Biology subjects

Dadi, P. K.

Publications and source records attributed to Dadi, P. K..

4 recordsLinked to original sources

bioRxiv2023

The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of {beta}-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and {beta}-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P 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 homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell {beta}-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/545631v3_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@19031e9org.highwire.dtl.DTLVardef@1bccc49org.highwire.dtl.DTLVardef@803e1org.highwire.dtl.DTLVardef@36c584_HPS_FORMAT_FIGEXP M_FIG Graphical Summary C_FIG

physiology↗

bioRxiv2022

Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation

Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing {beta}-cell Ca2+ entry, which is essential for maintenance of glucose homeostasis. However, the Gi/o-GPCR signaling mechanism that mediates inhibition of human islet hormone secretion has not been identified. Here we demonstrate that Gi/o-GPCRs cause hyperpolarization of the {beta}-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or 2-adrenergic receptors induced oscillations in {beta}-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of {beta}-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that {beta}-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of {beta}-cell Gi/o-GPCR signaling and NKAs by {delta}-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in {beta}-cell membrane potential and Ca2+ were dependent on NKA phosphorylation by Src tyrosine kinases; an effect that was mimicked by stimulating islet insulin receptor tyrosine kinases. Whereas {beta}-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of {beta}-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.

physiology↗

bioRxiv2020

TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation.

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic {beta}-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in {beta}-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, as well as -cell and {beta}-cell mass. This resulted in impaired glucose tolerance due to decreased serum insulin levels. However, ablation of TRPM7 following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences {beta}-cell hyperplasia under insulin resistant conditions. {beta}-cell proliferation induced by high-fat diet was significantly decreased in TRPM7 deficient {beta}-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters {beta}-cell intracellular Mg2+. Together, these findings reveal that TRPM7 controls pancreatic progenitor expansion and {beta}-cell proliferation, which is likely due to regulation of Mg2+ homeostasis. SummaryThis manuscript identifies a critical developmental role for TRPM7 channels in pancreatic progenitor cells. The manuscript also determines that TRPM7 plays a key role in {beta}-cell proliferation under insulin-resistant conditions.

developmental biology↗

bioRxiv2020

Antagonistic epistasis of Hnf4a and FoxO1 networks through enhancer interactionsin beta-cell function

Genetic and acquired abnormalities contribute to pancreatic {beta}-cell failure in diabetes. Transcription factors Hnf4 (MODY1) and FoxO1 are respective examples of these two components, and are known to act through {beta}-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature {beta}-cells leads to increased selection of FoxO1 enhancers by Hnf4. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4 in {beta}-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective {beta}-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of {beta}-cell dysfunction with an antagonistic network regulating glycolysis, including {beta}-cell "disallowed" genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of {beta}-cell dysfunction.

pathology↗