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Extra-hypothalamic growth hormone-releasing hormone (GHRH) plays an important role in reproduction. To study the treatment effect of Grin (a novel hGHRH homodimer), the infertility models of 85 male Chinese hamsters were established by intraperitoneally injecting 20 mg/kg of cyclophosphamide once in a week for 5 weeks and the treatment with Grin or human menopausal gonadotropin (hMG) as positive control was evaluated by performing a 3-week mating experiment. 2–8 mg/kg of Grin and 200 U/kg of hMG showed similar effect and different pathological characteristics. Compared to the single cyclophosphamide group (0%), the pregnancy rates (H-, M-, L-Grin 26.7, 30.8, 31.3%, and hMG 31.3%) showed significant difference, but there was no difference between the hMG and Grin groups. The single cyclophosphamide group presented loose tubules with pathologic vacuoles and significant TUNEL positive cells. Grin induced less weight of body or testis, compactly aligned tubules with little intra-lumens, whereas hMG caused more weight of body or testis, enlarging tubules with annular clearance. Grin presented a dose-dependent manner or cell differentiation-dependentincrease in testicular GHRH receptor, and did not impact the levels of blood and testicular GH, testosterone. Grin promotes fertility by proliferating and differentiating primitive cells through up-regulating testicular GHRH receptor without triggering GH secretion, which might solve the etiology of oligoasthenozoospermia.

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Background GLP-1R agonists play important role in T2D treatment. Methods Based on the GLP-1, Exendin-4, GIP-Exendin-4 chimeric peptide sequences, homodimerized GLP-1R agonists were synthesized and evaluated in normal and/or fat-diet-induced T2D mice. Results Dimers show opposite or similar water-solubility with their monomers. The H-like dimers 2G2-9 and 2G11-15 (internal single Cys→Ser substitution) respectively produced 5-20-11-3-14-14-2-7 and 2-8-4-9-16 days of hypoglycemic activities compared to their corresponding monomers G2-9 (2-9-3-1-4-4-1-2 day) and G11-15 (1-4-2-3-8 day) after 1.126-nmol of single administration, whereas the U-like dimer 2G1 or 2G10 (C-terminal Cys extension) did not impact glucose level, but it significantly promoted T2D pancreatic protection by inducing a dose-dependent decrease in TUNEL or amylase, and more Ki67 expression or HDL formation. The ultralente effect of dimer involves in delaying absorbance, the formations of 12Cys-12Cys in GLP-1 or 11Cys-11Cys in Exendin-4 and GIP-Exendin-4 analogues, symmetric fat-acid-chain-modulated 20Lys, αAib→2Ala substitution, and C-terminal amidation in one homodimer. 2G3 as a representative for the H-like dimers caused significant dose-dependent hypoglycemic effect in HbA1c changes (-1.6 ± 0.7, -4.6 ± 2.44, -6.4 ± 2.81 mmol/mol) from the Placebo (20.0 ± 5.03 mmol/mol) or FPG changes (-3.726 ± 3.09, -6.644 ± 4.31, -6.695 ± 3.96 mM) from the Placebo (14.149 ± 5.95 mM) as Liraglutide in HbA1c or FPG changes (-5.8 ± 2.83 mmol/mol or -7.107 ± 4.32 mM) from the Placebo. 2G3 induced the dose-dependent protections to T2D liver, heart, vascular wall integrity, or more ki67, HDL, islet number, or 1.92 times` insulin release without hypoglycemia than the same dose of Liraglutide by binding GLP-1R. Conclusions The better homodimerized GLP-1R agonists elucidates that the dimerization of hormone peptide produces better efficacy and may relieve serious concerns in course of therapy.