Regulation of proinsulin synthesis in pancreatic islets and a new aspect to insulin-dependent diabetes

Okamoto, Hiroshi

doi:10.1007/bf02355886

Cited by 146 publications

(102 citation statements)

References 87 publications

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“…Superoxide itself, or derivative radicals may be the direct cause of cell damage, Okamoto has proposed a model in which radical generation leads to breakage of cell DNA, This in turn sets in motion a repair process resulting in depletion of cellular NAD levels (14)(15). Depletion of cellular NAD leads to an inhibition of protein (pro-insulin) synthesis and renders the cell more sensitive to radieal damage because NAD is involved in the electron-transport process required for radical scavenging by the cell-Another possibility is that oxygen radicals are involved in the production of cytokines by cells of the inllammatory focus (16,17).…”

Section: Resultsmentioning

confidence: 99%

Involvement of O₂ radicals in ‘autoimmune’ diabetes

1989

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Summary Spontaneous diabetes in the non-obese diabetic (NOD) mice is a CD4 T cell-dependent process. We have suggested that specific p cell destruction results from free radical production at the site of islet inflammation; oxygen radicals are produced by activated inflammatory cells. We reported here that in vivo treatment of spontaneously diabetic NOD mice with the enzyme superoxide dismutase (2000 U for seven injections) and catalase (40 000 U for seven injections) protects islet tissue from disease recurrence following transplantation into spontaneously diabetic mice. Similar results were obtained when animals were treated with either enzyme alone. This effect was dose-dependent and little protection was observed when the dose of enzyme was reduced four-fold. These results indicate that oxygen metabolites, specially superoxide and hydrogen peroxide, are directly involved in the pathogenesis of immunology mediated diabetes.

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Section: Resultsmentioning

confidence: 99%

Involvement of O₂ radicals in ‘autoimmune’ diabetes

1989

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“…The short-term (<2 h) regulation of insulin biosynthesis appears to be independent of net preproinsulin mRNA synthesis and thus arises at a translational level [24][25][26][27]. There appears to be a shift of cytoplasmic free preproinsulin mRNA to membrane-bound polysomes leading to increased synthesis of proinsulin upon glucose stimulation [25,26].…”

Section: Discussionmentioning

confidence: 99%

Glucose stimulates the biosynthesis of rat I and II insulin to an equal extent in isolated pancreatic islets

1987

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The effects of glucose on insulin biosynthesis were studied by measuring the incorporation of radiolabelled amino acids into proinsulin/insulin in isolated rat islets. The islets were pulse labelled for 15 rain with [3H]ieucine (present in rat insulin I and II) or [35S]methionine (unique to rat insulin II) and then incubated for a 165 min post-label (chase) period during which the majority of labelled proinsulin was converted to insulin but under conditions whereby > 95% of radiolabelled proinsulin or insulin was retained in the islets. The newly synthesized, labelled, insulin was analyzed by high performance liquid chromatography. Rat I and II insulin biosynthesis was stimulated by 16.7 mM glucose to the same extent.

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“…Islets were cultured for 12 h in RPMI 1640 medium containing 11.1 mmol/l glucose, 10% heat-inactivated fetal bovine serum, 100 IU/ml penicillin and 100 μg/ml streptomycin, as previously described [28,29]. Then, sizematched islets were pre-incubated for 60 min at 37°C with KRB containing 0.2% BSA and 2.8 mmol/l glucose.…”

Section: Methodsmentioning

confidence: 99%

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice

2004

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Aims/hypothesis: During the pathogenesis of type 2 diabetes insulin resistance causes compensatory proliferation of beta cells. As beta cells have a limited replication potential, this compensatory proliferation might accelerate cellular senescence and lead to diabetes. We examined the cellular senescence of beta cells after proliferation during lipoglucotoxicity. Methods: Senescence-associated markers in beta cells were examined in nutrient-induced diabetic C57BL/6J mice that were fed a high-fat diet. After 4 and 12 months of the high-fat diet, intraperitoneal glucose tolerance tests (IPGTTs) and histochemical analyses of Ki-67, p38, senescence-associated beta-galactosidase, and beta cell mass were performed. Results: At 4 months, the AUC for plasma insulin levels during the IPGTT (AUC insulin ) was higher, beta cell mass was 3.1-fold greater, and the proliferation of beta cells was 2.2-fold higher than in the control group. However, at 12 months, AUC insulin declined, the frequency of Ki-67-positive beta cells decreased to one-third that of the control group, and the senescence-associated, beta-galactosidasepositive area increased to 4.7-fold that of the control group. Moreover, small amounts of p38, which is induced by oxidative stress and mediates cellular senescence, were found in beta cells from the high-fat diet group, but not in beta cells from the control group. Furthermore, the senescence-associated, beta-galactosidase-positive area in the high-fat diet group had a highly significant negative correlation with AUC insulin (r=−0.852, p<0.01). Conclusions/interpretation: Beta cell senescence occurred in diet-induced type 2 diabetes and led to insufficient insulin release. These findings suggest that cellular senescence contributes to the pathogenesis of diet-induced diabetes.

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Regulation of proinsulin synthesis in pancreatic islets and a new aspect to insulin-dependent diabetes

Cited by 146 publications

References 87 publications

Involvement of O₂ radicals in ‘autoimmune’ diabetes

Involvement of O₂ radicals in ‘autoimmune’ diabetes

Glucose stimulates the biosynthesis of rat I and II insulin to an equal extent in isolated pancreatic islets

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice

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Regulation of proinsulin synthesis in pancreatic islets and a new aspect to insulin-dependent diabetes

Cited by 146 publications

References 87 publications

Involvement of O2 radicals in ‘autoimmune’ diabetes

Involvement of O2 radicals in ‘autoimmune’ diabetes

Glucose stimulates the biosynthesis of rat I and II insulin to an equal extent in isolated pancreatic islets

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice

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Involvement of O₂ radicals in ‘autoimmune’ diabetes

Involvement of O₂ radicals in ‘autoimmune’ diabetes