Atrial natriuretic hormone secretion in patients with renal failure

To study the effects of volume overload and renal failure on plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH), we measured levels of this hormone in normal subjects, in patients with advanced chronic renal failure (CRF) with and without clinically evident volume overload, and in patients with end-stage renal disease (ESRD) treated with chronic hemodialysis. The levels were 13 +/- 2 pmol/l in normal volunteers, 77 +/- 24 pmol/l in patients with CRF without volume overload, and 219 +/- 50 pmol/l in patients with CRF and clinically evident volume overload (analysis of variance, p less than 0.001, alpha = 0.05 compared to normals). In patients with ESRD, the levels of IR-ANH were 145 +/- 46 pmol/l before dialysis and decreased to 87 +/- 31 after dialysis (p less than 0.025). No correlation was found between the decrease in IR-ANH levels and the decrease in weight during dialysis. A significant positive correlation was found between the IR-ANH levels and blood urea nitrogen in patients with CRF (r = 0.658, p less than 0.01). Volume overload appears to be the most important stimulatory factor for ANH secretion in renal failure patients but other mechanisms, especially a decrease in metabolic clearance, may also contribute to elevated plasma levels. The increased secretion of ANH in patients with renal failure may be an important adaptive response to volume overload and hypertension.     

Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.

OBJECTIVE--To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. DESIGN--Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING--One routine diabetic unit in a university teaching hospital. PATIENTS--23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. MAIN OUTCOME MEASURES--Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. RESULTS--There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). CONCLUSIONS--Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

Hyperglycemic myocardial damage is mediated by proinflammatory cytokine: macrophage migration inhibitory factor

Background

Diabetes has been regarded as an inflammatory condition which is associated with left ventricular diastolic dysfunction (LVDD). The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation.

Methods

83 patients in the age range of 30-64 years with type 2 diabetes and 30 matched healthy men were recruited. Left ventricular diastolic function was evaluated by cardiac Doppler echocardiography. Plasma MIF levels were determined by ELISA. To confirm the clinical observation, we also studied MIF expression in prediabetic rats with impaired glucose tolerance (IGT) and relationship between MIF and GRK2 expression in H9C2 cardiomyoblasts exposed to high glucose.

Results

Compared with healthy subjects, patients with diabetes have significantly increased levels of plasma MIF which was further increased in diabetic patients with Left ventricular diastolic dysfunction (LVDD). The increased plasma MIF levels in diabetic patients correlated with plasma glucose, glycosylated hemoglobin and urine albumin levels. We observed a significant number of TUNEL-positive cells in the myocardium of IGT-rats but not in the control rats. Moreover, we found higher MIF expression in the heart of IGT with cardiac dysfunction compared to that of the controls. In H9C2 cardiomyoblast cells, MIF and GRK2 expression was significantly increased in a glucose concentration-dependant manner. Furthermore, GRK2 expression was abolished by siRNA knockdown of MIF and by the inhibition of CXCR4 in H9C2 cells.

Conclusions

Our findings indicate that hyperglycemia is a causal factor for increased levels of pro-inflammatory cytokine MIF which plays a role in the development of cardiomyopathy occurring in patients with type 2 diabetes. The elevated levels of MIF are associated with cardiac dysfunction in diabetic patients, and the MIF effects are mediated by GRK2.     

Cardiac Autonomic Neuropathy,Estimated Cardiovascular Risk,and Circadian Blood Pressure Pattern in Diabetes Mellitus

This study was designed to investigate potential factors involved in the disruption of the circadian blood pressure (BP) pattern in diabetes mellitus, as well as the relation between BP, cardiac autonomic neuropathy, and estimated cardiovascular risk. We studied 101 diabetic patients (58% with type 2 diabetes; 59% men), age 21–65 yrs, evaluated by 48 h BP monitoring. We performed three autonomic tests in a single session: deep breathing, Valsalva maneuver, and standing up from a seated position. Patients were classified according to the number of abnormal tests and their 10 yr risk of coronary heart disease or stroke. The prevalence of non-dipping 24 h patterning ranged from 47.6% in type 1 to 42.4% in type 2 diabetes. The awake/asleep ratio of systolic BP (SBP) was comparable between patients with or without abnormal autonomic tests. Pulse pressure (PP) was significantly higher in patients with ≥1 abnormal autonomic test (p?<?0.001). Ambulatory SBP was significantly elevated in the group with higher risk of coronary heart disease (p?<?0.001). Patients with higher stroke-risk had higher SBP but lower diastolic BP, and thus an elevated ambulatory PP by 9 mmHg, compared to those with lower risk (p?<?0.001). Cardiac autonomic neuropathy is not the main causal-factor for the non-dipper BP pattern in diabetes mellitus. The most significant finding from this study is the high ambulatory PP found in patients with either cardiac autonomic dysfunction or high risk for coronary heart disease or stroke. After correcting for age, this elevated PP level emerged as the main cardiovascular risk factor in diabetes mellitus.     

Comparison of nerve growth factor mRNA expression in cardiac and skeletal muscle in streptozotocin-induced diabetic mice

To address the role of nerve growth factor (NGF) in diabetes mellitus (DM)-induced cardiac autonomic neuropathy, we quantitated and compared the expression of NGF mRNA in the cardiac and the skeletal muscle in experimental DM mice with the RT-PCR-HPLC method, which we have developed previously, using a NGF deletion mutant RNA as an internal standard. DM was induced in ICR mice via intraperitoneal injection of streptozotocin. RT-PCR was performed using total RNA extracted from left ventricle and soleus muscle, and the levels of NGF mRNA were quantitated by HPLC analysis. NGF mRNA content of the cardiac muscle was 17-fold higher than the skeletal muscles in control mice. NGF mRNA content of the cardiac muscle in diabetic mice at 6 weeks was 4.0-fold higher than that in the control mice, while that of the skeletal muscle in diabetic mice was not different from the controls. These results indicated that the DM-induced increase in NGF mRNA content was higher in cardiac muscle than skeletal muscle, and that NGF might play an important role in cardiac autonomic neuropathy.     

Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients

Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol. kg(-1). min(-1)) under either hypoglycemic (approximately 2.8 mmol/l) or euglycemic (approximately 5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects (n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (DeltaLVEF = 11 +/- 2%) and PFR [DeltaPFR = 0.88 +/- 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (DeltaLVEF = 13 +/- 2%; DeltaPFR = 0.79 +/- 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (DeltaLVEF = 7 +/- 1%) and nondiabetic (DeltaLVEF = 4 +/- 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study (P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.     

Elevated plasma levels of immunoreactive urotensin II and its increased urinary excretion in patients with Type 2 diabetes mellitus: association with progress of diabetic nephropathy

Urotensin II (UII) is the most potent vasoconstrictor peptide ever identified. In order to clarify the pathophysiological role of UII in diabetes mellitus, we examined plasma immunoreactive UII levels and urinary excretion of immunoreactive UII in 10 control subjects and 48 patients with Type 2 diabetes mellitus. The patients were divided into three groups according to the renal function: Group I with Ccr > or = 70 ml/min, group II with 30 < or = Ccr <70 ml/min and group III with Ccr <30 ml/min. Plasma immunoreactive UII levels were elevated in the three diabetic groups compared with normal controls (P <0.05). Group III patients had significantly higher plasma immunoreactive UII levels (15.9 +/- 2.2 fmol/ml, mean +/- S.E.M., n=6) by approximately 1.6-fold than did group I (10.9 +/- 0.9 fmol/ml, n=17) and group II (10.8 +/- 0.8 fmol/ml, n=25) (P <0.05). Urinary excretion of immunoreactive UII was significantly increased in group III patients (52.4 +/- 14.8 pmol/day) by more than 1.8-fold compared with control subjects, groups I and II (P <0.005). Fractional excretion of immunoreactive UII significantly increased as renal function decreased. Presence of diabetic retinopathy or neuropathy had negligible effects on plasma immunoreactive UII levels and urinary immunoreactive UII excretion. Reverse phase HPLC analyses showed three immunoreactive peaks in normal plasma extracts and multiple immunoreactive peaks in normal urine extracts. Thus, Type 2 diabetes mellitus itself is a factor to elevate plasma immunoreactive UII levels, and accompanying renal failure is another independent factor for the increased plasma immunoreactive UII levels in Type 2 diabetic patients. Increased urinary immunoreactive UII excretion in Type 2 diabetic patients with advanced diabetic nephropathy may be due not only to the elevated plasma immunoreactive UII levels but also to increased UII production and/or decreased UII degradation in the diseased kidney.     

High circulating vascular endothelial growth factor (VEGF) is related to a better systolic function in diabetic hypertensive patients

BACKGROUND: VEGF seems to have a protective role on cardiac microcirculation, but no data are available on its action on cardiac function and morphology in diabetic patients. We sought to test the hypothesis that circulating VEGF levels could influence the cardiac performance in type 2 diabetic hypertensive patients. METHODS: We studied 30 patients with type 2 diabetes and hypertension, without severe cardiac, retinal, renal and peripheral vascular damage. Ten non-diabetic hypertensive patients represented the control group. VEGF plasma levels (ELISA) and echocardiographic parameters were evaluated. RESULTS: Diabetic patients had VEGF plasma levels higher than hypertensive non-diabetic subjects [median 82 (IQR 12-190) vs 50.5 (IQR 28-77) pg/mL, p=0.05]. Simple linear regression analysis showed that VEGF levels are related to relative wall thickness (RWT) and both endocardial and midwall systolic parameters in the diabetic patients. Multiple linear regression analysis showed that RWT and ejection fraction (EF) were the only independent correlates of VEGF (r2=0.274, p=0.03, p=0.05; respectively). CONCLUSIONS: Our data showed that high VEGF plasma levels are associated to a better systolic function in diabetic hypertensive patients with cardiac remodeling. VEGF may play a role in the improvement of cardiac performance in diabetes.     

Ischemia-reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice

Diabetes is associated with higher incidence of myocardial infarction (MI) and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR) injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18)F)fluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes in cardiac function and remodeling, while a smaller infarct size and elevated levels of autophagy with similar cardiac function are observed in acute phase.     

Diabetes mellitus and cardiac function

Cardiovascular complications are the most common causes of morbidity and mortality in diabetic patients. Coronary atherosclerosis is enhanced in diabetics, whereas myocardial infarction represents 20% of deaths of diabetic subjects. Furthermore, re-infarction and heart failure are more common in the diabetics. Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a later systolic one, with intracellular retention of calcium and sodium and loss of potassium. In addition, diabetes mellitus accelerates the development of left ventricular hypertrophy in hypertensive patients and increases cardiovascular mortality and morbidity. Treating the cardiovascular problems in diabetics must be undertaken with caution. Special consideration must be given with respect to the ionic and metabolic changes associated with diabetes. For example, although ACE inhibitors and calcium channel blockers are suitable agents, potassium channel openers cause myocardial preconditioning and decrease the infarct size in animal models, but they inhibit the insulin release after glucose administration in healthy subjects. Furthermore, potassium channel blockers abolish myocardial preconditioning and increase infarct size in animal models, but they protect the heart from the fatal arrhytmias induced by ischemia and reperfusion which may be important in diabetes. For example, diabetic peripheral neuropathy usually presents with silent ischemia and infarction. Mechanistically, parasympathetic cardiac nerve dysfunction, expressed as increased resting heart rate and decreased respiratory variation in heart rate, is more frequent than the sympathetic cardiac nerve dysfunction expressed as a decrease in the heart rate rise during standing.     

Alterations in circulating angiogenic and anti‐angiogenic factors in type 2 diabetic patients with neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. There is an increased attention directed towards the role of angiogenic factors including vascular endothelial growth factor (VEGF) and anti‐angiogenic factors including soluble endoglin (sEng) as contributors to diabetic microvascular complications including neuropathy. The purposes of this study were to determine the role of these angiogenesis regulators in the prognosis of DPN. The study group included 60 patients with type 2 diabetes mellitus (T2DM) and 20 clinically healthy individuals. The patients were divided into two groups. Group I included 20 T2DM patients without peripheral neuropathy, and Group II consisted of 40 T2DM patients with DPN. In all groups, plasma VEGF, sEng and endothelin‐1 (ET‐1), nitric oxide and ET‐1 mRNA were estimated. Plasma levels of VEGF, sEng, ET‐1 and nitric oxide were significantly elevated in diabetic patients (Groups I and II) compared with healthy control subjects, with a higher increase in their levels in patients with DPN compared with diabetic patients without peripheral neuropathy. Measurement of plasma levels of angiogenesis‐related biomarkers in high‐risk diabetic patients might identify who later develop DPN, thus providing opportunities for early detection and targets for novel treatments. Copyright © 2013 John Wiley & Sons, Ltd.     

PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice

Background: Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.Aims: To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.Methods: Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.Results: Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.Conclusion: CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.     

Effect of telmisartan on cardiovascular complications associated with streptozotocin diabetic rats

Angiotensin receptor blockers provide cardiovascular protection in heart failure patients. We have studied the effect of 8 weeks treatment with telmisartan (5 mg kg(-1) day(-1)) on cardiovascular complications associated with streptozotocin (STZ) diabetic rats. Wistar rats were made diabetic with STZ (45 mg kg(-1), iv). Various biochemical and cardiac parameters were measured at the end of 8 weeks. STZ produced hyperglycemia, hypoinsulinemia, hyperlipidemia, increased blood pressure, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, reduction in heart rate and cardiac hypertrophy. Chronic treatment with telmisartan significantly (P < 0.05) prevented STZ induced hypertension and elevated fasting glucose level with simultaneous increase in serum insulin levels. It significantly (P < 0.05) reduced the elevated cholesterol, very low density lipoprotein (VLDL) and triglyceride levels in diabetic rats and increased the lower high density lipoprotein (HDL)-cholesterol levels. Further, telmisartan produced a significant (P < 0.05) reduction in the elevated creatinine levels, CRP and levels of other cardiac enzyme markers like Lactate de-hydrogenase and creatinine kinase of diabetic rats. STZ-induced bradycardia was also prevented by telmisartan treatment and it also produced beneficial effect by preventing cardiac hypertrophy as evident from left ventricular collagen levels, cardiac hypertrophy index and left ventricular hypertrophy index of diabetic rats. Our data suggest that telmisartan prevents not only the STZ-induced metabolic abnormalities, but also cardiovascular complications.     

The influences of islet transplantation on metabolic abnormalities and diabetic complications

To assess the long-term effect of islet transplantation on metabolic abnormalities and chronic complications of diabetic recipients, the long-term follow-up data of 36 type 1 diabetic subjects with functioning islet grafts for more than 1 year were analysed in this article. 36 type 1 diabetics, with mean age of 34.30 +/- 12.05 yr and mean duration of 11.53 +/- 5.29 yr, were followed up for a mean period of 29.39 +/- 9.50 mo after successfully transplanting with short-term cultured islet tissue of human fetal pancreases. The effect of islet transplants was identified as excellent in 13 subjects, good in 12 and fair in 11. The comparative studies were carried out of the mean levels of serum C-peptide, plasma glucose, GHb and GPP, serum lipids, and mean excretion of urine sugar, and the diabetic retinopathy, nephropathy as well as the autonomic neuropathy before transplantation in comparison with those of the present. The results of the study demonstrated that islet transplants could improve the function of islet B cells and the glucose metabolism, and might delay the development of diabetic retinopathy, nephropathy and autonomic neuropathy in successfully transplanted diabetic recipients, but not exert any influences on those of patients in fair group.     

Aldosterone responsiveness to an acute potassium load in diabetes mellitus and chronic renal insufficiency

The aldosterone response to increments in plasma potassium concentration in disease states associated with abnormal potassium tolerance remains undefined. We evaluated the plasma aldosterone response to an acute oral potassium load (0.25-0.50 mmol/kg body weight) in 30 patients (19 with chronic renal failure (CRF) and 11 with diabetes mellitus) with normal or decreased baseline plasma aldosterone levels and in 12 control subjects. In control subjects, plasma aldosterone levels increased initially and then declined below baseline, whereas in the patients the late decrease was not observed. In patients with CRF with and without hypoaldosteronism (5 undialyzed and all 9 dialyzed patients), plasma aldosterone increased significantly. Eight of the diabetic subjects had normal and 3 had low baseline aldosterone levels. In the former, plasma aldosterone levels did not increase above baseline following the KCI load. We conclude that diabetic patients and those with CRF manifest several abnormalities in aldosterone-potassium responsiveness that may contribute to the disturbed potassium homeostasis observed in these conditions.     

Plasma carnitine levels as a marker of impaired left ventricular functions

L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure.To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions.Plasma carnitine was significantly higher in patients with DCM (37.05 ± 7.62, p < 0.0001) and with RHD (47.2 ± 8.04, p < 0.0001) vs. the control subjects (14.4 ± 5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13 ± 14.11, p < 0.0001) and in RHD 43.53 ± 15.5, p < 0.0001), than the control (25.1 ± 5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: %FS < 25% (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m² (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions.     

Oxidative DNA damage and plasma antioxidant capacity in type 2 diabetic patients with good and poor glycaemic control

Diabetes mellitus is a complex metabolic disorder characterized by a disturbance in glucose metabolism. Recent evidence suggests that increased oxidative damage as well as reduction in antioxidant capacity could be related to the complications in patients with type 2 diabetes. The aim of this study was to measure plasma antioxidant status in type 2 diabetic patients with good and poor glycaemic control and its relationship with oxidative DNA damage. Thirty-nine type 2 diabetic patients and eighteen healthy subjects were recruited for this study. We found that diabetic patients had slightly, but not significantly lower antioxidant capacity, measured with the "ferric reducing ability of plasma" (FRAP) assay, than healthy subjects. On the contrary, oxidative DNA damage (measured by the Comet assay) in leukocytes obtained from diabetic patients was significantly higher compared to healthy subjects. Taking into account glucose control, we found that the FRAP level was significantly (p<0.05) lower in diabetic subjects with poor glycaemic control than healthy subjects, while patients with good glycaemic control had FRAP values similar to controls. We also observed an unexpected positive correlation between FRAP values and oxidative DNA damage in diabetic patients; moreover, a positive correlation was found between FRAP and glucose level or HbA(1c) in patients with poor glycaemic control. In conclusion, our results confirm that patients with type 2 diabetes have a higher oxidative DNA damage than healthy subjects and that plasma antioxidant capacity is significantly lower only in patients with poor glycaemic control, moreover, in these patients FRAP values are positively correlated with glycaemic levels and HbA(1c). These observations indicate that a compensatory increase of the antioxidant status is induced as a response to free radical overproduction in type 2 diabetes. Therefore, the addition of antioxidant supplements to the current pharmacological treatment could have potentially beneficial effects in diabetic patients with poor glycaemic control.     

The cardiac neural stem cell phenotype is compromised in streptozotocin‐induced diabetic cardiomyopathy

Neural stem cells were identified in the rat heart and during scar formation and healing participated in sympathetic fiber sprouting and angiogenesis. In the setting of diabetes, impaired wound healing represents a typical pathological feature. These findings provided the impetus to test the hypothesis that experimental diabetes adversely influenced the phenotype of cardiac neural stem cells. Streptozotocin (STZ)‐induced diabetic rats were associated with elevated plasma glucose levels, significant loss of body weight and left ventricular contractile dysfunction. In the heart of STZ‐diabetic rats, the density of nestin immunoreactive processes emanating from cardiac neural stem cells were reduced. The latter finding was reaffirmed as nestin protein expression was significantly decreased in the heart of STZ‐diabetic rats and associated with a concomitant reduction of nestin mRNA. Employing the TUNEL assay, the loss of nestin expression in STZ‐diabetic rats was not attributed to widespread cardiac neural stem cell apoptosis. Insulin administration to STZ‐diabetic rats with established hyperglycaemia led to a modest recovery of nestin protein expression in cardiac neural stem cells. By contrast, the administration of insulin immediately after STZ injection improved plasma glucose levels and significantly attenuated the loss of nestin protein expression. These data highlight the novel observation that nestin protein expression in cardiac neural stem cells was significantly reduced in STZ‐induced type I diabetic rats. The aberrant cardiac neural stem cell phenotype may compromise their biological role and predispose the diabetic heart to maladaptive healing following ischemic injury. J. Cell. Physiol. 220: 440–449, 2009. © 2009 Wiley‐Liss, Inc.     

Increased insulin-insensitive glucose transport in polymorphonuclear leukocytes from non-insulin-dependent diabetic patients.

We studied the transport rate of a non-metabolizable hexose analogue, 3-O-methyl-D-glucose, in polymorphonuclear leukocytes (insulin-insensitive cells) from patients with untreated non-insulin-dependent diabetes mellitus. The mean glucose transport rate was significantly elevated in the diabetic patients compared with healthy controls (13.3 +/- 3.7 vs 10.4 +/- 2.5 fl/cell.sec, mean +/- SD, p less than 0.01). In the diabetic subjects, glucose transport rates were positively correlated with HbA1c levels (r = 0.563, p less than 0.01) but had no relations with ambient plasma glucose concentrations. Short-term incubation with 20 mM D-glucose had no effect on glucose transport in those cells. When glucose transport rates, HbA1c and fasting plasma glucose levels were simultaneously measured at weekly intervals over a four-week period in three diabetic subjects, the alterations in transport rates generally paralleled the changes observed in HbA1c levels rather than plasma glucose concentrations. It can be concluded that unlike insulin-sensitive cells such as adipocytes and muscle, glucose transport in human polymorphonuclear leukocytes, which are insulin insensitive cells, is increased in patients with non-insulin-dependent diabetes mellitus. Long-term, not short-term, derangement of glucose metabolism seems to be associated with increased glucose transport rate found in those patients.