Dietary K+ intake may increase renal K+ excretion via increasing plasma [K+] and/or activating a mechanism independent of plasma [K+]. We evaluated these mechanisms during normal dietary K+ intake. After an overnight fast, [K+] and renal K+ excretion were measured in rats fed either 0% K+ or the normal 1% K+ diet. In a third group, rats were fed with the 0% K+ diet, and KCl was infused to match plasma [K+] profile to that of the 1% K+ diet group. The 1% K+ feeding significantly increased renal K+ excretion, associated with slight increases in plasma [K+], whereas the 0% K+ diet decreased K+ excretion, associated with decreases in plasma [K+]. In the KCl-infused 0% K+ diet group, renal K+ excretion was significantly less than that of the 1% K+ group, despite matched plasma [K+] profiles. We also examined whether dietary K+ alters plasma profiles of gut peptides, such as guanylin, uroguanylin, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, pituitary peptides, such as AVP, α-MSH, and γ-MSH, or aldosterone. Our data do not support a role for these hormones in the stimulation of renal K+ excretion during normal K+ intake. In conclusion, postprandial increases in renal K+ excretion cannot be fully accounted for by changes in plasma [K+] and that gut sensing of dietary K+ is an important component of the regulation of renal K+ excretion. Our studies on gut and pituitary peptide hormones suggest that there may be previously unknown humoral factors that stimulate renal K+ excretion during dietary K+ intake.
Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue. Am J Physiol Endocrinol Metab 300: E1012-E1021, 2011. First published March 8, 2011; doi:10.1152/ajpendo.00650.2010.-Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipidlowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (Ͼ60%, P Ͻ 0.01), and this effect was maintained for Ն5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P Ͻ 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment. hypolipidemic drug; free fatty acids; perilipin; phosphodiesterase; triglyceride synthesis; insulin resistance; nicotinic acid receptor; microarray analysis NICOTINIC ACID (NA; or niacin) is a B-group vitamin. In addition to its function as a vitamin, NA, in high doses, has been used as a lipid drug for five decades (6, 21); it produces very desirable effects such as decreasing plasma triglycerides (TG), VLDL, and LDL-cholesterol levels and increasing HDL-cholesterol levels (14,38). Major clinical trials have demonstrated that NA treatment reduces the progression of atherosclerotic cardiovascular disease (9, 18). The lipid-lowering effects of NA have traditionally been attributed to its antilipolytic effect in adipocytes (10). NA binds to and stimulates a G proteincoupled receptor [i.e., GPR109A or HM74A (37, 41)] in the plasma membrane of adipo...
Nicotinic acid (NA; or niacin) has been used as a hypolipidemic agent for more than four decades. However, the mechanisms underlying the effects of NA treatment (wanted and unwanted) are still poorly understood. In the present study, we discovered that NA infusion in rats resulted in dephosphorylation (i.e., activation) of the forkhead transcription factor FOXO1 in insulin sensitive tissues such as skeletal and cardiac muscles, liver, and adipose tissue. These NA effects were opposite to the effects of insulin to increase FOXO1 phosphorylation. To test whether NA alters gene expression in these tissues, rats were infused for 7 h with NA (30 μmol/h) and/or insulin (5 mU/kg/min), and gene expression was evaluated using a microarray analysis. NA had widespread effects on gene expression in all of the tissues studied, and the number of genes affected by NA greatly exceeded that of genes affected by insulin. A systematic (or strategic) analysis of the microarray data revealed that there were numerous genes whose expression was regulated inversely by insulin and NA in correlation with FOXO1 phosphorylation, representing potential FOXO1 target genes. We also identified a group of genes whose expression was altered by NA exclusively in adipose tissue, presumably due to stimulation of the NA receptor in this tissue. Finally, there were genes whose expression was altered by both NA and insulin, likely via lowering plasma FFA levels, including lipoprotein lipase and ATP-binding cassette A1 which play a major role in the regulation of circulating lipids. Thus, our data suggest that NA alters gene expression in insulin-sensitive tissues by various mechanisms. Some of the NA-induced changes in gene expression are discussed as potential mechanisms underlying wanted and unwanted effects of NA treatment.
The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. (Endocrinology 153: 3587-3592, 2012) T he brain plays a crucial role in energy homeostasis. When the blood glucose level falls, the brain senses it and activates various neuroendocrine mechanisms to restore blood glucose levels (1). These responses, known as glucose counterregulatory responses, are critical for the survival of the brain and have been extensively studied. According to the "selfish brain" theory (2), the brain places the highest priority on covering its own energy requirements when regulating energy homeostasis, activating stress responses upon a fall in cerebral energy (i.e. ATP) levels and suppressing insulin secretion to allocate glucose to the brain rather than the periphery. Free fatty acids (FFA) are another major fuel in mammals. It is established that FFA, like glucose, are sensed by the brain, and excess supply of FFA to the brain can suppress food intake and reduce hepatic glucose output (3). However, it is unclear whether the brain responds to a fall in plasma FFA, as it does with glucose, to activate mechanisms for its restoration. There is ample evidence that acute depression (or elevation) of plasma FFA stimulates (or inhibits) growth hormone secretion (4, 5). Because growth hormone is known to increase lipolysis in adipocytes, these effects of FFA on growth hormone secretion provide a negative feedback mechanism in the regulation of plasma FFA. The underlying mechanisms appear to be complex (4), but the brain (i.e. hypothalamus) may be responsible for at least some FFA effects (6). In addition, there are scattered data showing that nicotinic acid (NA) administration, which...
Background In clinically node-negative (cN0) breast cancer patients with triple negative (TN) and HER2+ disease and breast pathological complete response (breast pCR), low rates of nodal positivity after neoadjuvant chemotherapy (NAC) have been demonstrated. In these patients, the omission of surgical axillary staging has been proposed. However, this information is not routinely known preoperatively. We aimed to validate the correlation between pathologic breast response and pathologic nodal status, and evaluate the relationship between response of the breast tumor on MRI and pathologic nodal status after NAC in cN0 patients in the I-SPY2 trial. Methods We identified all patients with cT1-4 cN0 breast cancer prior to NAC from graduated arms of the I-SPY2 trial, a prospective neoadjuvant chemotherapy trial. Absence of residual disease post-NAC was defined as longest diameter (LD) of 0 mm on MRI. Breast pCR was defined as the absence of invasive tumor in the breast at surgery. Associations between ypN0 and patient, MRI, and tumor characteristics were assessed using chi-square tests and univariate regression. Results Of 365 cT1-4 cN0 patients included, 128 had HR+/HER2- tumors (35%), 60 HR+/HER2+ tumors (16%), 34 HR-/HER2+ tumors (9%) and 143 TN tumors (39%). Overall, 283 patients (78%) were ypN0 after NAC and 152 patients (42%) had a breast pCR. ypN0 rate was higher in patients with a breast pCR than those with residual disease (93% vs 66%, p<0.001). Patients with HR-/HER2+ and TN tumors were more likely to be ypN0 (97% and 87% respectively) than patients with HR+/HER2- and HR+/HER2+ disease (66% and 71% respectively, p<0.001). Other characteristics associated with ypN0 were tumor grade (grade I 57%, grade II 66%, grade III 84%; p=0.002), MammaPrint Classification (High Risk 1 68% and High Risk 2 87%; p<0.001) and absence of residual tumor in the breast on MRI (87% vs 72% in patients with evidence of tumor on MRI post-NAC/pre-surgery; p=0.003). In patients with HR-/HER2+, HR+/HER2+, HR-/HER2+ or TN disease and a breast pCR, ypN0 rate was respectively 82%, 96%, 96% and 97% (table 1). In patients with HR+/HER2-, HR+/HER2+, HR-/HER2+ or TN disease and with no evidence of residual disease in the breast on MRI, rate of ypN0 was 71%, 80%, 94% and 96% respectively. Conclusion In cT1-4 cN0 breast cancer patients with HR+/HER2+, HR-/HER2+ and TN tumors and a breast pCR, ypN0 rates after NAC are extremely high. In patients with HR-/HER2+ and TN tumors with no residual breast disease on MRI after NAC and pre-surgery, ypN0 rates are high enough to consider omission of axillary surgery. In patients with HR+ tumors, MRI is unsufficiently predictive for pathological response and can therefore not be used to select ypN0 patients. Research on the prediction of ypN0 in cN+ I-SPY2 patients is ongoing. Nodal status in patients with pCR and absence of residual disease on MRI Number of positive nodesBreast Cancer Subtype0123AllBreast pCR HR+/HER2-27(82)2(6)4(12)033(100)HR+/HER2+24(96)01(4)025(100)HR-/HER2+24(96)1(4)0025(100)TN67(97)2(3)0069(100)Absence of residual disease on MRI HR+/HER2-24(71)7(21)3(9)034(100)HR+/HER2+16(80)3(15)01(5)20(100)HR-/HER2+15(94)1(6)0016(100)TN54(96)2(4)0056(100) Citation Format: van der Noordaa ME, Esserman L, Yau C, Mukhtar R, Price E, Hylton N, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, van 't Veer L, Hirst G, Lancaster R, Wallace A, Alvaredo M, Symmans F, Asare S, Boughey JC, I-SPY2 Consortium. Role of breast MRI in predicting pathologically negative nodes after neoadjuvant chemotherapy in cN0 patients in the I-SPY2 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-04.
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