Supernormal insulin: [D-PheB24]-insulin with increased affinity for insulin receptors

Kobayashi, Masashi; Ohgaku, Seiji; Iwasaki, Makoto; Maegawa, Hiroshi; Shigeta, Yukio; Inouye, Ken

doi:10.1016/0006-291x(82)91708-9

Cited by 64 publications

(55 citation statements)

References 10 publications

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Section: Discussionmentioning

confidence: 99%

“…This may also explain the low potency (4%) observed when the D-isomer of phenylalanine is substituted at the B25 position [30]. By contrast when B24 phenylalanine, whose conformation is the same in native insulin and DPI, and presumably DHI, is substituted by the D-isomer potency in vitro increases to 180% [30]. This finding is consistent with the possibility of conformational changes at the B-chain C-terminus, like those seen at B 25 in DHI, actually extending further to B 24 phenylalanine before or during the binding event.…”

Section: Discussionmentioning

confidence: 99%

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An examination of the role of insulin dimerisation and negative cooperativity using the biological properties of the despentapeptide and deshexapeptide insulins

et al. 1987

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Summary. The C-terminus of the insulin B chain is essential for dimerisation and expression of negative cooperativity. In order to evaluate the possible physiological role of these phenomena, we have studied the properties in vivo and in vitro of despentapeptide insulin (B26-30 deleted), derived from beef insulin, and deshexapeptide insulin (B25-30 deleted), derived from pork insulin. These materials do not dimerise and have 15% and 0% retention of negative cooperativity respectively. Lipogenesis potencies in rat adipocytes were: despentapeptide insulin 19.9+0.3%; deshexapeptide insulin 19.9 + 1.5%. Binding potencies in adipocytes were: despentapeptide insulin 22.6+7.8%; deshexapeptide insulin 13.2+ 3.3%. Metabolic clearance rates were reduced compared to insulin (insulin = 19.1 +_ 0.9; despentapeptide insulin = 9.7 _ 0.8; deshexapeptide insulin=6.4_0.6ml.min-l.kg -1 at plasma concentration 0.5 nmol/1). Hypoglycaemic potencies were reduced for both analogues (40% and 30%) when calculated on the basis of plasma concentration although both analogues and insulin were equally effective at lowering plasma glucose concentration in equimolar doses. Plasma half-disappearance time was prolonged (despentapeptide insulin = 7.3 + 0.5; deshexapeptide insulin = 9.1 + 0.2 min). Both analogues were full agonists and conformed to the general relationship between in vitro and in vivo properties seen with a wide range of modified insulins. They resemble other analogues with modifications which reduce receptor affinity without impairing dimerisation or negative cooperativity. The results do not support a physiological role for dimerisation or negative cooperativity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An examination of the role of insulin dimerisation and negative cooperativity using the biological properties of the despentapeptide and deshexapeptide insulins

et al. 1987

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“…3)) by glycine leads to an altered turn structure with near-native activity (4,40). Further, the activity of insulin is enhanced by chiral substitution of Phe B24 by D-Phe or D-Ala (20,50); these substitutions appear to be incompatible with native structure. Whereas the C-terminal segment of the B chain functions to contact the Nand C-terminal domains of the receptor ␣-subunit (56), its reorganization is proposed to expose an otherwise hidden functional surface in the A chain (4,54,(57)(58)(59).…”

Section: B25mentioning

confidence: 98%

Chiral Mutagenesis of Insulin

Nakagawa

Hua

et al. 2006

Journal of Biological Chemistry

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Insulin contains a ␤-turn (residues B20 -B23) interposed between two receptor-binding elements, the central ␣-helix of the B chain (B9 -B19) and its C-terminal ␤-strand (B24 -B28). The turn contains conserved glycines at B20 and B23. Although insulin exhibits marked conformational variability among crystal forms, these glycines consistently maintain positive dihedral angles within a classic type-I ␤-turn. Insulin, a small globular protein secreted by pancreatic ␤ cells, plays a central role in the control of vertebrate metabolism (1). The hormone is stored in glucose-regulated secretory granules as microcrystalline arrays of Zn 2ϩ -stabilized hexamers (2) and functions as a Zn 2ϩ -free monomer. The protein contains two chains, designated A (21 residues) and B (30 residues). The structure of insulin is well characterized (3). In the T state, 3 the predominant conformation of the monomer in solution (4 -6), the A chain contains N-and C-terminal ␣-helices; the B chain contains a central ␣-helix flanked by N-and C-terminal extended segments (Fig. 1A). The product of a single-chain precursor, designated proinsulin (7), insulin contains three disulfide bridges required for its folding, stability, and function (5, 8 -10). Structure-function relationships have been extensively investigated (for review, see Ref. 11).The B chain of insulin contains two ␤-turns (boxed in Fig. 1A, see below). The first is a type-IIЈ ␤-turn comprising residues B7-B10 (black box); the second is a type-I ␤-turn comprising residues B20 -B23 (red box; ball-and-stick model in Fig. 1B). Each contains one or more conserved glycines: Gly B8 , Gly B20 , and Gly B23 (Fig. 1C). These residues exhibit positive angles ("D-glycines") and, therefore, reside on the right side of the Ramachandran plane in regions unfavorable for L-amino acids. Gly B8 , which adjoins the A7-B7 inter-chain disulfide bridge, is invariant among vertebrate insulins and highly conserved among insulin-related growth factors (black box in Fig. 1C). Mutations at B8 markedly impair the stability of insulin and the yield of chain combination (12, 13); the efficiency of recombinant expression of a single-chain precursor (mini-proinsulin) in Saccharomyces cerevisiae is likewise reduced (14,15). Whereas such unstable insulin analogs can be highly active, D-amino acid substitutions at B8 augment stability but markedly impair activity (12,13). Despite these profound stereospecific differences, the overall structures of D and L B8 analogs closely resemble native insulin (13,16).In this report we employ "chiral mutagenesis" to investigate the B20 -B23 ␤-turn. The turn sequence is notable for conserved negative and positive charges (Glu B21 and Arg B22 in eutherian mammals) flanked by glycines (Fig. 1C). Experimental design is motivated by the pattern of main-chain dihedral angles (Table 1). To investigate the interrelation of structure, activity, and stability, isomeric analogs have been synthesized in which Gly B20 or Gly B23 is substituted by D-or L-Ala; control * This work was supported i...

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Section: Insulin Structure-function Relationshipsmentioning

confidence: 99%

“…Several mutations were identified in these regions that reduce the affinity to the insulin receptor, including LeuB25 for PheB25 (insulin Chicago), SerB24 for PheB24 (insulin Los Angeles) and LeuA3 for ValA3 (insulin Wakayama). Patients harboring these mutations display glucose intolerance and hyperinsulinemia [14][15][16][17][18][19].The A chain contains several regions that are important for receptor binding. The amino terminus, when N-acetylated, shows reduced receptor binding by 30 %, indicating that a free positively charged amino terminus is critical for receptor binding [20].…”

mentioning

confidence: 99%

Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

Fu¹,

Gilbert²,

Liu³

2012

CDR

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Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca 2+ ] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes. Keywords β-cell; diabetes; glucose; hormones; insulin secretion; insulin synthesis INSULIN Insulin structureThe crystal structure of insulin is well documented as well as the structural features that confer receptor binding affinity and activity. This has been extensively reviewed and readers are encouraged to visit [1] and [2] for excellent discussions on insulin structure and structure-activity relationships. As discussed in this review, insulin receptor downstream signaling intersects with the signaling pathways of other growth factors, including IGF1 and Correspondence: Dongmin Liu, Ph.D, Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24061, Tel: 540-231-3402, Fax: 540-231-3916, doliu@vt.edu. CONFLICTS OF INTERESTThe authors declare that they have no conflict of interest. NIH Public Access Author ManuscriptCurr Diabetes Rev. Author manuscript; available in PMC 2014 February 25. Published in final edited form as:Curr Diabetes Rev. 2013 January 1; 9(1): 25-53. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript IGF2 [3]. This demonstrates the importance of identifying receptor ligand agonists as potential insulin-mimetic therapeutic agent...

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Supernormal insulin: [D-PheB24]-insulin with increased affinity for insulin receptors

Cited by 64 publications

References 10 publications

An examination of the role of insulin dimerisation and negative cooperativity using the biological properties of the despentapeptide and deshexapeptide insulins

An examination of the role of insulin dimerisation and negative cooperativity using the biological properties of the despentapeptide and deshexapeptide insulins

Chiral Mutagenesis of Insulin

Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

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