The evolving place of incretin-based therapies in type 2 diabetes

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available

Angiotensin II stimulates H-ATPase activity in intercalated cells from isolated mouse connecting tubules and cortical collecting ducts

Intercalated cells in the collecting duct system express V-type H(+)-ATPases which participate in acid extrusion, bicarbonate secretion, and chloride absorption depending on the specific subtype. The activity of H(+)-ATPases is regulated by acid-base status and several hormones, including angiotensin II and aldosterone. Angiotensin II stimulates chloride absorption mediated by pendrin in type B intercalated cells and this process is energized by the activity of H(+)-ATPases. Moreover, angiotensin II stimulates bicarbonate secretion by the connecting tubule (CNT) and early cortical collecting duct (CCD). In the present study we examined the effect of angiotensin II (10 nM) on H(+)-ATPase activity and localization in isolated mouse connecting tubules and cortical collecting ducts. Angiotensin II stimulated Na(+)-independent intracellular pH recovery about 2-3 fold, and this was abolished by the specific H(+)-ATPase inhibitor concanamycin. The effect of angiotensin II was mediated through type 1 angiotensin II receptors (AT(1)-receptors) because it could be blocked by saralasin. Stimulation of H(+)-ATPase activity required an intact microtubular network - it was completely inhibited by colchicine. Immunocytochemistry of isolated CNT/CCDs incubated in vitro with angiotensin II suggests enhanced membrane associated staining of H(+)-ATPases in pendrin expressing intercalated cells. In summary, angiotensin II stimulates H(+)-ATPases in CNT/CCD intercalated cells, and may contribute to the regulation of chloride absorption and bicarbonate secretion in this nephron segment

Impact of bicarbonate, ammonium chloride, and acetazolamide on hepatic and renal SLC26A4 expression

SLC26A4 encodes pendrin, a transporter exchanging anions such as chloride, bicarbonate, and iodide. Loss of function mutations of SLC26A4 cause Pendred syndrome characterized by hearing loss and enlarged vestibular aqueducts as well as variable hypothyroidism and goiter. In the kidney, pendrin is expressed in the distal nephron and accomplishes HCO(3)(-) secretion and Cl(-) reabsorption. Renal pendrin expression is regulated by acid-base balance. The liver contributes to acid-base regulation by producing or consuming glutamine, which is utilized by the kidney for generation and excretion of NH(4)(+), paralleled by HCO(3)(-) formation. Little is known about the regulation of pendrin in liver. The present study thus examined the expression of Slc26a4 in liver and kidney of mice drinking tap water without or with NaHCO(3) (150 mM), NH(4)Cl (280 mM) or acetazolamide (3.6 mM) for seven days. As compared to Gapdh transcript levels, Slc26a4 transcript levels were moderately lower in liver than in renal tissue. Slc26a4 transcript levels were not significantly affected by NaHCO(3) in liver, but significantly increased by NaHCO(3) in kidney. Pendrin protein expression was significantly enhanced in kidney and reduced in liver by NaHCO(3). Slc26a4 transcript levels were significantly increased by NH(4)Cl and acetazolamide in liver, and significantly decreased by NH(4)Cl and by acetazolamide in kidney. NH(4)Cl and acetazolamide reduced pendrin protein expression significantly in kidney, but did not significantly modify pendrin protein expression in liver. The observations point to expression of pendrin in the liver and to opposite effects of acidosis on pendrin transcription in liver and kidney

Inhibition of the Na-H + exchanger isoform-1 and the extracellular signal-regulated kinase induces apoptosis: A time course of events

Aims: The present study attempts to shed light on the role and the relative position of the Na +/H + exchanger isoform 1 (NHE1) and the extracellular signal-regulated kinase (ERK) in HEp-2 cell signaling pathways concerning a diverse range of cellular functions such as regulation of intracellular pH (pHi), DNA synthesis, production of reactive oxygen species (ROS) and apoptosis. Methods: Pharmacological inhibition with cariporide (highly specific inhibitor of NHE1) and PD98059 (specific inhibitor of the upstream activator of ERK) was implemented. Fluorescence spectrometry, atomic absorption spectrometry and ELISA methods were used in order to obtain the results. Results: NHE1 and ERK take part in all of the aforementioned cellular functions, as their inhibition had an effect on all of them. Additionally, inhibition of NHE1 resulted in ERK inhibition as well. Moreover, continuous inhibition of NHE1 or ERK for up to 24h led HEp-2 cells to apoptosis, as assessed through caspase-3 activation, DNA fragmentation and annexin-V binding levels. Conclusion: Our data shows a time course of events in relation to NHE1 and ERK and suggests the existence of a positive feedback loop between NHE1 and ERK which could pose a barrier against apoptosis. Copyright © 2006 S. Karger AG