The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. The phase 2b study was a 26-week, randomized, placebo-controlled study comparing the effects of four doses (1 mg, 5 mg, 10 mg, 15 mg) of Lilly's novel long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist to dulaglutide 1.5 mg and placebo in people with type 2 diabetes. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. The rationale for this approach was to investigate if GLP-1 signalling could cause metabolic reprograming that would persist after removal of receptor stimulation (Fig. 1A). Glucose consumption, lactate production, total ATP content and insulin secretion were determined after 24 hours of incubation in the absence of Exendin-4 (Fig. 1B-G). All parameters were significantly enhanced in cells pre-conditioned with Exendin-4 relative to control cells treated with high glucose alone. As shown in Figure 2C, NLY01 pretreatment significantly reduced inflammatory cytokine expression induced by LPS stimulation.

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