Thursday, November 21, 2024
11/21/2024
Project Summary Up to 95% of diabetic population suffer from type 2 diabetes (T2D) with its prevalence rising rapidly. A gradual decrease in β-cell function closely associated with hyperglycemia is the critical determinant to progress to T2D. Globally, obesity is the major driver of T2D. Energy expenditure and fat oxidation, rather than the appetite control with multiple fundamental concerns, are considered the key determining factors of weight loss to enhance glycemic control. Nonetheless, many of the drugs stimulating energy expenditure have failed in clinical development or been withdrawn from the market due to lack of efficacy or side effects. The non-canonical IkB kinases (IKKs), TANK-binding kinase 1 (TBK1) and its homolog IkB kinase e (IKKe), are key players responding to obesity-dependent inflammation to regulate glucose and energy metabolism. Nevertheless, a well-known TBK1/IKKe inhibitor amlexanox demonstrated modest efficacy in obese mice and humans; acute amlexanox treatment led to noticeably reduced food intake in obese mice; it was effective in lowering blood sugar only in a subset of obese patients with T2D and non-alcoholic fatty liver disease without significant body weight-reducing efficacy. To date, no synthesized analog of amlexanox has displayed a greater response than amlexanox in vivo. Our published studies identified a cinnamic acid derivative (E)-3-(3- phenylbenzo[c]isoxazol-5-yl)acrylic acid (abbreviated PIAA) as a novel TBK1/IKKe inhibitor showing higher efficacy than amlexanox in diabetogenic condition in vivo; we further provided the first evidence that the expression of TBK1 and IKBKE (encoding IKKe) was elevated in islets of obese T2D patients . Treatment of PIAA augmented glucose-stimulated insulin secretion and expression of pivotal β-cell functional markers in multiple animal and cell models, including human T2D islets. Our preliminary data demonstrated that while PIAA improved glycemic control with significant weight loss in diet-induced obese mice, its oral administration was found to be ineffective. To overcome orally inactive efficacy of PIAA, we developed a new orally active analog of PIAA based on our structure-activity relationship studies. Oral treatment of a new analog produced substantial weight loss without altering food intake in obese mice. Based on these preliminary supportive findings, the objective of this proposal is to evaluate the therapeutic potential of a new orally active small molecule in obesity-linked diabetic models. First, we will analyze the pharmacokinetic profiles of a new small molecule; investigation of the efficacy and mechanisms of a new small molecule in improving pancreatic islet cell function and mitigating adiposity via stimulating energy expenditure to enhance glycemic control will be performed in high-fat diet (HFD)-fed obese and overtly hyperglycemic/diabetic mice. Second, we will evaluate the efficacy of a new small molecule in ameliorating β- and α-cell dysfunctions in human islets exposed to a diabetic milieu. We will examine whether the inherent anti-hyperglycemic effect of a new small molecule translates from animal models to humans.
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