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Retention of this unmodified histidine in retatrutide preserves potent glucagon receptor agonism, which is a defining structural distinction compared to tirzepatide, where this position is also histidine but the molecule lacks meaningful glucagon receptor activity due to other sequence differences

doi: 10.1159/000442155 43 MiholicJrskovCHolstJJKotzerkeJMeyerHJ

Neeland, I

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For comparative research, this distinction is fundamental glucagon receptor engagement introduces lipolytic and energy expenditure pathways that dual agonist studies cannot address