Ezetimibe is the first agent of a novel class of selective cholesterol absorption inhibitors and acts on the brush borders of rat small intestinal mucosal cells. Ezetimibe can inhibit the Niemann-Pick C1 Like 1 Protein (NPC1Ll) activity and selectively suppress the transportation of cholesterol in the diet and bile across the small intestine into the liver. Thus, the cholesterol stored in the liver is reduced which leads to reduction of synthesis of LDL receptor in the liver, promotion of LDL metabolism, and decrease in plasma LDL-C [5
To date, studies have confirmed the NPC1Ll expression in not only the small intestine but the liver, pancreas, gallbladder, testis, and stomach [6
]. Chan et al. found that, in patients with nonalcoholic fatty liver disease, ezetimibe could not only reduce the intrahepatic triglyceride and plasma levels of hsCRP, IL-6 and RBP-4 but also increase the adiponectin, which attributed to the improvement of hepatic steatosis, hepatic inflammation, and dyslipidemia and increase in the insulin sensitivity [7
]. Nomura et al. [8
] found that ezetimibe could inhibit the hepatic NPC1Ll activity, reduce the production of reactive oxygen species, suppress the JNK activity, reduce the unfolded or misfolded protein induced endoplasmic reticulum stress, promote the phosphorylation of PI-3K/AKT in the insulin signaling pathway, and then improve the insulin resistance in the liver. Although numerous studies have been conducted to investigate the hepatic insulin resistance, few studies report the effect of ezetimibe on the pancreatic islets. In the present study, we for the first time showed that ezetimibe-treated db/db mice not only reduce the blood lipids, but also alleviate blood high glucose, improve the glucose tolerance and first phase insulin secretion, elevate the insulin sensitivity, reduce the β
cell loss, and protect the function of β
Although there was no significant difference in the blood glucose level of db/db diabetic mice before and after ezetimibe treatment, the fasting glucose level, glucose tolerance, and glycosylated hemoglobin were all significantly lowered as compared with the control group. The abnormality of first phase insulin secretion is an early manifestation of dysfunction of β
cells. Currently, methods aiming to evaluate the insulin secretion are used to detect the total insulin, which cannot reflect the changes in insulin in two phases and those in the amount of insulin. In the present study, we for the first time applied in vitro perfusion of pancreatic islets [9
] to evaluate the changes in the first phase insulin secretion in db/db mice. Results revealed, in the ezetimibe group, the insulin secretion remained unchanged following perfusion with low glucose solution. However, at 1
min after perfusion with 16.7
mM glucose solution, the insulin secretion was markedly increased. Thus, we speculate that the improvement of hyperlipidemia in ezetimibe-treated mice might be attributed to the improvement of first phase insulin secretion. Naples et al. also found that ezetimibe treatment improved glucose tolerance, decreased fasting insulin levels in FFC-fed hamsters [10
]. Hiramitsu et al. also found ezetimibe therapy reduced the fasting serum insulin level and HbA1c [11
]. Although in SANDS study, there was an increase in blood glucose values in diabetes patients the treatment with statin and ezetimibe after 36 months of followup, the possible reason is probably related to the development of diabetes itself and the use of stains [12
In our study, after ezetimibe treatment for 6 weeks, quantitative analysis showed ezetimibe could significantly reduce the β
cell loss and increase the β
-cell staining intensity. Consistent with our results, Yang et al. [13
] found that, in diabetes mice with hyperlipidemia, long-term treatment with ezetimibe (20 weeks) could increase the number of β
cells and the content of cytoplasmic insulin.
The mechanism underlying the ezetimibe induced improvement of glucose metabolism under diabetic status is still poorly understood. Studies show that this might be related to the improvement of peripheral insulin resistance and regulation of signaling pathways. The persistent increase in plasma free fat acid (FFA) may elicit the insulin resistance in the muscles and liver, elevate the gluconeogenesis, and reduce the glucose uptake in the muscles. On the contrary, persistent reduction in FFA may improve the glucose tolerance and elevate the peripheral insulin sensitivity [14
]. Ezetimibe can directly inhibit the cholesterol absorption, reduce the FFA, improve the insulin resistance, and reduce blood glucose. In addition, ezetimibe may promote the phosphorylation of PI-3K/AKT via suppressing the hepatic NPC1Ll activity and inhibit the JNK activity [8
], which then improves the insulin resistance. However, the effect of ezetimibe on the insulin signaling pathway in the pancreatic islets is required to be further studied.
Of course, there may be other mechanisms related to the ezetimibe improvement of insulin secretion. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) are produced by the intestine and are released into the circulation in response to ingestion of macronutrients. Yang et al. had found that ezetimibe significantly active glucagon-like peptide-1
]. But Kikuchi et al. [15
] had reported that the active glucagon-like peptide-1 (GLP-1) was not significantly affected by ezetimibe treatment in obese men. The inconsistent results and the mechanisms need to be further studied.
Taken together, our results demonstrate that ezetimibe not only can reduce the serum lipids, but also can improve the first phase insulin secretion in β cells, alleviate blood high glucose, increase the insulin sensitivity, and protect the function of β cells in mice. Our findings provide a new strategy for the treatment of diabetes with concomitant hyperlipidemia and atherosclerosis.