Quantitative Estimation of the Pancreatic Islet Tissue in Diabetic Subjects

MacLean, Nancy; Ogilvie, Robertson F.

doi:10.2337/diab.4.5.367

Cited by 239 publications

(142 citation statements)

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“…In noninsulin-dependent diabetes mellitus the deficit of insulin production is less well characterized. Reductions of B cell number (6,7) and of extractable pancreatic insulin (8,9) have been observed at autopsy, although these findings have not been consistent (3)(4)(5) and their functional significance is unknown. Insulin resistance has been shown to be important in increasing the metabolic demands for insulin, but pathogenetic relationships between insulin sensitivity and capacity to produce insulin remain unclear (10).…”

Section: Introductionmentioning

confidence: 98%

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Orland¹,

Chyn²,

Permutt³

1985

J. Clin. Invest.

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These studies of partial pancreatectomy assess pancreatic proinsulin messenger RNA (mRNA) levels as an index of in vivo insulin biosynthesis, and show relationships to glucose homeostasis. Rats were subjected to sham operation, 50% pancreatectomy (Px), or 90% Px, and were examined after 1, 3, or 14 wk. Proinsulin mRNA was measured by dot hybridization to complementary DNA. After 50% Px there was a nearly complete adaptation of proinsulin mRNA. After 90% Px a marked increase of proinsulin mRNA occurred, but it was insufficient and it was not maintained with time. The deficit in insulin production is related to development of hyperglycemia.Sham-operated controls showed no worsening of fasting or fed blood glucose or of intraperitoneal glucose tolerance within the period of observation. Total proinsulin mRNA and pancreatic insulin content rose in proportion to body weight. 50% PN produced no change from controls in body weight or blood glucose. The concentration of proinsulin mRNA in the 50% pancreatic remnant paralleled that of controls after 1 and 3 wk, but then increased after 14 wk, such that total proinsulin mRNA approached control levels. This adaptive response was reflected by changes in serum insulin, but not by pancreatic insulin content, which was only 30% of control after 14 wk. Intraperitoneal glucose tolerance was impaired mildly, and did not worsen with time after pancreatectomy.90% Px led to elevated fed blood glucose and reduced serum insulin after 3 wk, and fasting hyperglycemia was seen after 14 wk. Proinsulin mRNA concentration in the 10% pancreatic remnant showed an adaptive increase after 1 and 3 wk, such that total proinsulin mRNA reached 40% of control. After 14 wk, however, remnant proinsulin mRNA concentration was no longer increased; total proinsulin mRNA and pancreatic insulin content were severely reduced. Intraperitoneal glucose tolerance was impaired more dramatically than with the 50% Px animals, and worsened with time after operation.These observations indicate ability to increase proinsulin mRNA levels as an adaptation to pancreatectomy. Insufficiency of this adaptation is associated with the development of hyperglycemia, and the loss of this adaptation correlates with a worsening of glucose tolerance.

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Section: Introductionmentioning

confidence: 98%

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Orland¹,

Chyn²,

Permutt³

1985

J. Clin. Invest.

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“…In addition to reduced insulin action and beta cell function, a reduction in beta cell mass is also thought to be a key factor in type 2 diabetes [10,15]; however, the extent to which this is involved in the development of the disease remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

et al. 2004

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Aims/hypothesis. A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass. Methods. The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine. Results. Beta cell mass was reduced in the beta-cellreduced animals compared with the control minipigs (182±76 vs 464±156 mg, p<0.01). AUC glucose was increased in the beta-cell-reduced animals (1383±385 vs 853±113 mmol·l −1 ·min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123±84 vs 56±24 pmol·l -1 ·min·mg -1 , p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7±45.9 vs 34.6±14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine. Conclusions/interpretation. A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.

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“…Gi-GPCR gene variants associated with human diseases are thought to influence disease risk by modifying acute cellular behaviors such as insulin release (3)(4)(5)(6)(7)(8)(9). However, diabetes also is associated with decreased pancreatic β-cell mass (10)(11)(12)(13), and little is known about the role Gi-GPCR signaling plays in organ development or size or whether Gi-GPCR variants could impact disease risk by altering organ size.…”

mentioning

confidence: 99%

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Berger

Scheel

Macias

et al. 2015

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

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Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

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Quantitative Estimation of the Pancreatic Islet Tissue in Diabetic Subjects

Cited by 239 publications

References 0 publications

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

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Quantitative Estimation of the Pancreatic Islet Tissue in Diabetic Subjects

Cited by 239 publications

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Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

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Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion