fumarates and Hyperglycemia

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy.. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days.. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005).. The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Topics: Adult; Amides; Chemokines; Cytokines; Diabetes Mellitus, Type 1; Female; Fumarates; Humans; Hyperglycemia; Insulin; Male; p-Aminohippuric Acid; Proteomics; Young Adult

Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study.. In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months' aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA(1c) levels.. Patients were divided into tertiles of HbA(1c) (<7.1%, 7.1 to <8.4% and ≥8.4%). There were no differences between tertiles, except patients in the highest tertile group more frequently used insulin. The antiproteinuric effect of aliskiren was consistent across tertiles, with the largest effect in the highest tertile (HbA(1c) ≥8.4%).. This post-hoc analysis of the AVOID study suggests that renin inhibition with aliskiren 300 mg once daily added to losartan 100 mg once daily plus optimal antihypertensive therapy provides reductions in urinary albumin creatinine ratio that are efficacious in all, but particularly in poorly controlled, diabetic patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Body Mass Index; Diabetes Complications; Female; Fumarates; Glycated Hemoglobin; Health Surveys; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Placebos; Proteinuria; Renin; Young Adult

The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-β expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control.

Topics: Adenylate Kinase; Animals; Blood Glucose; Diabetes Mellitus, Experimental; DNA, Mitochondrial; Fasting; Fumarates; Hyperglycemia; Kidney; Male; Malondialdehyde; Mitochondria; Models, Biological; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Rats, Wistar; Transforming Growth Factor beta

1. The rise in blood glucose and the fall in body temperature which follows the injection of a glucose analogue, 2-deoxy-D-glucose (2-DG) into the lateral cerebral ventricle (I.C.V) of unanaesthetized rats were studied and found to be dose-dependent. These 2-DG induced responses are elicited by the impairment of glucose metabolism within central "glucoreceptors'. 2. 2DG induced hyperglycaemia and hypothermia were completely prevented and even the converse effects occurred when fivefold equimolar amounts of D-fructose were simultaneously injected I.C.V.; fructose, at equimolar doses, did not modify the effects of 2-DG. 3. D-xylose and D-ribose, even at high doses, did not influence 2-DG hyperglycaemia, but increased slightly the 2-DG induced hypothermia. This suggests that the pentose phosphate pathway is unable to support the metabolism within the glucoreceptors. 4. Pyruvate suppressed the 2-DG induced hyperglycaemia with a marked delay, while acetate (as ethyl ester) and a mixture of malate plus oxaloacetate did not prevent 2-DG induced effects. These results may be accounted for by the low dosage used. 5. Acetoacetate and 3-hydroxybutyrate did not prevent 2-DG hypothermia and hyperglycaemia. 6. An effective prevention of the 2-DG induced hyperglycaemia and hypothermia was achieved with fumarate and glutamate, indicating that the stimulation of the Krebs cycle within "glucoreceptors' removes the glucoprivic effects. 7. The results indicate that prevention of 2-DG induced effects occurred only with alternate source of metabolic fuel which can support high respiratory rates in brain tissue. It is concluded that central chemoreceptors are not specifically responsive to glucose, or hexoses, but to the rate of oxidative metabolism.

Topics: Acetates; Animals; Blood Glucose; Body Temperature; Brain; Chemoreceptor Cells; Deoxyglucose; Dose-Response Relationship, Drug; Female; Fructose; Fumarates; Glutamates; Hydroxybutyrates; Hyperglycemia; Hypothermia; Pyruvates; Rats; Ribose; Xylose