No abstract

No abstract

No abstract

Structure-activity relationships of neurokinin A (NKA) and the two analogues NKA(4-10) and [Nle¹⁰]NKA(4-10) were investigated at the rat fundus NK-2 receptor, using selected amino acid substitutions. Both radioligand binding with [¹²⁵I][Lys⁵,Tyr(I₂)⁷,MeLeu⁹, Nle¹⁰] NKA(4-10) and functional studies were performed and correlated. In membrane binding experiments loss of His¹ and Lys², or replacement of Lys² with Ala did not substantially alter binding affinity of NKA. NKA(4-10) free acid was unable to compete with the radioligand. [Nle¹⁰]NKA(4-10) binding affinity to rat fundus membrane preparations was decreased when substituting Asp⁴ with Gln or Asn, or Val⁷ with either Tyr or Ile. Replacement of Ser⁵ with the negatively charged Glu also decreased the binding affinity, but substitution with the positively charged Lys substantially increased the affinity of [Nle¹⁰] NKA(4-10) for the NK-2 receptor. Lengthening NKA(4-10) or [Nle¹⁰]NKA(4-10) with Ala¹¹ or Nle¹¹, respectively, decreased the binding affinity of the peptide. In both binding and functional studies, replacement of any of the residues of NKA(4-10), except for Ser⁵, with alanine decreased the affinity of the peptide for the NK-2 receptor. Ala substitutions at positions 4, 6, and very obviously at 8, 9 and 10 of NKA(4-10) yielded peptides unable to achieve a maximum contractile response, although they did not demonstrate antagonist activity. These data confirm the importance of the NKA carboxyl terminus, and the requirement for Phe⁶, Val⁷, Gly⁸, Leu⁹ and Met¹⁰ integrity for interaction with the NK-2 receptor. They also suggest that Ser⁵ is a good site to target modifications leading to the design of new potential drugs.

AimTo identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.MethodFasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.ResultsThere were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15–120 min), in South East/East Asians (60–120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B.ConclusionsElevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.