(4-(n-hydroxyamino)-2r-isobutyl-3s-methylsuccinyl)-l-phenylglycine-n-methylamide and Body-Weight

Insulin resistance is associated with hypertension, obesity, dyslipidemia, and type 2 diabetes. It is well known that tumor necrosis factor (TNF)-alpha is one of the factors linked to obesity-induced insulin resistance; however, there have been no reports on the role of TNF-alpha in insulin resistance in nonobese insulin-resistant hypertensives. We tested the hypothesis that TNF-alpha affects insulin resistance in nonobese insulin-resistant hypertensive fructose-fed rats (FFR) and that a TNF-alpha--converting enzyme (TACE) inhibitor that blocks TNF-alpha secretion improves insulin resistance in FFR. Six-week-old male Sprague-Dawley rats were fed either standard chow (control) or fructose-rich chow (FFR) for 6 weeks. For the last two weeks of a six-week period of either diet, the rats were treated with a vehicle (control or FFR) or a TACE inhibitor (100 mg/kg/d of KB-R7785; FFR+TACE-I) in peritoneal injection. At the age of 12 weeks, insulin sensitivity was assessed in all conscious rats by the euglycemic hyperinsulinemic glucose clamp technique. While FFR had higher blood pressure than the control rats (P<0.01), the TACE inhibitor did not change blood pressure. Insulin sensitivity (M-value) was reduced in FFR compared with that in the control rats (16.7 +/- 1.1 mg/kg per min and 10.3 +/- 0.6 mg/kg per min in the control rats and FFR, respectively, P<0.001), and the TACE inhibitor improved insulin sensitivity to the level of the control rats (14.3 +/- 1.2 mg/kg per min in FFR+TACE-I, P<0.01). These data indicate that TNF-alpha plays a major role in insulin resistance in nonobese insulin-resistant models and also suggest that TACE would be a good target for controlling insulin resistance not only in obese models but also in nonobese insulin-resistant models.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Blood Glucose; Blood Pressure; Body Weight; Diet; Fasting; Fructose; Glycine; Heart Rate; Hydroxamic Acids; Insulin Resistance; Male; Metalloendopeptidases; Protease Inhibitors; Rats; Rats, Sprague-Dawley

It has been suggested that tumor necrosis factor-alpha (TNF-alpha) is a key mediator of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha is synthesized as a membrane-bound precursor; this is proteolytically processed to an active form by a matrix metalloproteinase (MMP)-like enzyme. In this study, we have used KKAy mice which show insulin resistance like NIDDM to investigate the effects of KB-R7785, a novel MMP inhibitor, on blood glucose and insulin levels. Subcutaneous administration of KB-R7785 at 100 mg/kg twice daily (i.e., 200 mg/kg/day) for 4 weeks resulted in a significant decrease in plasma glucose levels which was observed after 3 weeks. Oral administration of pioglitazone (20 mg/kg twice daily or 40 mg/kg/day for 4 weeks), an agent known to ameliorate insulin sensitivity, significantly decreased plasma glucose levels during the treatment period. KB-R7785, but not pioglitazone, also significantly decreased plasma insulin levels. Lipopolysaccharide (LPS) increased plasma TNF-alpha levels to a significantly greater degree in KKAy mice than in normal C57BL mice; this was inhibitable in KKAy mice by KB-R7785. In contrast, pioglitazone did not affect the LPS-induced increase in plasma TNF-alpha levels in KKAy mice. These results suggest that KB-R7785 exerts its antidiabetic effect by ameliorating insulin sensitivity through the inhibition of TNF-alpha production.

Topics: Animals; Blood Glucose; Body Weight; Glycine; Hydroxamic Acids; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Pioglitazone; Protease Inhibitors; Thiazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha