Hypertension and Diabetic Nephropathy.

Diabetic nephropathy (DN) is a major complication of both type 1 and type 2 diabetes. DN is the most common cause of end-stage renal disease, and it markedly enhances the risk of cardiovascular events. An elevated urinary albumin excretion rate, increased blood pressure (BP), and a continual loss of renal function are characteristics of DN. Screening for microalbuminuria is central to diabetes care, and antihypertensive agents are used for the primary prevention and treatment of DN. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers play central roles and have protective properties beyond their BP-lowering effects. BP control in relation to DN is the main focus of this review, but tight control of the glucose level is equally important. There is an unmet need for new treatment options, and while a few promising candidates exist, their roles in clinical practice have not yet been determined.

Effects of GLP-1 in the kidney.

The incretin hormone, glucagon-like peptide-1 (GLP-1), stimulates insulin secretion and forms the basis of a new drug class for diabetes treatment. GLP-1 has several extra-pancreatic properties which include effects on kidney function. Although renal GLP-1 receptors have been identified, their exact localization and physiological role are incompletely understood. GLP-1 increases natriuresis through inhibition of the sodium-hydrogen ion exchanger isoform 3 in the proximal tubule. This may in part explain why GLP-1 receptor agonists have antihypertensive effects. Glomerular filtration rate is regulated by GLP-1, but the mechanisms are complex and may depend on e.g. glycaemic conditions. Atrial natriuretic peptide or the renin-angiotensin system may be involved in the signalling of GLP-1-mediated renal actions. Several studies in rodents have shown that GLP-1 therapy is renoprotective beyond metabolic improvements in models of diabetic nephropathy and acute kidney injury. Inhibition of renal inflammation and oxidative stress probably mediate this protection. Clinical studies supporting GLP-1-mediated renal protection exist, but they are few and with limitations. However, acute and chronic kidney diseases are major global health concerns and measures improving renal outcome are highly needed. Therefore, the renoprotective potential of GLP-1 therapy need to be thoroughly investigated in humans.

Tissue Renin-Angiotensin systems: a unifying hypothesis of metabolic disease.

The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans. Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations, we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

GLP-1 infusion reduces IGFBP-1 serum level in humans.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) and the insulin-like growth factor (IGF) system are important factors in metabolic regulation and cellular growth. Interactions between the systems exist but these are vaguely explored and only in vitro, where GLP-1 has been reported to stimulate IGF-binding protein 1 (IGFBP-1). This study, therefore, aimed to elucidate the effects of GLP-1 on IGF-I and the IGFBPs, which regulate IGF-I bioactivity. DESIGN: We investigated the effects of a 2-hour intravenous GLP-1 infusion on the IGF system in 12 overnight fasted healthy humans, using a randomized, double-blinded, cross-over study design. Serum samples were assessed for immunoreactive levels of IGF-I, IGFBP-1 and -2 as well as for bioactive IGF-I, which was determined by a cell-based IGF-I kinase receptor activation assay. RESULTS: GLP-1 infusion markedly increased insulin levels (p<0.0001), reduced IGFBP-1 levels (p=0.02), and tended to increase IGF-I bioactivity (p=0.06). There were no significant changes in IGFBP-2 or immunoreactive IGF-I levels. CONCLUSION: In this short-term study, GLP-1 reduced IGFBP-1 levels in vivo and tended to increase IGF-I bioactivity. The IGFBP-1 outcome is opposite to the in vitro situation, hereby demonstrating that in vivo the ability of GLP-1 to stimulate insulin and hereby suppress IGFBP-1 outweighs any direct stimulatory effects of GLP-1 on IGFBP-1.

Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males.

The antihypertensive actions of glucagon-like peptide-1 (GLP1) receptor agonists have been linked to the release of atrial natriuretic peptide (ANP) in mice. Whether a GLP1-ANP axis exists in humans is unknown. In this study, we examined 12 healthy young males in a randomized, controlled, double-blinded, single-day, cross-over study to evaluate the effects of a 2-h native GLP1 infusion. Plasma proANP concentrations were measured by an automated mid-region-directed proANP immunoassay and N-terminal pro B-type natriuretic peptide (BNP) on Roche Modular E170. Urine was collected for measurements of sodium excretion. Although GLP1 infusion increased the urinary sodium excretion markedly, there were no significant changes in either proANP or proBNP concentrations. When GLP1 infusion was stopped, sodium excretion declined rapidly. As proANP concentration reflects ANP secretion, our data could not confirm the existence of a GLP1-ANP axis in humans. Especially, the natriuretic effects of GLP1 seem unlikely to be mediated exclusively via ANP.

Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) is an incretin hormone with multiple actions in addition to control of glucose homeostasis. GLP-1 is known to cause natriuresis in humans, but the effects on basic renal physiology are still partly unknown. SUBJECTS AND METHODS: Twelve healthy young males were examined in a randomized, controlled, double-blinded, single-day, crossover trial to evaluate the effects of 2 hours GLP-1 infusion on kidney functions. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed with (51)Cr-EDTA and (123)I-hippuran, respectively, using a constant infusion renal clearance technique based on timed urine sampling. RESULTS: GLP-1 had no significant effect on either GFR [+1.9%, 95% confidence interval (-0.8; 4.6%)] or RPF [+2.4%, 95% confidence interval (-3.6; 8.8%)]. Fractional urine excretion of lithium increased 9% (P = .013) and renal sodium clearance increased 40% (P = .007). Angiotensin II decreased 19% (P = .003), whereas renin, aldosterone, and the urinary excretion of angiotensinogen showed no significant changes. glp-1 did not affect blood pressure but induced a small transient increase in heart rate. CONCLUSION: The results indicate that although GLP-1 markedly reduces proximal tubule sodium reabsorption, the acute effects on GFR and RPF are very limited in healthy humans. The finding of GLP-1's ability to reduce angiotensin II concentration is novel and should be further elucidated.