Impact of uncoupling protein-2 overexpression on proinsulin processing

Kashemsant, Narudee; Chan, Catherine B.

doi:10.1677/jme.1.02091

Cited by 6 publications

(3 citation statements)

References 60 publications

(54 reference statements)

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“…There was no difference in accumulation of total insulin (data not shown); however, there was substantially more proinsulin in the media of CMPF-treated islets compared to controls, consistent with an altered proinsulin:insulin ratio observed in T2D patients (Kamoda et al, 2006) (Figure 5A). Impaired insulin processing has previously been associated with elevations in ER stress and/or reactive oxygen species (ROS) production (Wu and Kaufman, 2006;Kashemsant and Chan, 2006). CMPF treatment did not induce markers of ER stress including Chop, Bip, and XBP-1 as examined by microarray and qPCR (Figures S5A and S5B).…”

Section: Cmpf Directly Impairs B Cell Functionmentioning

confidence: 87%

The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction

et al. 2014

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Gestational diabetes (GDM) results from failure of the β cells to adapt to increased metabolic demands; however, the cause of GDM and the extremely high rate of progression to type 2 diabetes (T2D) remains unknown. Using metabolomics, we show that the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is elevated in the plasma of humans with GDM, as well as impaired glucose-tolerant and T2D patients. In mice, diabetic levels of plasma CMPF induced glucose intolerance, impaired glucose-stimulated insulin secretion, and decreased glucose utilization. Mechanistically, we show that CMPF acts directly on the β cell, causing impaired mitochondrial function, decreasing glucose-induced ATP accumulation, and inducing oxidative stress, resulting in dysregulation of key transcription factors and ultimately reduced insulin biosynthesis. Importantly, specifically blocking its transport through OAT3 or antioxidant treatment could prevent CMPF-induced β cell dysfunction. Thus, CMPF provides a link between β cell dysfunction and GDM/T2D that could be targeted therapeutically.

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Section: Cmpf Directly Impairs B Cell Functionmentioning

confidence: 87%

The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction

et al. 2014

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“…The primary physiological function of mild uncoupling is to suppress oxygen radical production accompanied by restricting mitochondrial permeability transition pore opening and Ca 2 + accumulation (20). It also plays an important role in regulating the energy balance in many tissues such as pancreas, liver, and brain (10). It has been reported that UCP2 modulated intracellular energy metabolism and thus was involved in aging, diabetes, and neurodegeneration (5,34).…”

Section: Ucp2 Mediates Neuroprotective Effect Of H 2 Smentioning

confidence: 99%

The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels

Zhao²,

Tang³

et al. 2012

Antioxidants & Redox Signaling

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“…Ucp2 is expressed in many tissues, including the pancreatic β cell [4], which relies heavily on glucose metabolism coupled to ATP production for efficient and appropriate insulin secretion. Not surprisingly, numerous gain-of-function [5], [6], [7], [8], [9], [10] and loss-of-function [11], [12], [13], [14], [15], [16] studies have been used to interrogate the function of UCP2 in the β cell and, for the most part, have established a negative relationship between UCP2 and glucose-stimulated insulin secretion (GSIS). For example, whole body ( Ucp2 -/- ) [11], [12] and β cell Ucp2 knockout ( Ucp2- βKO) mice [14] show augmented GSIS, whereas overexpression of Ucp2 in clonal β cell cultures and rat islets impairs GSIS [5], [9].…”

Section: Introductionmentioning

confidence: 99%

Uncoupling protein 2 regulates daily rhythms of insulin secretion capacity in MIN6 cells and isolated islets from male mice

Seshadri

Jonasson

Hunt

et al. 2017

Molecular Metabolism

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ObjectiveUpregulation of uncoupling protein 2 (UCP2) is associated with impaired glucose-stimulated insulin secretion (GSIS), which is thought to be an important contributor to pathological β cell failure in obesity and type 2 diabetes (T2D); however, the physiological function of UCP2 in the β cell remains undefined. It has been suggested, but not yet tested, that UCP2 plays a physiological role in β cells by coordinating insulin secretion capacity with anticipated fluctuating nutrient supply, such that upregulation of UCP2 in the inactive/fasted state inhibits GSIS as a mechanism to prevent hypoglycemia. Therefore, we hypothesized that daily cycles of GSIS capacity are dependent on rhythmic and predictable patterns of Ucp2 gene expression such that low Ucp2 in the active/fed phase promotes maximal GSIS capacity, whereas elevated Ucp2 expression in the inactive/fasted phase supresses GSIS capacity. We further hypothesized that rhythmic Ucp2 expression is required for the maintenance of glucose tolerance over the 24 h cycle.MethodsWe used synchronized MIN6 clonal β cells and isolated mouse islets from wild type (C57BL6) and mice with β cell knockout of Ucp2 (Ucp2-βKO; and respective Ins2-cre controls) to determine the endogenous expression pattern of Ucp2 over 24 h and its impact on GSIS capacity and glucose tolerance over 24 h.ResultsA dynamic pattern of Ucp2 mRNA expression was observed in synchronized MIN6 cells, which showed a reciprocal relationship with GSIS capacity in a time-of-day-specific manner. GSIS capacity was suppressed in islets isolated from wild type and control mice during the light/inactive phase of the daily cycle; a suppression that was dependent on Ucp2 in the β cell and was lost in islets isolated from Ucp2-βKO mice or wild type islets treated with a UCP2 inhibitor. Finally, suppression of GSIS capacity by UCP2 in the light phase was required for the maintenance of normal patterns of glucose tolerance.ConclusionsOur study suggests that Ucp2/UCP2 in the β cell is part of an important, endogenous, metabolic regulator that controls the temporal capacity of GSIS over the course of the day/night cycle, which, in turn, regulates time-of-day glucose tolerance. Targeting Ucp2/UCP2 as a therapeutic in type 2 diabetes or any other metabolic condition must take into account the rhythmic nature of its expression and its impact on glucose tolerance over 24 h, specifically during the inactive/fasted phase.

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Impact of uncoupling protein-2 overexpression on proinsulin processing

Cited by 6 publications

References 60 publications

The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction

The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction

The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels

Uncoupling protein 2 regulates daily rhythms of insulin secretion capacity in MIN6 cells and isolated islets from male mice

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