Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets. — VialBase Research

Summary

This is a fetal sheep study — animal data only, no human subjects. IGF-1 is a critical fetal growth hormone that has been proposed as a therapy for intrauterine growth restriction, and the same group had previously demonstrated that a 1-week IGF-1 LR3 infusion into fetal sheep reduces both in vivo and in vitro insulin secretion, a pattern suggesting an intrinsic islet defect. The objective here was to determine whether that defect depended on chronicity of exposure, so the investigators tested a much shorter 90-minute IGF-1 LR3 infusion on fetal glucose-stimulated insulin secretion (GSIS) and on insulin secretion from isolated fetal islets. Late gestation fetal sheep (n = 10) were infused with either IGF-1 LR3 or vehicle control (CON) while basal insulin secretion and in vivo GSIS were measured using a hyperglycemic clamp. Fetal islets were then isolated immediately following a 90-minute in vivo infusion (IGF-1, n = 6; CON, n = 6) and exposed to glucose or potassium chloride to measure in vitro insulin secretion. Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion (P < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 compared with control (P < 0.0001). Insulin secretion in the isolated fetal islets, by contrast, was not different based on the infusion given at the time of islet collection. The authors therefore speculate that while acute IGF-1 LR3 infusion may directly suppress insulin secretion, the fetal beta cell in vitro retains the ability to recover GSIS — with important implications for the long-term effects of treatments for fetal growth restriction.

Key Findings

• Acute (90-minute) IGF-1 LR3 infusion decreased fetal plasma insulin concentrations (P < 0.05)
• Insulin concentrations during a hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion than with vehicle control (P < 0.0001) — a large suppression of glucose-stimulated insulin secretion in vivo
• The group’s earlier work showed a 1-week IGF-1 LR3 infusion reduces insulin secretion both in vivo and in vitro, which they interpreted as an intrinsic islet defect; this study asked whether that depended on duration of exposure
• Islets isolated immediately after the 90-minute infusion secreted insulin no differently from control islets in response to glucose or potassium chloride, so the acute in vivo suppression did not persist ex vivo
• Sample sizes were small: n = 10 fetal sheep for the in vivo clamp work and n = 6 per group for the isolated islet experiments
• The authors’ interpretation is that acute IGF-1 LR3 may directly suppress insulin secretion while the beta cell retains recovery capacity in vitro — a speculation, stated as such

Relevance to IGF-1-LR3

This is a metabolic safety signal and should be read as one. IGF-1-LR3 is sold on the premise of muscle growth, but in this model an infusion of the analogue attenuated glucose-stimulated insulin secretion sharply — insulin during a hyperglycemic clamp was 66% lower than control — and the same laboratory’s longer 1-week infusion reduced insulin secretion both in vivo and in vitro. Suppressed insulin response to a glucose load is not a peripheral finding for a compound whose whole rationale is metabolic signalling; it is a direct effect on the pancreatic beta cell axis. The mitigating detail is real and should be reported alongside it: after a 90-minute exposure, isolated islets responded normally, so the acute effect did not persist once the tissue was removed from the infusion. What this evidence cannot tell anyone is what happens in a human adult self-administering LR3, because there are no human trials of IGF-1 LR3 in this evidence set — this is fetal sheep, in small numbers, in a therapeutic context (intrauterine growth restriction) that has nothing to do with recreational use.

Citation

White A, Stremming J, Brown LD, et al. Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets. Journal of developmental origins of health and disease. 2023;14(3):353-361. doi:10.1017/S2040174423000090.

See Also

• Parent compound: IGF-1-LR3