Graphical Abstract Highlights d KCNH6 regulates insulin secretion and glucose hemostasis in humans and mice d KCNH6 dysfunction causes a phenotype from hyper-to hypoinsulinemia and diabetes d KCNH6 dysfunction increases intracellular calcium levels and hyperinsulinemia d Chronic elevation of intracellular calcium causes b cell loss and hypoinsulinemia In Brief Yang et al. show that KCNH6 plays a key role in insulin secretion and glucose hemostasis in humans and mice. Dysfunction of KCNH6 results in a hyperinsulinemia phenotype in the short term and hypoinsulinemia and diabetes in the long term. SUMMARYGlucose-stimulated insulin secretion from islet b cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP K + channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of b cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and b cell failure in the long term.
Abstract. Our previous immunofluorescence studies support the conclusion that the temporal appearance and subcellular distribution of TS28 (a marker of transverse (T) tubules and caveolae in adult skeletal muscle [Jorgensen, A. O., W. Arnold, A. C.-Y. Shen, S. Yuan, M. Gover, and K. P. . J. Cell Biol. 110:1173-1185), correspond very closely to those of T-tubules forming de novo in developing rabbit skeletal muscle (Yuan, S., W. Arnold, and A. O. . J. Ceil Biol. 110:1187-1198.To extend our morphological studies of the biogenesis of T-tubules and triads, the temporal appearance and subcellular distribution of the o~t-subunit of the 1,4-dihydropyridine receptor (a marker of the T-tubules and caveolae) was compared to (a) that of TS28; and (b) that of the ryanodine receptor (a marker of the junctional sarcoplasmic reticulum) in rabbit skeletal muscle cells developing in situ (day 19 of gestation to 10 d newborn) by double immunofluorescence labeling.The results presented show that the temporal appearance and relative subcellular distribution of the ct~-subunit of the 1,4-dihydropyridine receptor (otI-DHPR) are distinct from those of TS28 at the onset of the biogenesis of T-tubules. Thus, in a particular developing myotube the al-DHPR appeared before TS28 (secondary myotubes; day 19-24 of gestation). Furthermore, the otI-DHPR was distributed in discrete foci at the outer zone of the cytosol, while TS28 was confined to foci and rod-like structures at the cell periphery. As development proceeded (primary myotubes; day 24 of gestation) ,050% of the foci were positively labeled for both TS28 and the o~-DHPR, while ,020 and 30% of the foci were uniquely labeled for TS28 and the otl-DHPR, respectively. The foci labeled for both TS28 and the t~1-DHPR and the foci uniquely labeled for TS28 were generally confined to the cell periphery, while the foci uniquely labeled for the aI-DHPR were mostly confined to the outer zone of the cytosol.
BackgroundAngiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM).MethodsWe studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively.ResultsWe demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 μg/mL apoA-I but decrease of 11.70 μg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors.ConclusionsANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0450-1) contains supplementary material, which is available to authorized users.
Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4/3-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoylphorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoylglycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4a-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions. (Circulation Research 1987;61:372-378) C ardiac functions are regulated by various hormones, neurotransmitters, and drugs, which are thought to interact with specific receptors located on the sarcolemmal membrane.1 Activation of /3-adrenergic receptor elevates cyclic adenosine 3',5' monophosphate (cAMP) in the myocardium and induces positive inotropic and chronotropic responses. Cyclic AMP-dependent protein kinase in the heart phosphorylates Ca 2+ channels, thereby increasing Ca 2+ concentration inside the cell. 2 However, the cellsurface-transducing system of Ca 2+ -mobilizing receptors in the heart, and the second messenger system that mediates the inhibitory response of cardiac tissue, have yet to be elucidated.Nishizuka and his colleagues 3 first demonstrated that diacylglycerol (DAG) activates protein kinase C. Since then, a link between phosphatidylinositol (PI) turnover and protein kinase C activation in a variety of cellular responses to hormonal stimulation has been established. Intracellular activation of protein kinase C can be achieved by the addition of cell-membrane- This work supported by grant Tl-51 from the Ontario Heart Foundation. S. Y. was the recipient of a studentship from Connaught Award Foundation, University of Toronto.Address for correspondence: Amar K. Sen, MD, PhD, Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.Received July 7, 1986; accepted April 10, 1987. permeable DAG analogues. Tumor-promoting phorbol esters such as 4/3-phorbol 12,13-dibutyrate (PDBu) and 12-0-tetradecanoylp...
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