Des-Acyl Ghrelin

Mechanism of Action

• Does not activate GHSR-1a (no growth hormone release, no orexigenic effect); lacks acylation needed for GHSR-1a binding
• Insulin sensitizing: UAG opposes acylated ghrelin-mediated glucose impairment; improves insulin receptor signaling in muscle and adipose
• Anti-adipogenic: UAG reduces lipid uptake and adipocyte differentiation in vitro; opposes AG pro-adipogenic effects
• Cardioprotective: UAG independently reduces cardiac apoptosis after ischemia-reperfusion injury via PI3K/Akt activation
• Some evidence for UAG/AG heterodimerization at a distinct binding site on cells co-expressing both ligands, modifying AG signaling

Research Findings

• AZP-531 (acyl-ghrelin analog that displaces UAG binding): in Phase II trials, reduced caloric intake and improved glycemic control in Prader-Willi syndrome patients
• UAG infusion in healthy subjects and type 2 diabetics improved insulin sensitivity without changing GH or appetite (confirming GHSR-1a-independent effects)
• UAG protects against glucose toxicity in pancreatic beta cells in vitro and in streptozotocin diabetic mice
• AG/UAG ratio is elevated in obesity, type 2 diabetes, and Prader-Willi syndrome; normalization of this ratio correlates with metabolic improvement
• UAG reduces endoplasmic reticulum stress markers in pancreatic beta cells, providing cytoprotection under metabolic overload

Research Protocols

• Insulin sensitivity: 1 pmol/kg/min IV UAG infusion (3 hours) with euglycemic-hyperinsulinemic clamp in T2D patients
• In vitro adipogenesis: 100 nM UAG during 3T3-L1 differentiation protocol; measure lipid accumulation by Oil Red O
• Cardiac protection: 30-100 nmol/kg IP UAG 1 hour before myocardial ischemia in rodent model; measure infarct size
• Pancreatic beta cell protection: 10-100 nM UAG with glucose toxicity (25 mM) in MIN6 or human islets; measure viability

Interactions

• Acylated ghrelin (AG): functional antagonist in many metabolic contexts; UAG/AG ratio determines net metabolic outcome
• Ghrelin O-acyltransferase (GOAT): the enzyme that converts UAG to AG; GOAT inhibitors shift balance toward UAG
• GHSR-1a: UAG does not bind but may allosterically modulate via heterodimerization or membrane effects at high concentrations

Safety Profile

Endogenous peptide well tolerated in IV infusion studies. AZP-531 (UAG-derived analog) showed acceptable safety in Phase II. No approved therapeutic; promising metabolic target for obesity, T2DM, and Prader-Willi syndrome.

Legal & Regulatory

Research peptide; AZP-531 (UAG analog) in Phase II clinical trials for Prader-Willi syndrome