A Novel MitoNEET Ligand, TT01001, Improves Diabetes and Ameliorates Mitochondrial Function in db/db Mice

Abstract

The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl-4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure. In this study, we assessed the pharmacological properties of TT01001 in both in vitro and in vivo studies. We found that TT01001 bound to mitoNEET without peroxisome proliferator-activated receptor-g activation effect. In type II diabetes model db/db mice, TT01001 improved hyperglycemia, hyperlipidemia, and glucose intolerance, and its efficacy was equivalent to that of pioglitazone, without the pioglitazone-associated weight gain. Mitochondrial complex II 1 III activity of the skeletal muscle was significantly increased in db/db mice. We found that TT01001 significantly suppressed the elevated activity of the complex II 1 III. These results suggest that TT01001 improved type II diabetes without causing weight gain and ameliorated mitochondrial function of db/db mice. This is the first study that demonstrates the effects of a mitoNEET ligand on glucose metabolism and mitochondrial function in an animal disease model. These findings support targeting mitoNEET as a potential therapeutic approach for the treatment of type II diabetes.

The Flower Tea Coreopsis tinctoria Increases Insulin Sensitivity and Regulates Hepatic Metabolism in Rats Fed a High-Fat Diet

“…But the PIO group showed a substantial increase in total food intake or water consumption and in weight gain compared with the HFD group. Our result is consistent with previous findings that show weight gain is one of the major side effects of PIO in clinical use (27). The histopathology of the liver ( Figure 2) demonstrated a significant effect of CT and PIO on insulin-resistant rats, which could be ascribed to the protection of flavonoids (36).…”

“…The control group was given deionized distilled water to drink and fed standard rat chow (24) mellitus (T2DM) in humans is approximately 60 -120 mg/kg, which is equivalent to approximately 1000 mg/kg in rats (25). Pioglitazone, a potent insulin sensitizer for the treatment of type 2 diabetes, has the apparent effects on glucose metabolism and was used as a positive control (5 mg/kg) (26,27). Therefore, the rats were then divided randomly into six groups of 10 animals in each group.…”

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

“…To confirm that pioglitazone alleviated signs of type 2 diabetes in ZDF, we measured blood glucose and HbA1c. The average dose of pioglitazone (mg · kg −1 · d −1 ) received by ZL (35.53 ± 1.94) and ZDF (32.19 ± 2.52) was similar over the 7 wk treatment period, and was comparable to previous studies in db/db mice (4 wks of 30 mg · kg −1 · d −1 ) 95 and ZDF rats (6 wks of 10 mg · kg −1 · d −1 ) 105 . As illustrated in Figure 5A, pioglitazone decreased blood glucose in ZDF [F (1, 18) = 16.51; P = 0.0007] but not in ZLs [F (1, 18) = 3.51; P=0.077] from 13 to 19 wks of age.…”

“…Numerous reports indicate that oral administration of pioglitazone or rosiglitazone reduces hyperglycemia in db/db mice 95 , ZDF rats 73 , and humans 3, 72, 108 as well as HbA1c levels in ZDF 105 and diet-induced type 2 diabetes 34 . To confirm that pioglitazone alleviated signs of type 2 diabetes in ZDF, we measured blood glucose and HbA1c.…”

“…First, the non-TZD PPARγ agonists FK614 60 , MBX-102 10, 29 , or MDG548 46 reduce insulin insensitivity, hyperglycemia, and inflammation and are neuroprotective 46 . Second, TZDs 28, 111 or the novel ligand TT01001 95 reduce diabetic mitochondrial dysfunction by targeting the mitochondrial protein mitoNEET, which is thought to alleviate other neurological diseases 23, 111 . Finally, a multiple drug strategy, such as coadministration of pioglitazone with canagliflozin 105 or geraniol 34 might reduce diabetes without the adverse effects of adipocyte differentiation, fat deposition, and weight gain associated with pioglitazone-only treatment.…”