Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes
Introduction
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have published a position statement on type 2 diabetes mellitus (T2DM) that stresses the importance of a patient-centered approach [1], [2]. In this statement, metformin (MET) is recommended as initial drug therapy to be provided simultaneously with or soon after commencing lifestyle modification because of its high efficacy for reducing HbA1c, low cost, low risk of hypoglycemia, and neutral effect on body weight (or weight loss). If the target HbA1c is not achieved, the second and third agents to be combined with MET are selected from among five drug classes: sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP-4I), glucagon-like peptide-1 (GLP-1) agonists, or basal insulin. The unique and important point of the statement is comparison of the characteristics of these five drug classes to allow selection of suitable therapy for each patient.
In the statement, DPP-4I are characterized as showing intermediate efficacy for HbA1c reduction, with a low risk of hypoglycemia, neutral effect on body weight, and few major side effects. DPP-4I increase the plasma concentration of active GLP-1, which increases insulin secretion in a glucose-dependent manner and simultaneously suppresses the secretion of glucagon. Thus, DPP-4I reduce fasting and postprandial plasma glucose levels with a relatively low risk of hypoglycemia [4], [5]. A recent study showed that HbA1c reduction by DPP-4I is greater in Asian patients than Caucasians [3], so these agents are widely used for Japanese patients.
The GLP-1 receptor (GLP-1R) has been detected on human hepatocytes and adipocytes [6], and a GLP-1 analog (exendin-4) has been demonstrated to attenuate triglyceride synthesis by primary cultured human hepatocyte [7]. Furthermore, another GLP-1 agonist (liraglutide) achieved 42% reduction of the intrahepatic lipid (IHL) content and 11% reduction of the visceral fat volume in obese patients with T2DM after 6 months of treatment [8]. However, the plasma concentration of active GLP-1 is much lower during DPP4-I treatment compared with the levels during treatment with these GLP-1 agonists [9], [10]. According to the ADA/EASD statement, the effect of DPP4-I on body weight is neutral, but not marked [1], [2]. The effects of DPP-4I on body weight and hepatic fat accumulation have not been fully evaluated in patients with diabetes, although animal experiments have shown attenuation of hepatic steatosis by DPP-4I administration [11], [12].
Therefore, the aim of the present study was to investigate the effects of sitagliptin, one of the DPP-4I, on IHL and body fat compared with low-dose SU therapy using glimepiride in Japanese patients with type 2 diabetes with a BMI ≥ 25 kg/m2 or fatty liver on abdominal ultrasonography.
Section snippets
Subjects
The subjects were 20 Japanese patients with T2DM (11 men and 9 women aged 58.5 (40.0, 77.0) years, median (interquartile range (IQR)) with a BMI ≥ 25 kg/m2 or fatty liver detected by ultrasonography. The ultrasonography was carried out by using convex-array probe (3.5 MHz) for assessing the liver, and after a fasting period of 12 h. Diagnosis of fatty liver was attempted based on the difference between the echo intensities of the liver and kidney [13]. They were recruited from the outpatient clinic
Results
The baseline clinical characteristics of the patients are shown in Table 1. There were no significant differences between the two groups with regard to the age, blood pressure, BMI, HbA1c, GA, FPG, LDL-C, HDL-C, TG, FFA, HMW-Ad, leptin, and hsCRP. A comparison of laboratory parameters between the two groups during study period is displayed in Table 2. At 24 weeks, HbA1c and GA showed a similar significant decrease from their baseline levels in both groups. FPG was significantly decreased from
Discussion
The present study demonstrated that the reduction of HbA1c and GA was similar after treatment with sitagliptin or low-dose glimepiride for 24 weeks, but only sitagliptin (not glimepiride) significantly decreased IHL and total body fat mass.
In the liver, TG are not only produced from free fatty acids (FFA) that are released from adipose tissue by lipolysis, but also by intrahepatic fatty acid synthesis from dietary glucose via the malonyl–CoA pathway. Intake of a carbohydrate (CH)-restricted low
Conflict of interest statement
The authors declare that they have no conflict of interest.
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ZD-2, a novel DPP4 inhibitor, protects islet β-cell and improves glycemic control in high-fat-diet-induced obese mice
2022, Life SciencesCitation Excerpt :DPP-4 inhibitors can exert anti-inflammatory effects by inhibiting DPP-4 enzymes via suppressing T cell proliferation, and reducing the expression of cellular inflammatory factors [34]. Previous studies have been reported that DPP-4 inhibitors play anti-inflammatory roles in the liver and adipose tissues [35,36]. In our experiments, obvious steatosis and lipid droplets in the liver and increased fat mass were observed in the HFD group, while they were significantly alleviated under ZD-2 treatment, with the increasing of UCP1 expression in brown fat at the same time.
Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis
2020, Metabolism: Clinical and ExperimentalThe efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes
2020, Metabolism: Clinical and ExperimentalEffects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box!
2019, Metabolism: Clinical and ExperimentalCitation Excerpt :In contrast, Kato et al., compared the effects of sitagliptin (25 mg titrated up to 50 mg) with glimepiride (0.5 mg titrated up to 1 mg) on intrahepatic lipid content and body fat in 20 overweight Japanese patients with T2DM, reported that only sitagliptin significantly reduced intrahepatic lipid content and total body fat mass after 24 weeks [38]. On the other hand, a randomized clinical trial carried out on 50 NAFLD patients with prediabetes or early DM, found that sitagliptin (100 mg/day) administered for 24 weeks did not affect liver fat count [measured by magnetic resonance imaging (MRI)-derived proton density-fat fraction], ALT, AST, low-density lipoprotein (LDL), homeostatic model assessment insulin resistance, and magnetic resonance elastography (MRE) [39]. Similarly, a randomized clinical trial of 20 weeks with sitagliptin (100 mg/day) in T2DM patients showed no significant effects on hepatic fat content and fibrosis (assessed by proton magnetic resonance spectroscopy) [40].
Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity
2019, Life SciencesCitation Excerpt :They can potentially modulate some microRNAs (miR) involved in lipid metabolism such as miR-200b, miR-200c, miR-34a, miR-338 and miR-21 [113–116]. Therefore, recent evidence suggested these hypoglycemic medications are promising therapeutic agents for dyslipidemia-induced disorders such as NAFLD (non-alcoholic fatty liver disease) and atherosclerosis in the diabetic milieu [117–120]. Ejarque et al. in 2019 demonstrated that GLP-1 expressed on adipocytes regulates the adipose tissue metabolism leading to higher insulin sensitivity [121].