title: Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes.
abstract: Recent data demonstrate that accumulation of misfolded proteins within the early part of the secretory track of β-cells causes impaired insulin synthesis and development of diabetes. The molecular mechanism of this cellular dysfunction remains largely unknown. Using basic molecular principles and computer simulations, we suggested recently that hyperglycemic conditions can generate substantial molecular crowding effects in the secretory track of β-cells leading to significant alterations of the insulin biosynthesis capabilities. Here, we review the major molecular mechanisms that may be implicated in the alteration of insulin synthesis in susceptible β-cells. Steric repulsions and volume exclusion in the endoplasmic reticulum (ER) increase the propensity of misfolding of proinsulin (the precursor molecule of insulin). In addition, similar forces might act in the next secretory compartments (Golgi and vesicles) leading to (i) altered packaging of proinsulin in vesicles (ii) entrapment of proinsulin convertases and/or restricted accessibility for these convertases to the cleavage sites on the surface of the proinsulin and (iii) depressed kinetic rate of the transformation of the native proinsulin in active insulin and C-peptide. These concepts are expressed in simple mathematical terms relating the kinetic coefficient of proinsulin to insulin conversion to the levels of proinsulin misfolding and hyperglycemic stress. The present approach is useful for understanding molecular phenomena associated with the pathogenesis of diabetes. It also offers practical means for predicting the state of pancreatic β-cells from measurements of the insulin to proinsulin ratio in the blood. This is of immediate clinical relevance and may improve the diagnosis of diabetes.
authors.affiliation: Institute of Diabetes N. Paulescu, Bucharest, Romania.
authors.forename: Constantin
authors.initials: C
authors.lastname: Ionescu-Tirgoviste
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008954:Models, Biological; D017510:Protein Folding
chemical_list: D007328:Insulin