to promote insulin activation in adipose cells by increasing protein kinase B (Akt) activity.24 These data suggest that adipocytes may mediate the effects of sitagliptin and Pro3(GIP) on diabetes metabolism. Pro3(GIP) and sitagliptin decreased the infiltration of inflammatory cells into the adipose tissue of diabetic mice. The greatest reduction of adipocytes with CLSs was observed in mice receiving combination therapy with sitagliptin and Pro3(GIP), suggesting that combination therapy could significantly reduce adipose tissue inflammation. Insulin resistance and inflammatory factors, such as IL-6 and TNF-α, have been linked to chronic inflammation in the adipose tissue of diabetic patients.25 Some trials have demonstrated benefits of immunomodulatory therapy in diabetic patients.26
Both sitagliptin and Pro3(GIP) markedly decreased plasma leptin concentrations in diabetic mice. Combination therapy resulted in a larger decrease in leptin levels than either monotherapy. However, leptin concentrations were still higher in treated diabetic mice than in normal mice. The adipocytokines leptin and adiponectin produced by adipose tissue play central roles in insulin resistance.27 Adiponectin is an insulin-sensitizing cytokine that augments fatty acid oxidation in muscle, increasing glucose uptake in adipose tissue and reducing free fatty acid influx and gluconeogenesis in the liver.28 Leptin blocks insulin biosynthesis and secretion upon binding to leptin receptors on pancreatic β-cells.29,30 In obese or diabetic patients, dysregulated leptin function results in upregulated plasma leptin levels, dysfunctional leptin signaling in the hypothalamus and increased insulin levels. Our results suggested that the mechanism underlying combination therapy with sitagliptin and Pro3(GIP) involved leptin, but not adipocytokines, because serum adiponectin was unaffected by either monotherapy or combination therapy.
In conclusion, combination therapy with Pro3(GIP) and sitagliptin more significantly decreased plasma glucose, insulin resistance, and adipose tissue inflammation than either monotherapy in a mouse model of type 2 diabetes. Combination therapy with sitagliptin and Pro3(GIP) had a greater effect on diabetic mice than either monotherapy, providing more metabolic benefits than administration of either single agent. Regulation of inflammatory infiltrates in adipose tissue and plasma leptin concentrations may be responsible for the superiority of combination therapy. Sitagliptin combined with Pro3(GIP), or similar combination regimens, may be effective for treating diabetes through modulation of adipose tissue metabolism.
Footnotes
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Bingyin Shi https://orcid.org/0000-0002-0005-4231
References
- 1.Campbell JE andDrucker DJ.. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17: 819–837. [DOI] [PubMed] [Google Scholar]
- 2.Lee M andRhee MK.. Sitagliptin for type 2 diabetes: A 2015 update. Expert Rev Cardiovasc Ther 2015; 13: 597–610. [DOI] [PubMed] [Google Scholar]
- 3.Wu T, Ma J, Bound MJet al. Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans and patients with type 2 diabetes treated with or without metformin. Diabetes 2014; 63: 2776–2787. [DOI] [PubMed] [Google Scholar]
- 4.Kim JH. Effects of sitagliptin on insulin and glucagon levels in type 2 diabetes mellitus. Diabetes Metab J 2015; 39: 304–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zhan M, Xu T, Wu Fet al. Sitagliptin in the treatment of type 2 diabetes: A meta-analysis. J Evid Based Med 2012; 5: 154–165. [DOI] [PubMed] [Google Scholar]
- 6.Fan M Li Y andZhang S.. Effects of sitagliptin on lipid profiles in patients with type 2 diabetes mellitus. Medicine (Baltimore) 2016; 95: e2386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Derosa G, Tritto I, Romano Det al. Effects of sitagliptin on lipid profile in patients with type 2 diabetes mellitus After 7 years of therapy. J Clin Pharmacol 2019; 59: 1391–1399. [DOI] [PubMed] [Google Scholar]
- 8.Shimasaki T, Masaki T, Mitsutomi Ket al. The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity. PLoS One 2013; 8: e63626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tremblay AJ, Lamarche B, Deacon CFet al. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism 2014; 63: 1141–1148. [DOI] [PubMed] [Google Scholar]
- 10.Shirakawa J, Fujii H, Ohnuma Ket al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes 2011; 60: 1246–1257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dobrian AD, Ma Q, Lindsay JWet al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab 2011; 300: E410–E421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Suh S, Kim MY, Kim SKet al. Glucose-dependent insulinotropic peptide level is associated with the development of type 2 diabetes mellitus. Endocrinol Metab (Seoul) 2016; 31: 134–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Coon SD, Schwartz JH, Rajendran VMet al. Glucose-dependent insulinotropic polypeptide regulates dipeptide absorption in mouse jejunum. Am J Physiol Gastrointest Liver Physiol 2013; 305: G678–G684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Nakayama K, Watanabe K, Boonvisut Set al. Common variants of GIP are associated with visceral fat accumulation in Japanese adults. Am J Physiol Gastrointest Liver Physiol 2014; 307: G1108–G1114. [DOI] [PubMed] [Google Scholar]
- 15.Shibue K, Yamane S, Harada Net al. Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion. Am J Physiol Endocrinol Metab 2015; 308: E583–E591. [DOI] [PubMed] [Google Scholar]
- 16.Chen S, Okahara F, Osaki Net al. Increased GIP signaling induces adipose inflammation via a HIF-1alpha-dependent pathway and impairs insulin sensitivity in mice. Am J Physiol Endocrinol Metab 2015; 308: E414–E425. [DOI] [PubMed] [Google Scholar]
- 17.Irwin N, McClean PL, Hunter Ket al. Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice. Diabetes Obes Metab 2009; 11: 603–610. [DOI] [PubMed] [Google Scholar]
- 18.Liu Y Deng J andFan D.. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct 2019; 10: 2538–2551. [DOI] [PubMed] [Google Scholar]
- 19.Asai S, Ohta A, Kato Het al. Effect of sitagliptin on glycemic control and beta cell function in Japanese patients given basal-supported oral therapy for type 2 diabetes. Endocr J 2014; 61: 1213–1220. [DOI] [PubMed] [Google Scholar]
- 20.Karagiannis T Boura P andTsapas A.. Safety of dipeptidyl peptidase 4 inhibitors: A perspective review. Ther Adv Drug Saf 2014; 5: 138–146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Saad MI Kamel MA andHanafi MY.. Modulation of adipocytokines production and serum NEFA level by metformin, glimepiride, and sitagliptin in HFD/STZ diabetic rats. Biochem Res Int 2015; 2015: 138134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Irwin N, McClean PL, O'Harte FPMet al. Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice. Diabetologia 2007; 50: 1532–1540. [DOI] [PubMed] [Google Scholar]
- 23.Narita T. [Effects of GIP receptor antagonist for treatment of obesity]. Nihon Rinsho 2011; 69: 939–945. [PubMed] [Google Scholar]
- 24.McClean PL, Irwin N, Cassidy RSet al. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab 2007; 293: E1746–E1755. [DOI] [PubMed] [Google Scholar]
- 25.Rohrborn D, Brückner J, Sell Het al. Reduced DPP4 activity improves insulin signaling in primary human adipocytes. Biochem Biophys Res Commun 2016; 471: 348–354. [DOI] [PubMed] [Google Scholar]
- 26.Premanath M, Basavanagowdappa H, Mahesh Met al. Chronic sub-clinical inflammation in the abdominal adipose tissue - Evaluation of inflammatory cytokines and their link with insulin resistance in metabolically obese South Indians: A cross-sectional observational study. Indian J Endocrinol Metab 2016; 20: 84–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Donath MY. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia 2016; 59: 679–682. [DOI] [PubMed] [Google Scholar]
- 28.Lima LCF, Braga VA, Do Socorro de França Silva Met al. Adipokines, diabetes and atherosclerosis: An inflammatory association. Front Physiol 2015; 6: 304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Knights AJ, Funnell AP, Pearson RCet al. Adipokines and insulin action: A sensitive issue. Adipocyte 2014; 3: 88–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Balsan GA, Da Costa Vieira JL, De Oliveira AMet al. Relationship between adiponectin, obesity and insulin resistance. Rev Assoc Med Bras (1992) 2015; 61: 72–80. [DOI] [PubMed] [Google Scholar]