Insulin and IGF-I Analogs: Novel Approaches to Improved Insulin Pharmacokinetics

Slieker, Lawrence J.; Brooke, G. S.; Chance, Ronald E.; Fan, Ludi; Hoffmann, J. A.; Howey, Daniel C.; Long, H B; Mayer, John P.; Shields, James E.; Sundell, Karen

doi:10.1007/978-1-4615-2988-0_3

Cited by 20 publications

(7 citation statements)

References 24 publications

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“…The B16 site, which is altered in EQF insulin, is one of the earliest cleavage sites in insulin (26). This study confirms the increased binding affinity of B10 (24), the reduced receptor binding of EQF (27), and the unaltered binding of LysPro. Similar results were seen with H4 hepatocytes, HepG2 hepatocytes, and L6 myotubes.…”

Section: H4-ii-e Hepatoma Cells-becausesupporting

confidence: 76%

“…The effects of this analogue on glucose metabolism are identical to insulin (34,36). Other effects, including cell growth and mitogenesis, are also similar to insulin (27,34). B10 has an increased affinity for the insulin receptor and correspondingly greater effects on glucose metabolism and on mitogenesis (29,34).…”

Section: Insulin Analogues and Protein Degradationmentioning

confidence: 98%

“…The B10 position is an early cleavage site for the degradation of insulin (26) and the Asp for His substitution alters cellular processing in several ways, including slower receptor dissociation and intracellular processing (25). EQF has several substitutions that decrease both binding and susceptibility to degradation (27). The B16 site, which is altered in EQF insulin, is one of the earliest cleavage sites in insulin (26).…”

Section: H4-ii-e Hepatoma Cells-becausementioning

confidence: 99%

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Insulin and Analogue Effects on Protein Degradation in Different Cell Types

Fawcett¹,

Hamel²,

Bennett³

et al. 2001

Journal of Biological Chemistry

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In adult animals, the major effect of insulin on protein turnover is inhibition of protein degradation. Cellular protein degradation is under the control of multiple systems, including lysosomes, proteasomes, calpains, and giant protease. Insulin has been shown to alter proteasome activity in vitro and in vivo. We examined the inhibition of protein degradation by insulin and insulin analogues (Lys B28 Despite similar binding, LysPro was 11-to 18-fold more potent than insulin at inhibiting protein degradation. Conversely, although EQF showed lower binding to H4 cells than insulin, its action was similar. The relative binding potencies of analogues in HepG2 cells were similar to those in H4 cells. Examination of protein degradation showed insulin, LysPro, and B10 were equivalent while EQF was less potent. L6 cells showed no difference in the binding of the analogues compared with insulin, but their effect on protein degradation was similar to that seen in HepG2 cells except B10 inhibited intermediate-lived protein degradation better than insulin. These studies illustrate the complexities of cellular protein degradation and the effects of insulin. The effect of insulin and analogues on protein degradation vary significantly in different cell types and with different experimental conditions. The differences seen in the action of the analogues cannot be attributed to binding differences. Post-receptor mechanisms, including intracellular processing and degradation, must be considered.,The major effect of insulin on whole body protein turnover is inhibition of protein degradation (1). Insulin also stimulates the synthesis of selected proteins and overall protein synthesis under certain conditions such as growth and development (2, 3). In the adult animal, however, total protein synthesis is not increased by insulin, and the protein anabolic effect of the hormone is actually an anti-catabolic property, i.e. inhibition of degradation (1).The mechanisms of cellular protein degradation and the control of these processes are poorly understood. Currently, the major degradative systems are considered to be the lysosome, the proteasome, and various cytoplasmic and cellular proteases such as the calpain family and a recently described giant protease (4 -7), which may functionally overlap proteasome activities. In general, lysosomes appear responsible for degradative processing of most endocytosed proteins and for autophagy under extreme catabolic states (4). The proteasome is a multifunctional organelle with multiple forms, e.g. 20 S and 26 S, which degrades abnormal and targeted proteins (ubiquitin, ATP-dependent pathway) and has various specific functions (antigen processing, etc.) (5). Calpains participate in Ca 2ϩ -mediated degradative activity (6). Various other proteases have specialized or uncertain roles but have a relatively minor contribution to cellular protein balance.Overall, cellular protein degradation can also be divided according to the half-lives of the proteins. This is particularly relevant, because many of ...

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Section: H4-ii-e Hepatoma Cells-becausesupporting

confidence: 76%

Section: Insulin Analogues and Protein Degradationmentioning

confidence: 98%

Section: H4-ii-e Hepatoma Cells-becausementioning

confidence: 99%

See 1 more Smart Citation

Insulin and Analogue Effects on Protein Degradation in Different Cell Types

Fawcett¹,

Hamel²,

Bennett³

et al. 2001

Journal of Biological Chemistry

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“…89 The introduction of this sequence into IGF-1 significantly increased the affinity while an analogous change in insulin to the IGF-1 sequence of Gln-Phe reduces insulin activity, without increasing IGF-1 receptor affinity. 89 Alanine substitution at B16 or B17 in insulin does not dramatically alter insulin receptor affinity, suggesting that the insertion of an aromatic residue at B17 is the primary basis for the reduced insulin receptor affinity. 83 A series of IGF-1 and IGF-2 hybrid proteins illustrated that the nature of the C and D domains can influence the relative activity at the two insulin receptor isoforms.…”

Section: Figure 11mentioning

confidence: 98%

Insulin structure and function

2007

Self Cite

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Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported.

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“…Insulin lispro is closely similar to regular human insulin in action, except for having a faster onset and shorter duration of action. 12 To understand the unique properties of insulin lispro, one must review the structure of regular human insulin. Regular human insulin is a protein hormone comprised of two polypeptide chains, an A chain and B chain linked together.…”

Section: Pharmacologymentioning

confidence: 99%

Insulin Lispro: Its Role in the Treatment of Diabetes Mellitus

Campbell¹,

Campbell²,

White³

1996

Ann Pharmacother

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Insulin lispro is equipotent to human insulin and has a much more rapid onset and shorter duration of action than human insulin does, which may reduce the risk of hypoglycemia. In addition, insulin lispro improves the dosing convenience for patients with diabetes and provides a more natural control of blood glucose concentrations. Insulin lispro is a useful new agent in the treatment of diabetes mellitus.

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Insulin and IGF-I Analogs: Novel Approaches to Improved Insulin Pharmacokinetics

Cited by 20 publications

References 24 publications

Insulin and Analogue Effects on Protein Degradation in Different Cell Types

Insulin and Analogue Effects on Protein Degradation in Different Cell Types

Insulin structure and function

Insulin Lispro: Its Role in the Treatment of Diabetes Mellitus

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