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  • Proinsulin maturation, misfolding, and proteotoxicity. 17898179

    As a tool to explore proinsulin (PI) trafficking, a human PI cDNA has been constructed with GFP fused within the C peptide. In regulated secretory cells containing appropriate prohormone convertases, the hProCpepGFP construct undergoes endoproteolytic processing to CpepGFP and native human insulin, which are specifically detected and cosecreted in parallel with endogenous insulin. Expression of C(A7)Y mutant PI results in autosomal dominant diabetes in Akita mice. We directly identify the misfolded PI in Akita islets and also show that C(A7)Y mutant PI, either in the context of the hProCpepGFP chimera or not, engages directly in protein complexes with nonmutant PI, impairing the trafficking and recovery of nonmutant PI. This trapping mechanism decreases insulin production in beta cells. Thereafter we observe a loss of beta cell viability. The data imply that PI misfolding leading to impaired endoplasmic reticulum exit of nonmutant PI may be a key early step in a chain reaction of beta cell dysfunction and demise leading to onset and progression of diabetes.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Differential effects of proinsulin C-peptide fragments on Na+, K+-ATPase activity of renal tubule segments. 9541168

    Proinsulin C-peptide has been shown to stimulate the activity of Na+ K+ ATPase of rat renal tubule segments. Thirty-six peptides and amino acids, corresponding to parts of the intact rat C-peptide and suitable controls were screened for capacity to stimulate Na+, K+-ATPase in an attempt to determine potential active sites in the C-peptide molecule. The carboxy-terminal tetra and penta peptides were found to elicit 92-103% of the intact molecule's activity, and the remaining segment, des-(27-31) C-peptide, did not possess stimulatory activity. Peptides from the middle C-peptide segment, however, centering around a GGPEAG sequence, stimulated Na+, K+-ATPase activity (36-80% of the intact molecule's effect) but this effect was not balanced by corresponding inactivity of other parts. Furthermore, it was paralleled by activity of a non-native dipeptide D-form. It is concluded that the latter effect and that of the middle segment may represent complex interactions other than the apparently specific effects of the C-terminal segment.
    Document Type:
    Reference
    Product Catalog Number:
    17-176

  • The impact of insulin resistance on proinsulin secretion in pregnancy: hyperproinsulinemia is not a feature of gestational diabetes. 16249544

    OBJECTIVE: Excessive secretion of the insulin precursor proinsulin, as manifested by an increased serum proinsulin-to-insulin ratio, has been associated with beta-cell dysfunction. In women with gestational diabetes mellitus (GDM), previous studies of the proinsulin-to-insulin ratio have yielded conflicting results, despite the presence of beta-cell dysfunction. The interpretation of the proinsulin-to-insulin ratio, however, may be confounded by the variable effects of hepatic insulin extraction. Thus, we sought to determine whether GDM is characterized by relative hyperproinsulinemia as measured by the proinsulin-to-C-peptide ratio, an alternate measure of proinsulin secretion that is not affected by hepatic insulin extraction. RESEARCH DESIGN AND METHODS: Serum proinsulin, C-peptide, and insulin were measured in a cross-sectional study of 180 women undergoing oral glucose tolerance tests (OGTTs) in the late second or early third trimester. Based on the OGTT, participants were stratified into three groups: 1) normal glucose tolerance (NGT; n = 93), 2) impaired glucose tolerance (IGT; n = 39), and 3) GDM (n = 48). Insulin sensitivity (IS) was measured using the IS(OGTT) index of Matsuda and DeFronzo, which has been previously validated in pregnant women. RESULTS: There were no significant differences in mean fasting proinsulin-to-C-peptide ratio between the three glucose tolerance groups (NGT, 0.024; IGT, 0.022; GDM, 0.019; P = 0.4). Furthermore, adjustment for age, weeks' gestation, prepregnancy BMI, ethnicity, previous GDM, and family history of diabetes did not reveal any association between the proinsulin-to-C-peptide ratio and glucose tolerance status. Using Spearman univariate correlation analysis, fasting proinsulin-to-C-peptide ratio was significantly correlated with IS(OGTT) (r = 0.29, P 0.0001) and inversely related to the homeostasis model assessment of insulin resistance (r = -0.36, P 0.0001) and prepregnancy BMI (r = -0.23, P 0.005). On multiple linear regression analysis, IS(OGTT) emerged as the strongest independent correlate of the dependent variable proinsulin-to-C-peptide ratio. Furthermore, after adjustment for potential covariates, a stepwise decrease in proinsulin-to-C-peptide ratio was observed per decreasing tertile of IS(OGTT) (trend P = 0.0019), consistent with enhanced efficiency of proinsulin processing (i.e., reduced proinsulin-to-C-peptide ratio) as insulin resistance increases. CONCLUSIONS: GDM is not independently associated with hyperproinsulinemia as measured by the proinsulin-to-C-peptide ratio. Instead, in pregnant women, increased insulin resistance is associated with decreased proinsulin-to-C-peptide ratio, independently of glucose tolerance status. These data suggest that relative proinsulin secretion in late pregnancy is primarily related to insulin resistance and does not necessarily reflect beta-cell function.
    Document Type:
    Reference
    Product Catalog Number:
    HPI-15K
    Product Catalog Name:
    Human Proinsulin RIA

  • Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. 16081777

    The natural expression of tissue-specific genes in the thymus, e.g., insulin, is critical for self-tolerance. The transcription of tissue-specific genes is ascribed to peripheral Ag-expressing (PAE) cells, which discordant studies identified as thymic epithelial cells (TEC) or CD11c+ dendritic cells (DC). We hypothesized that, consistent with APC function, PAE-DC should constitutively display multiple self-epitopes on their surface. If recognized by Abs, such epitopes could help identify PAE cells to further define their distribution, nature, and function. We report that selected Abs reacted with self-epitopes, including a proinsulin epitope, on the surface of CD11c+ cells. We find that Proins+ CD11c+ PAE cells exist in human thymus, spleen, and also circulate in blood. Human thymic Proins+ cells appear as mature DC but express CD8alpha, CD20, CD123, and CD14; peripheral Proins+ cells appear as immature DC. However, DC derived in vitro from human peripheral blood monocytes include Proins+ cells that uniquely differentiate and mature into thymic-like PAE-DC. Critically, we demonstrate that human Proins+ CD11c+ cells transcribe the insulin gene in thymus, spleen, and blood. Likewise, we show that mouse thymic and peripheral CD11c+ cells transcribe the insulin gene and display the proinsulin epitope; moreover, by using knockout mice, we show that the display of this epitope depends upon insulin gene transcription and is independent of Ag capturing. Thus, we propose that PAE cells include functionally distinct DC displaying self-epitopes through a novel, transcription-dependent mechanism. These cells might play a role in promoting self-tolerance, not only in the thymus but also in the periphery.
    Document Type:
    Reference
    Product Catalog Number:
    AB1511

  • Misfolded proinsulin affects bystander proinsulin in neonatal diabetes. 19880509

    It has previously been shown that misfolded mutant Akita proinsulin in the endoplasmic reticulum engages directly in protein complexes either with nonmutant proinsulin or with hProCpepGFP (human proinsulin bearing emerald-GFP within the C-peptide), impairing the trafficking of these bystander proinsulin molecules (Liu, M., Hodish, I., Rhodes, C. J., and Arvan, P. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 15841-15846). Herein, we generated transgenic mice, which, in addition to expressing endogenous proinsulin, exhibit beta-cell-specific expression of hProCpepGFP via the Ins1 promoter. In these mice, hProCpepGFP protein levels are physiologically regulated, and hProCpepGFP is packaged and processed to CpepGFP that is co-stored in beta-secretory granules. Visualization of CpepGFP fluorescence provides a quantifiable measure of pancreatic islet insulin content that can be followed in live animals in states of health and disease. We examined loss of pancreatic insulin in hProCpepGFP transgenic mice mated to Akita mice that develop neonatal diabetes because of the expression of misfolded proinsulin. Loss of bystander insulin in Akita animals is detected initially as a block in CpepGFP/insulin production with intracellular accumulation of the precursor, followed ultimately by loss of pancreatic beta-cells. The data support that misfolded proinsulin perturbs bystander proinsulin in the endoplasmic reticulum, leading to beta-cell failure.
    Document Type:
    Reference
    Product Catalog Number:
    HI-14K
    Product Catalog Name:
    Human Insulin-Specific RIA

  • Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. 21555585

    As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic β-cells, we generated β-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from β-cells. Ablation of XBP1 markedly decreased the number of insulin granules in β-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in β-cells but also caused constitutive hyperactivation of its upstream activator, IRE1α, which could degrade a subset of mRNAs encoding proinsulin-processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1α caused β-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1α has dual and opposing roles in β-cells, and that a precisely regulated feedback circuit involving IRE1α and its product XBP1s is required to achieve optimal insulin secretion and glucose control.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple