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Abstract
Insulin resistance is the key feature of type 2 diabetes and is manifested as attenuated insulin receptor (IR) signaling in response to same levels of insulin binding. Several small molecule IR activators have been identified and reported to exhibit insulin sensitization properties. One of these molecules, TLK19781 (Cmpd1), was investigated to examine its IR sensitizing action in vivo. Our data demonstrate that Cmpd1, at doses that produced minimal efficacy in the absence of insulin, potentiated insulin action during an OGTT in non-diabetic mice and enhanced insulin-mediated glucose lowering in diabetic mice. Interestingly, different from insulin alone, Cmpd1 combined with insulin showed enhanced efficacy and duration of action without increased hypoglycemia. To explore the mechanism underlying the apparent glucose dependent efficacy, tissue insulin signaling was compared in healthy and diabetic mice. Cmpd1 enhanced insulin’s effects on IR phosphorylation in both healthy and diabetic mice. In contrast, the compound potentiated insulin’s effects on Akt phosphorylation in diabetic but not in non-diabetic mice. These differential effects on signaling corresponding to glucose levels could be part of the mechanism for reduced hypoglycemia risk. The in vivo efficacy of Cmpd1 is specific and dependent on IR expression. Results from these studies support the idea of targeting IR for insulin sensitization, which carries low hypoglycemia risk by standalone treatment and could improve the effectiveness of insulin therapies.
Highlights
As the insulin resistant and diabetic population expands worldwide at an increasing pace, insulin analogs and insulin sensitizers continue to be highly demanded therapeutic options
The effects of Cmpd1 on glucose lowering were first tested in STZ-diabetic mice
Addition of insulin to Cmpd1 led to more potent glucose lowering than with corresponding doses of insulin alone, reaching 46% AUC reduction at 1 U/kg insulin when compared with insulin only group (Fig. 1A-B)
Summary
As the insulin resistant and diabetic population expands worldwide at an increasing pace, insulin analogs and insulin sensitizers continue to be highly demanded therapeutic options. Since the introduction of purified insulin to clinical use nearly a century ago, there have been continuous efforts to develop analogs
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