Insulin Constitutively Secreted by β-Cells Is Necessary for Glucose-Stimulated Insulin Secretion

Srivastava, Siddhartha; Goren, H. Joseph

doi:10.2337/diabetes.52.8.2049

Cited by 28 publications

(28 citation statements)

References 50 publications

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“…3A and D) compared with the number observed with insulin alone (10 Ϯ 1 spikes per stimulation; n ϭ 7, P Ͻ 0.05 glucose vs. insulin stimulation). This can be interpreted as glucose inducing a greater secretory response than insulin or as the secretory response to glucose also including the autocrine effect of secreted insulin (46). Moreover, these changes were in parallel to the observations in [Ca 2ϩ ] i responses described above.…”

Section: Methodssupporting

confidence: 66%

Islet Secretory Defect in Insulin Receptor Substrate 1 Null Mice Is Linked With Reduced Calcium Signaling and Expression of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)-2b and -3

et al. 2004

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Mice with deletion of insulin receptor substrate (IRS)-1 (IRS-1 knockout [KO] mice)show mild insulin resistance and defective glucose-stimulated insulin secretion and reduced insulin synthesis. To further define the role of IRS-1 in islet function, we examined the insulin secretory defect in the knockouts using freshly isolated islets and primary ␤-cells. T he insulin/IGF-1 receptor signaling pathway plays a significant role in the regulation of both insulin secretion and synthesis (1-5). We and other laboratories have shown that the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway is involved in the growth and function of islets (6 -9). Further evidence for a role for this substrate in islet function is derived from IRS-1 knockout (KO) mice that exhibit hyperplastic islets but show a reduced insulin content, decreased insulin mRNA, and decreased secretion in response to glucose and L-arginine (8,10,11). Overexpression of the arginine-to-glycine polymorphism at position 972 in the IRS-1 gene in ␤-cells leads to apoptosis (12) and a reduced insulin secretory response (13), whereas, conversely, overexpression of IRS-1 in ␤-cells has been shown to increase insulin secretion (14).Cytoplasmic calcium is a ubiquitous messenger that is essential for physiological responses in most mammalian cells including pancreatic ␤-cells. Glucose and several other insulin secretagogues depolarize ␤-cells, leading to activation of voltage-sensitive Ca 2ϩ channels and an influx of Ca 2ϩ ions across the plasma membrane. This increase in intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ) triggers exocytosis of insulin (15). The Ca 2ϩ store in the endoplasmic reticulum is an important source that can also trigger insulin secretion (16). In either case, the increase in [Ca 2ϩ ] i , observed just before insulin secretion, is followed by rapid lowering of intracellular Ca 2ϩ concentrations either by extrusion and/or by uptake into the endoplasmic reticulum against a concentration gradient. In islet ␤-cells, similar to other eukaryotic cells, these active movements of Ca 2ϩ ions are mediated by Ca 2ϩ pumps (17). The sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) is one such intrinsic membrane protein with a single polypeptide chain of 110 -115 kDa. Among the SERCA isoforms that have been identified so far, SERCA-2a, -2b, and -3 are also expressed in pancreatic ␤-cells (18,19). The SERCA proteins have been shown to lower intracellular Ca 2ϩ levels in ␤-cells by sequestering the ions into the endoplasmic reticulum (20,21).Abnormalities in Ca 2ϩ signaling have been related to the development of some forms of type 2 diabetes in several rodent models and in humans (20,22). In the db/db mouse (20) and in Goto-Kakizaki rats (19), a loss of SERCA activity is associated with defects in the patterns of glucose-stimulated changes in [Ca 2ϩ ] i and potentially in insulin secretion. Furthermore, in humans with type 2 diabetes, alteration in the normal pulsatility of insulin secretion has been recognized as a signif...

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Section: Methodssupporting

confidence: 66%

Islet Secretory Defect in Insulin Receptor Substrate 1 Null Mice Is Linked With Reduced Calcium Signaling and Expression of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)-2b and -3

et al. 2004

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“…At +0.88 V vs. Ag/AgCl (2 M KCl), the potential where insulin is detected with the MWCNT/DHP composite film, somatostatin is a possible interferent as it is secreted by the δ-cells of the islet [55] and has a peak oxidation potential of + 0.80 V vs. Ag/AgCl [56]. The dramatic current increase seen in Figure 7 (228 %) is unlikely to be due to somatostatin as β cells are stimulated to secrete insulin when islets are exposed to high levels of glucose [11] and the function of somatostatin is to inhibit β cells [57,58].…”

Section: Resultsmentioning

confidence: 99%

A multiwalled carbon nanotube/dihydropyran composite film electrode for insulin detection in a microphysiometer chamber

Snider

Ciobanu

Rue

et al. 2008

Analytica Chimica Acta

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We have developed a multiwalled carbon nanotube/dihydropyran (MWCNT/DHP) composite sensor for the electrochemical detection of insulin in a microfluidic device. This sensor has been employed for physiological measurements of secreted insulin from pancreatic islets in a Cytosensor® previously modified to be a multianalyte microphysiometer (MAMP). When compared with other established electrochemical insulin sensors, the MWCNT/DHP composite film sensor presented improved resistance to fluidic shear forces, while achieving enhanced electrode kinetics. In addition, the preparation of the composite film is straightforward and facile with a self-polymerizing monomer, DHP, used to add mechanical stability to the film. The sensor film was able to detect insulin concentrations as low as 1 µM in the MAMP during calibration experiments. The MWCNT/DHP composite sensor has been successfully used for the direct detection of insulin secreted by islets in the microphysiometer.

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“…In spite of the rich vascularization of pancreas, extracellular glucose concentration will decrease as the distance from vessels increases, and a wide range of glucose concentrations is likely to be found. Moreover, it is known that insulin itself, acting as a paracrine signal, sensitizes ␤-cells to glucose stimuli and may thus participate in cell recruitment (47).…”

Section: The ␤-Cell Populationmentioning

confidence: 99%

Insulin granule trafficking in β-cells: mathematical model of glucose-induced insulin secretion

Bertuzzi¹,

Salinari²,

Mingrone³

2007

American Journal of Physiology-Endocrinology and Metabolism

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A mathematical model that represents the dynamics of intracellular insulin granules in β-cells is proposed. Granule translocation and exocytosis are controlled by signals assumed to be essentially related to ATP-to-ADP ratio and cytosolic Ca2+ concentration. The model provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. Values of most of the model parameters were inferred from available experimental data. The numerical simulations represent a variety of experimental conditions, such as the stimulation by high K+ and by different time courses of extracellular glucose, and the predicted responses agree with published experimental data. Model capacity to represent data measured in a hyperglycemic clamp was also tested. Model parameter changes that may reflect alterations of β-cell function present in type 2 diabetes are investigated, and the action of pharmacological agents that bind to sulfonylurea receptors is simulated.

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Insulin Constitutively Secreted by β-Cells Is Necessary for Glucose-Stimulated Insulin Secretion

Cited by 28 publications

References 50 publications

Islet Secretory Defect in Insulin Receptor Substrate 1 Null Mice Is Linked With Reduced Calcium Signaling and Expression of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)-2b and -3

Islet Secretory Defect in Insulin Receptor Substrate 1 Null Mice Is Linked With Reduced Calcium Signaling and Expression of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)-2b and -3

A multiwalled carbon nanotube/dihydropyran composite film electrode for insulin detection in a microphysiometer chamber

Insulin granule trafficking in β-cells: mathematical model of glucose-induced insulin secretion

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