Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

Abstract

ObjectiveRecently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice.MethodsTallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined.ResultsPlasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis.ConclusionsOur data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

Dissociation of Fatty Liver and Insulin Resistance in I148M PNPLA3 Carriers: Differences in Diacylglycerol (DAG) FA18:1 Lipid Species as a Possible Explanation

“…NAFLD/NASH patients are advised to lose weight with lifestyle intervention (mostly consisting of healthy diet and exercise [ 4 ]), however, not all patients benefit from these interventions [ 5 ]. To treat NAFLD/NASH, several drugs have been shown to be beneficial in animal models [ 6 , 7 ], and novel activators for peroxisome proliferator-activated receptor (PPAR) (elafibranor) and farnesoid X receptor (FXR) (obeticholic acid) are currently under phase 3 studies in human cohorts with promising results [ 4 ]. NAFLD is a strong determinant of insulin sensitivity and the development of type 2 diabetes, however, some distinct genetic causes for the dissociation of liver fat content and insulin sensitivity have been identified [ 1 ].…”

Prevention of Elevation in Plasma Triacylglycerol with High-Dose Bezafibrate Treatment Abolishes Insulin Resistance and Attenuates Glucose Intolerance Induced by Short-Term Treatment with Dexamethasone in Rats

“…The mechanisms by which bezafibrate acts include the increase in plasma triacylglycerol clearance through increased lipoprotein lipase and hepatic lipase activities [ 24 , 25 ]. This increased plasmatic clearance of triacylglycerol is also associated with augmented mitochondrial performance and mass, energy expenditure, and a better metabolic flexibility [ 26 , 27 ], which altogether support, at least in part, the disposal and oxidation of glucose and NEFA. The improvement in insulin sensitivity caused by bezafibrate administration, as discussed hereafter, may also explain the improvement of the insulin-suppressive effect on fat lipolysis and the hepatic gluconeogenesis (not directly investigated in the present study), favoring a better control of blood glucose and plasma lipids levels.…”

“…The improvement in insulin sensitivity caused by bezafibrate administration, as discussed hereafter, may also explain the improvement of the insulin-suppressive effect on fat lipolysis and the hepatic gluconeogenesis (not directly investigated in the present study), favoring a better control of blood glucose and plasma lipids levels. There are numerous laboratory evidences demonstrating the positive impact of bezafibrate treatment on lipid and glucose metabolism in rodents, including diet-induced metabolic dysfunctions [ 28 , 29 ] and monogenic/polygenic phenotypes of obesity/diabetes, such as db/db mice [ 30 ], TallyHo mice [ 27 ], OLEFT rats [ 13 , 14 ], and models of diabetes induced by streptozotocin [ 26 ]. Studies with dyslipidemic nonobese humans [ 31 ] who are overweight [ 32 ] and have diabetes [ 33 – 35 ] also revealed the positive impact of bezafibrate treatment on lipid and glucose metabolism.…”

Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

“…Liver and kidney tissues were fixed in 4% paraformaldehyde and paraffin sections were stained with hematoxylin and eosin as described previously 48 .…”

“…Pancreata were fixed in 4% paraformaldehyde and cryosections were stained with anti-fibril (91D7E8), anti-insulin antibodies and cell nuclei with DAPI staining as described previously 48 . Slides were scanned using a NanoZoomer 2.0 HT (Hamamatsu, Japan) fluorescence scanner; pancreatic islets were evaluated using Definiens Developer XD 2 image analysis software (Definiens AG, Germany) as described previously 45 .…”