Role of Na/H exchange in insulin secretion by islet cells

Deisl, Christine; Albano, Giuseppe; Fuster, Daniel

doi:10.1097/01.mnh.0000447013.36475.96

Cited by 12 publications

(8 citation statements)

References 49 publications

(51 reference statements)

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“…RNA isolation was performed using Trizol reagent (ThermoFisher Scientific, Waltham, MA, USA) as described [ 5 , 8 ]. Real-time PCR was performed using pre-synthesized Assays-on-Demand (AoD; Life Technologies/ABI, Rotkreuz, Switzerland) on an ABI ViiA 7 System.…”

Section: Methodsmentioning

confidence: 99%

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Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice

et al. 2016

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We previously demonstrated that the sodium/hydrogen exchanger NHA2, also known as NHEDC2 or SLC9B2, is critical for insulin secretion by β–cells. To gain more insights into the role of NHA2 on systemic glucose homeostasis, we studied the impact of loss of NHA2 during the physiological aging process and in the setting of diet-induced obesity. While glucose tolerance was normal at 2 months of age, NHA2 KO mice displayed a significant glucose intolerance at 5 and 12 months of age, respectively. An obesogenic high fat diet further exacerbated the glucose intolerance of NHA2 KO mice. Insulin levels remained similar in NHA2 KO and WT mice during aging and high fat diet, but fasting insulin/glucose ratios were significantly lower in NHA2 KO mice. Peripheral insulin sensitivity, measured by insulin tolerance tests and hyperinsulinemic euglycemic clamps, was unaffected by loss of NHA2 during aging and high fat diet. High fat diet diminished insulin secretion capacity in both WT and NHA2 KO islets and reduced expression of NHA2 in WT islets. In contrast, aging was characterized by a gradual increase of NHA2 expression in islets, paralleled by an increasing difference in insulin secretion between WT and NHA2 KO islets. In summary, our results demonstrate that loss of the sodium/hydrogen exchanger NHA2 exacerbates obesity- and aging-induced glucose intolerance in mice. Furthermore, our data reveal a close link between NHA2 expression and insulin secretion capacity in islets.

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Section: Methodsmentioning

confidence: 99%

“…NHA2, also known as SLC9B2 or NHEDC2, is a recently cloned, poorly characterized NHE isoform [ 3 ]. Previous studies suggested that NHA2 is the correlate of the long sought sodium/lithium countertransporter that was linked to the pathogenesis of diabetes mellitus and essential hypertension in humans [ 2 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice

et al. 2016

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“…In murine islets, mRNA of eight NHE isoforms has been found: NHE1, NHE5 through NHE9, as well as NHA1 and NHA2, although only the roles of NHE1 and NHA2 have been studied in detail, beyond the expression level (72, 201, 285). The involvement of NHE1 and NHA2 in β-cell functions have been discussed in detail by Deisl et al (71). In brief, glucose uptake into β cells followed by its metabolism lead to an increase in cellular ATP/ADP ratio which triggers the closure of ATP-sensitive potassium (K ATP ) channels, a main determinant of the β-cell membrane potential.…”

Section: Na+/h+ Exchange In the Exocrine And Endocrine Pancreasmentioning

confidence: 99%

“…Within the digestive organs, NHA1 protein has been detected in the pancreatic β cells, but its role has not been extensively studied (71). NHA2 (also known as Na + /H + exchanger domain-containing protein 2) is expressed more broadly in the digestive tract, where it was detected in the stomach, jejunum, and colon (94).…”

Section: Mammalian Monovalent Cation Proton Antiporter Superfamilymentioning

confidence: 99%

“…Two members of this family have been described, NHA1 (encoded by the Slc9b1 gene) and NHA2 (Slc9b2) and are best known for controlling sperm motility (47). Within the digestive organs, NHA1 protein has been detected in the pancreatic β cells, but its role has not been extensively studied (71). NHA2 (also known as Na + /H + exchanger domain-containing protein 2) is expressed more broadly in the digestive tract, where it was detected in the stomach, jejunum, and colon (94).…”

Section: Mammalian Monovalent Cation Proton Antiporter Superfamilymentioning

confidence: 99%

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SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

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The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

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Sodium-Proton (Na+/H+) Antiporters: Properties and Roles in Health and Disease

Padan

Landau

2016

The Alkali Metal Ions: Their Role for Life

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The transmembranal Na(+)/H(+) antiporters transport sodium (or several other monovalent cations) in exchange for H(+) across lipid bilayers in all kingdoms of life. They are critical in pH homeostasis of the cytoplasm and/or organelles. A particularly notable example is the SLC9 gene family, which encodes Na(+)/H(+) exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na(+)/H(+) antiporter is Ec-NhaA, the main Na(+)/H(+) antiporter of Escherichia coli.The crystal structure of down-regulated Ec-NhaA, determined at acidic pH, has provided the first structural insights into the antiport mechanism and pH regulation of an Na(+)/H(+) antiporter. It reveals a unique structural fold (called the NhaA fold) in which transmembrane segments (TMs) are organized in inverted-topology repeats, including two antiparallel unfolded regions that cross each other, forming a delicate electrostatic balance in the middle of the membrane. This unique structural fold (The NhaA fold) contributes to the cation binding site and facilitates the rapid conformational changes expected for Ec-NhaA. The NhaA fold has now been recognized to be shared by four Na(+)/H(+) antiporters (bacterial and archaeal) and a Na(+) symporter. Remarkably, no crystal structure of any of the human Na(+)/H(+) antiporters exists. Nevertheless, the Ec-NhaA crystal structure has enabled the structural modeling of NHE1, NHE9, and NHA2, three human plasmalemmal proteins that are members of the SLC9 family that are involved in human pathophysiology. Moreover, as outlined in this review, developments in the field, including cellular and biophysical methods that enable ion levels and fluxes to be measured in intact cells as well as in knockout mice, have led to striking advances in the identification and characterization of plasma membrane NHEs and NHA.Very little is known about the endomembrane isoforms of NHE. These intracellular exchangers may serve a function in cation homeostasis and/or osmoregulation, and not in pH regulation as is the case for the plasmalemmal isoforms. This intriguing possibility should be borne in mind when designing future studies. Future progress towards gaining an understanding of the SLC9 gene family, including its structure-function relationships and regulatory mechanisms in health and in disease, is likely to include insights into the pathophysiology of multiple diseases.

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Role of Na/H exchange in insulin secretion by islet cells

Cited by 12 publications

References 49 publications

Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice

Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice

SLC9 Gene Family: Function, Expression, and Regulation

Sodium-Proton (Na+/H+) Antiporters: Properties and Roles in Health and Disease

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