Postnatal maturation of calcium signaling in islets of Langerhans from neonatal mice

West, Hannah L; Corbin, Kathryn L.; D'Angelo, Cathleen V; Donovan, Lauren M.; Jahan, Ishrat; Gu, Guoqiang; Nunemaker, Craig S.

doi:10.1016/j.ceca.2020.102339

Cited by 9 publications

(4 citation statements)

References 83 publications

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“…Additionally, Pdk4 expression, a marker for the shift from utilization of glucose to fatty acids as the primary fuel source, is higher in Kcnk16 L114P islets (2.78-fold). Elevated islet PDK4 expression is also observed in patients with T2D and in animals on a HFD (37). Although hyperglycemia would be predicted to negatively impact Kcnk16 L114P islet function, no overt changes in β-cell mass were observed in these mice.…”

Section: Discussionmentioning

confidence: 89%

“…Following birth, a shift to intermittent feeding and elevated plasma glucose requires an increase in β-cell insulin secretion for efficient nutrient absorption, as well as a suppression of insulin release during fasting to avoid hypoglycemia (40). Glucose-sensitivity in mouse β-cell Ca 2+ handling and insulin secretion develops over the first 4 postnatal days due to changes in β-cell metabolism, K ATP surface localization, and Ca 2+ -dependent secretory machinery (41). Thus, mice expressing severe gain-of-function ATP-insensitive K ATP channels die shortly after birth due to hypoinsulinemia, severe hyperglycemia, and ketoacidosis (42).…”

Section: Discussionmentioning

confidence: 99%

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The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Nakhe

Dadi

Kim

et al. 2023

Preprint

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A strong association of the gain-of-function mutation in the TALK-1 K+channel (p.L114P) with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS).KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell–restricted K+channel transcript andKCNK16locus is strongly associated to type-2 diabetes. To investigate the impact of TALK-1-L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing theKcnk16L114P mutation was generated. Heterozygous and homozygousKcnk16L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygousKcnk16L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increases whole-cell β-cell K+currents resulting in blunted glucose-stimulated Ca2+entry and a complete loss of glucose-induced Ca2+oscillations. Thus, adultKcnk16L114P mice have reduced GSIS and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Nakhe

Dadi

Kim

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…The major transcriptomic changes observed during the maturation process strongly support the functional immaturity of neonatal islets. These include low expression of genes coding for mitochondrial shuttles (malate dehydrogenase, glycerol-3-phosphate dehydrogenase, glutamate oxaloacetate transaminase, malate-aspartate-NADH (nicotinamide adenine dinucleotide)) [8,10,24], for key enzymes involved in the metabolism of glucose (pyruvate carboxylase, glucose-6 phosphatase 2), and fatty acids (carnitine palmitoyl transferase 2, fatty acid-binding protein 5 (FABP5)) [8,24], for components of the calcium signaling pathway [25], for transcription factors [26] such as MAFA and PDX1 involved in insulin biosynthesis and secretion [27], as well as for different classes of non-coding RNAs including PIWI-interacting RNAs, microRNAs, and long non-coding RNAs [18,28,29]. Extensive characterization of the transcriptomic profile coupled with the analysis of histone marks in the promoters of genes associated with endocrine cell maturation from human juvenile and adult pancreas confirmed age-specific changes in the expression of β-cell transcription factors, including MAFA [20].…”

Section: Signaling Pathways Driving the Acquisition Of Functional β-C...mentioning

confidence: 99%

Mechanisms Underlying the Expansion and Functional Maturation of β-Cells in Newborns: Impact of the Nutritional Environment

Jacovetti

Regazzi

2022

IJMS

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The functional maturation of insulin-secreting β-cells is initiated before birth and is completed in early postnatal life. This process has a critical impact on the acquisition of an adequate functional β-cell mass and on the capacity to meet and adapt to insulin needs later in life. Many cellular pathways playing a role in postnatal β-cell development have already been identified. However, single-cell transcriptomic and proteomic analyses continue to reveal new players contributing to the acquisition of β-cell identity. In this review, we provide an updated picture of the mechanisms governing postnatal β-cell mass expansion and the transition of insulin-secreting cells from an immature to a mature state. We then highlight the contribution of the environment to β-cell maturation and discuss the adverse impact of an in utero and neonatal environment characterized by calorie and fat overload or by protein deficiency and undernutrition. Inappropriate nutrition early in life constitutes a risk factor for developing diabetes in adulthood and can affect the β-cells of the offspring over two generations. A better understanding of these events occurring in the neonatal period will help developing better strategies to produce functional β-cells and to design novel therapeutic approaches for the prevention and treatment of diabetes.

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“…The anti-obesity effect of THADA may be mediated through enhanced thermogenesis or reduced ER (endoplasmic reticulum) calcium. Of note, in mice changes of calcium levels in the endoplasmic reticulum during pancreatic maturation were correlated with the expression of THADA (West et al, 2021). Overall, an in depth characterization of the metabolic effects of the THADA-driven network will not only aim at a better understanding of its function in general but might also provide new therapeutic targets for the treatment of both conditions associated with THADA by GWAS (Chatterjee et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Unique genetic features of the naked mole-rat’s THADA gene

Bullerdiek

Banjar

Holzmann

2021

Preprint

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Thyroid Adenoma Associated (THADA) is a protein-coding gene that maps to chromosomal band 2p21 and first has been described as a target of recurrent translocation partner in thyroid tumors. Many genome-wide association studies have revealed an association between THADA and two frequent human diseases, i.e. type 2 diabetes and polycystic ovary syndrome. Nevertheless, the function of its protein is not been completely understood. However, recent evidence suggests that in a Drosophila model THADA can act as a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)-interacting protein which uncouples SERCA from this function. Once being uncoupled, SERCA produces an increased amount of heat without transporting calcium thus triggering nonshivering thermogenesis. This data prompted us to compare human THADA with that of 65 other eutherian mammals. This includes a comparison of THADA of a variety of eutherian mammals with that of the naked-mole rat (Heterocephalus glaber) which is known to display unique features of thermoregulation compared to other mammals. Our analysis revealed five positions where only the naked-mole rat presented differences. These latter positions included four single amino acid substitutions and one unique deletion of six or seven amino acids, respectively, between residues 858 and 859. In future studies these changes will be analyzed further in detail for their functional relevance.

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Postnatal maturation of calcium signaling in islets of Langerhans from neonatal mice

Cited by 9 publications

References 83 publications

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Mechanisms Underlying the Expansion and Functional Maturation of β-Cells in Newborns: Impact of the Nutritional Environment

Unique genetic features of the naked mole-rat’s THADA gene

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