Proinsulin processing in the diabetic Goto-Kakizaki rat

Guest, Paul C.; Abdel‐Halim, Samy M.; Gross, David J.; Clark, Anne; Poitout, Vincent; Amaria, Rodabe N.; Östenson, C.-G.; Hutton, John C.

doi:10.1677/joe.0.1750637

Cited by 37 publications

(32 citation statements)

References 66 publications

(60 reference statements)

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“…It should be noted that GK ␤-cells were not depleted of insulin as compared with ␤-cells of the control Wistar rat (data not shown); indeed, other studies also revealed no deficiency in insulin synthesis or storage in the GK rat (36). Furthermore, the degree of expression of PKC␣ was reduced in the GK ␤-cell, confirmed both histochemically and by Western blot analysis.…”

Section: Dynamics Of Glucose-induced Pkc Localizationsupporting

confidence: 53%

“…Nagamatsu et al (15) as well as Gaisano et al (48) demonstrated reduced levels of key components of the SNARE system, an important part of the distal exocytotic complex. While Guest et al (36) reported an intact insulin biosynthetic machinery and unaltered insulin content in GK ␤-cells, Nagamatsu's studies (15) pointed toward increased rate of insulin degradation and diminished insulin stores. Thus, diminished translocation of PKC into GK ␤-cell nuclei could be related to the impaired activation of one or more genes involved in production of the SNARE proteins, while the failure of PKCε to relocalize may reflect a disturbed step in trafficking of insulin granules toward the exocytotic site.…”

Section: Dynamics Of Glucose-induced Pkc Localizationmentioning

confidence: 99%

“…Using ␤-cell-targeted PKC knockout mice, Hashimoto et al (32) linked that isoenzyme with glucose-regulated insulin release by direct regulation of the GLUT2 and HNF3␤ genes and of downstream control of Sur1, Kir6.2, hexokinase 1, and hexokinase 2. It should be noted that the defective insulin response in the GK rat has not been linked to reduced insulin stores and changes in ␤-cell mass or apoptotic activity have, with few exceptions, been absent (14,36,47). In previous studies using cultured rat islets we have seen glucose-induced localization of PKC␦ in perinuclear regions (5).…”

Section: Dynamics Of Glucose-induced Pkc Localizationmentioning

confidence: 99%

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Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic β-Cells

et al. 2006

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Glucose metabolism affects most major signal pathways in pancreatic ␤-cells. Multiple protein kinases, including protein kinase C (PKC) isoenzymes, are involved in these effects; however, their role is poorly defined. Moreover, the dynamics of kinase isoenzyme activation in reference to the biphasic insulin secretion is unknown. In perfused pancreas of Wistar rats, PKC␣ staining was strongly associated with insulin staining, jointly accumulating in the vicinity of the plasma membrane during early first-phase insulin response. The signal declined before the onset of second phase and reappeared during second-phase insulin release as foci, only weekly associated with insulin staining; this signal persisted for at least 15 min after glucose stimulation. In the GK rat, glucose had minimal effect on ␤-cell PKC␣. In control ␤-cells, PKC␦ stained as granulated foci with partial association with insulin staining; however, no glucose-dependent translocation was observed. In the GK rat, only minimal staining for PKC␦ was observed, increasing exclusively during early first-phase secretion. In Wistar ␤-cells, PKC concentrated near the nucleus, strongly associated with insulin staining, with dynamics resembling that of biphasic insulin response, but persisting for 15 min after cessation of stimulation. In GK rats, PKC staining lacked glucose-dependent changes or association with insulin. PKC exhibited bimodal dynamics in control ␤-cells: during early first phase, accumulation near the cell membrane was observed, dispersing thereafter. This was followed by a gradual accumulation near the nucleus; 15 min after glucose stimulus, clear PKC staining was observed within the nucleus. In the GK rat, a similar response was only occasionally observed. In control ␤-cells, glucose stimulation led to a transient recruitment of PKC, associated with first-phase insulin release, not seen in GK ␤-cell. Data from this and related studies support a role for PKC␣ in glucose-induced insulin granule recruitment for exocytosis; a role for PKC in activation of insulin granules for exocytosis and/or in the glucose-generated time-dependent potentiation signal for insulin release; and a dual function for PKC in initiating insulin release and in a regulatory role in the transcriptional machinery. Furthermore, diminished levels and/or activation of PKC␣, PKC, PKC, and PKC could be part of the defective signals downstream to glucose metabolism responsible for the deranged insulin secretion in the GK rat. Diabetes 55: 590 -599, 2006 G lucose metabolism is the primary initiator and regulator of most pancreatic ␤-cell functions: multiple ␤-cell genes are controlled by signals originating from glucose metabolism, as are all functions related to production, storage, and exocytosis of insulin. While the sequence of events involved in initiating glucose-induced insulin response have been well studied, those of extended release (second phase; see below) or insulin biosynthesis are considerably less clear.Multiple protein kinases are known to participate in relayi...

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Section: Dynamics Of Glucose-induced Pkc Localizationsupporting

confidence: 53%

Section: Dynamics Of Glucose-induced Pkc Localizationmentioning

confidence: 99%

Section: Dynamics Of Glucose-induced Pkc Localizationmentioning

confidence: 99%

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Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic β-Cells

et al. 2006

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“…This antiserum recognizes the various proSAAS truncated forms described below by both Western blotting as well as by ELISA, and exhibits 30% cross-reactivity with frog proSAAS (22). Antiserum LS45 has been previously used to demonstrate proSAAS immunoreactivity in pancreatic islets (71) and brains from patients with Alzheimer's disease (29). Deidentified human tissues were procured from the NIH NeuroBioBank.…”

Section: Methodsmentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

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“…This enhanced ratio could depend on changes in expression or activity of the prohormone convertases (28). Islet PC2 expression in the diabetic Goto-Kakizaki rat is markedly reduced relative to the PC2 levels in the nondiabetic Wistar rat (29). This decrease does not result in elevated levels of proinsulin or proinsulin processing intermediates.…”

mentioning

confidence: 95%

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

2005

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The amyloid present in the islets of Langerhans in type 2 diabetes is polymerized islet amyloid polypeptide (IAPP). The precursor protein proIAPP is posttranslationally modified, a process involving the removal of NH 2 -and COOH-terminal flanking peptides. This step is performed by the prohormone convertases PC2 and PC1/3. PC2 processes proIAPP preferably at the NH 2 -terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site. Little is known regarding the exact circumstances leading to islet amyloid formation. In this study, we have examined the possible significance of aberrant processing of proIAPP on amyloid formation in several in vitro cellular systems. In our studies, human (h)-proIAPP was transfected into ␤-TC-6 cells expressing both prohormone convertases and in which proIAPP is processed into IAPP. Additionally P ancreatic islet amyloid is a frequent and characteristic pathological feature of type 2 diabetes. The amount of amyloid deposited varies, but it is present to some degree in 40 -95% of the patients (1-3), and a decrease in the number of ␤-cells follows the accumulation of islet amyloid (4 -6). The main amyloid constituent is the 37-amino acid polypeptide hormone islet amyloid polypeptide (IAPP) (7) or amylin (8). This ␤-cell product is stored (9) and released together with insulin upon stimulation (10,11). In humans, IAPP is synthesized as a 67-amino acid proIAPP molecule from which NH 2 -terminal and COOH-terminal flanking peptides are subsequently removed proteolytically (12). This posttranslational processing within the secretory granules occurs at di-basic amino acids and is performed by the prohormone convertases 2 and 1/3 (PC2 and PC1/3). These are the same enzymes that process proinsulin to insulin at the same cellular location (13). In in vitro studies on the processing of human proIAPP (h-proIAPP) by recombinant converting enzymes, PC2 favored processing at the NH 2 -terminal flanking region and PC1/3 had its initial activity at the COOH-terminal region. However, during extended incubation time, both PC2 and PC1/3 could, to some degree, process proIAPP at both cleavage sites (14). In contrast, the in vivo results from studies on the processing of proIAPP performed in PC2 (15) and PC1/3 (16) null mice showed that PC2 is required for cleavage at the NH 2 -terminal region and that PC1/3 processes the COOHterminal flanking region. However, in the absence of PC1/3, this cleavage site can be processed by PC2.Little is known about the mechanisms that precede the deposition of islet amyloid. The use of human IAPP (h-IAPP)-expressing transgenic animals has demonstrated that increased expression of IAPP by itself is not sufficient for amyloid to develop (17-19). However, introduction of the h-IAPP gene into mouse strains with diabetic traits resulted in the formation of islet amyloid (20,21). Amyloid was also detected in transgenic animals fed a high-fat diet (22). In mouse IAPP (mIAPP)-null mice expressing the gene for h-IAPP, amyloid developed within 9 months ...

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Proinsulin processing in the diabetic Goto-Kakizaki rat

Cited by 37 publications

References 66 publications

Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic β-Cells

Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic β-Cells

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

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