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Figure 3. Metabolic activity of insulin glargine and its metabolites in rat adipocytes.

To compare the metabolic activity of glargine and its metabolites insulin-stimulated lipid synthesis in isolated primary rat adipocytes was analyzed by incorporation of [3- 3 H]glucose into toluene-extractable lipids and subsequent measurement of radioactivity by liquid scintillation counting. The adipocytes were treated with increasing concentrations of insulin, analogs, metabolites or IGF-1 for 90 min at 37°C in the presence of [3- 3 H]glucose. Each point represents the mean ± SEM of five different adipocyte preparations with activity measurements done in duplicate.

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The relative metabolic activities of human insulin > insulin glargine  =  glargine metabolites correlate well with their binding affinities and autophosphorylation of IR-A and IR-B. This is compatible with previous studies demonstrating that ligand affinity and activation (i.e. autophosphorylation) of the IR are the key events for initiation of downstream signaling to the metabolic effector systems of insulin and its analogs Maison Margiela Satin Tabi Flats Pb5WnRDmJk
, [40] .

The maintenance of binding, autophosphorylation and metabolic activities of insulin analogs with modified carboxy-terminus confirm the previous findings that amino acid modifications at the insulin B-chain beyond position B25, in particular the B26-B30 region, do not play a critical role in its recognition by both isoforms of the IR Ivanka Trump Womens Camryn Suede amp; Patent Leather Ankle Strap Sandals upJiqopzw
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and thus in metabolic signaling in insulin target cells [6] , LD Tuttle The Door Suede Platform Boots 0Q1pT
. The slightly lower binding, autophosphorylation and metabolic activities of M1 relative to those of human insulin are in agreement with the previous suggestion that the minor structural change caused by loss of the salt bridge between Asn A21 and Arg B22 leads to a (small) reduction in IR affinity Oscar de la Renta Womens Charlee Crystal Embellished Satin Slide Sandals pld2Vx
. In consequence, the slight reduction in metabolic activity of insulin glargine vs. human insulin derives predominantly from altered structural features at the carboxy-terminus of the B-chain and rather than from the amino acid substitution at A21.

Taken together, the present data clearly demonstrate that the major metabolites of insulin glargine detected in rats, dogs, and humans [9] , Patricia Green Womens Bonnie Bow Slipper HZ7YUu
are metabolically active. Since a ratio of 50∶50 for parent compound and M1/M2 was reported in tissue samples derived from the site of injection in humans 8FaALIP7U1 Floral element sandals VuoVver8z
and in vitro metabolism of insulin glargine resulted into 46% to 98% appearance of M1 TOGA PULLA Ornate buckle wedge loafers Lt8XjhcS
, it is reasonable to assume that the metabolites of insulin glargine will contribute to the blood glucose lowering profile observed after administration of insulin glargine, dependent on the extent of their generation at the subcutaneous injection site and in plasma in the course of carboxypeptidase action Bottega Veneta Antique gold calf Mary Jane ballerina P0DJi

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