Association of physical activity with glycaemic control and cardiovascular risk profile in 65 666 people with type 2 diabetes from Germany and Austria.

AIMS: To provide representative data from routine diabetes care concerning the physical activity levels of people with type 2 diabetes, and to show the association of activity level with cardio-metabolic risk profile in a gender-specific analysis. METHODS: The anonymized data from 65 666 subjects with type 2 diabetes, who have been receiving treatment in specialized diabetes institutions, were analysed using a large multi-centre database. The population was categorized as physically inactive (PA0), active 1-2 times per week (PA1), active >2 times per week (PA2), and then stratified by age (20-59 and 60-80 years). BMI, glycaemic control (measured by HbA(1c) levels), blood pressure, lipid profile and therapeutic regimen were adjusted for age, gender and diabetes duration. RESULTS: Most subjects were inactive (PA0: 90%; PA1: 6%, PA2: 4%). BMI, HbA(1c) and lipid profiles were better in older subjects and hypertension rates were lower in younger subjects. In both age groups, BMI, HbA(1c) (both P < 0.0001) and triglycerides (P < 0.002) were lower in the most active group PA2 compared with the inactive group PA0. HDL was higher in elderly (P < 0.0001) and pulse pressure (P = 0.03) lower in younger most active subjects only. Insulin therapy was used more frequently by the physically inactive and by older people. CONCLUSIONS: This survey indicates that glycaemic control and cardio-metabolic risk profiles in people with type 2 diabetes are positively related to physical activity. The effects of physical activity were beneficial in younger as well as in older people. The high number of inactive people with diabetes underlines the need to promote physical activity and sport.

Explaining the enigmatic K(M) for oxygen in cytochrome c oxidase: a kinetic model.

We present a mathematical model for the functioning of proton-pumping cytochrome c oxidase, consisting of cyclic conversions between 26 enzyme states. The model is based on the mechanism of oxygen reduction and linked proton translocation postulated by Wikström and Verkhovsky (2007). It enables the calculation of the steady-state turnover rates and enzyme-state populations as functions of the cytochrome c reduction state, oxygen concentration, membrane potential, and pH on either side of the inner mitochondrial membrane. We use the model to explain the enigmatic decrease in oxygen affinity of the enzyme that has been observed in mitochondria when the proton-motive force is increased. The importance of the 26 transitions in the mechanism of cytochrome oxidase for the functional properties of cytochrome oxidase is compared through Metabolic Control Analysis. The control of the K(M) value is distributed mainly between the steps in the mechanism that involve electrogenic proton movements, with both positive and negative contributions. Positive contributions derive from the same steps that control enzyme turnover rate in the model. Limitations and possible further applications of the model are discussed.

The influence of the ACE inhibitor lisinopril on the glomerular metabolism of proteolytic enzymes in diabetic rats.

Clinical studies indicate a nephro-protective effect in conjunction with the use of ACE inhibitors. This study's aim was to determine whether ACE inhibitors influence the metabolism of glomerular cells in addition to their known hemodynamic effects. Streptozotocin diabetic rats were treated with lisinopril (DLis 1.5 mg/l water), or hydralazine (Dhyd, 50 mg/l water) over 4 weeks. Untreated diabetic rats (DC) and non-diabetic rats (C) served as controls. After four weeks of treatment, urinary excretion of albumin, blood pressure and metabolic control (Glyc-Hb) were measured. After treatment glomeruli were isolated and homogenized, and beta-NAG and total proteolytic activity against azocasein were measured. Glycated hemoglobin levels were similar in all diabetic groups (DC, 12%, Dhyd, 10%; DLis 11%). Blood pressure of DLis rats (79 +/- 3 mmHg) and DHyd rats (46 +/- 2 mmHg) was lower than that of DC rats (111 +/- 3 mmHg). Urinary albumin excretion of diabetic groups was lowest in DLis. Diabetic rats showed a decrease in glomerular beta-NAG (10 vs. 60.5 U/g protein) and total proteolytic activity against azocasein (148 vs. 170 U/mg protein hour) compared to non-diabetic rats. Lisinopril increased beta-NAG (30 vs. 14 U/g protein) and total proteolytic activity (160.5 vs. 141.5 U/mg protein hour) compared with hydralazine. Our study confirms that the nephro-protective effect of ACE inhibitors is partially due to modulatory effects on the metabolism of basement membrane proteins.

Plasma thrombomodulin: a marker for microvascular complications in diabetes mellitus.

Thrombomodulin (TM), a marker of endothelial cell damage was studied in 183 patients with diabetes mellitus and different stages of complications. Thrombomodulin plasma levels correlated with duration of diabetes in patients with type I and type II diabetes. Thrombomodulin levels were higher in patients with increasing numbers of complications (nephropathy, retinopathy, arterio-occlusive disease, neuropathy). Neither the presence of retinopathy, nor neuropathy alone significantly increased plasma thrombomodulin in patients with similar urinary albumin concentration. The plasma level of thrombomodulin was more prominent in hypertensive than normotensive patients. Multivariate analysis showed that albuminuria is the factor which influences the most the increase of thrombomodulin in serum of diabetic patients.

Circadian variation of blood pressure in normo- and hypertensive diabetic patients with and without nephropathy.

Blood pressure control over 24 h is an important influence factor for prevention of diabetic angiopathy, i.e., diabetic nephropathy. We performed 24 h-measurements of blood pressure in normotensive and hypertensive type I- and type II-diabetic patients with different stages of nephropathy and observed the variation of circadian changes of blood pressure. The patients were divided into "dippers", whose nightly decrease in mean arterial pressure was greater than 10% and non-dippers with less than 10%. Even 30% of patients without nephropathy are non-dippers. We conclude that 24 h-blood pressure measurements must be required in all diabetic patients with or without nephropathy. An early therapy may prevent or slow the development of an end-stage renal failure.

Effect of metabolic factors and blood pressure on kidney function in proteinuric type 2 (non-insulin-dependent) diabetic patients.

Decline of kidney function with time and its influencing factors were investigated in the present longitudinal study in Type 2 (non-insulin-dependent) diabetic patients with clinical diabetic nephropathy. Compared to a control group of Type 2 diabetic patients without proteinuria, the proteinuric patients showed a higher prevalence of hypertension, higher systolic blood pressure values and serum triglyceride levels. The annual loss of glomerular kidney function was much higher in the proteinuric patients (5.3 ml.min-1 x 1.73 m2) than in the control subjects (0.9 ml.min-1 x 1.73 m2). Correlation analyses revealed a close correlation between the annual decrease of kidney function and the factors, systolic and diastolic blood pressure, triglyceride and postprandial blood glucose level as well as body mass index. Regression analyses showed for the first time that in addition to the systolic blood pressure and metabolic control, the triglyceride level is also an independent factor influencing the progression of nephropathy. Higher values of these parameters were associated with a more rapid deterioration of kidney function.

ACE inhibitors and diabetic nephropathy: clinical and experimental findings.

Apart from near normal metabolic control, early treatment of an increase in blood pressure in diabetic patients with nephropathy, is one of the most important therapeutic methods to prevent further progression of this complication. Long-term studies, recently published, suggest that ACE inhibitors have a beneficial effect on albuminuria and progression of nephropathy, irrespective of their hemodynamic effects. However, the mechanism by which ACE inhibitors exert these positive effects on glomerular pathology is still unclear. Several non-hemodynamic factors have been identified as being involved in the pathogenesis of diabetic nephropathy: (a) changes in the composition of glomerular basement membrane due to a changed metabolism of the proteins which make up this structure; consequences are an impairment of the filtration properties, onset of proteinuria as well as thickening of basement membrane; (b) Mesangial expansion due to an overproduction of mesangial matrix and deposition of proteins as well as (c) impairment of mesangial clearance function; consequences are development of glomerulosclerosis and reduction of filtration surface. It is known that the renin-angiotensin-system is stimulated in diabetic patients with nephropathy and that angiotensin II influences the synthesis of glomerular and mesangial proteins as well as the function of mesangial cells. Hypothetically, these points could explain the beneficial effects of ACE-inhibitors on the progression of diabetic nephropathy.

[ACE inhibitor effects on structure and function of the glomerular basement membrane]. / ACE-Hemmer-Wirkungen auf Struktur und Funktion der glomerulären Basalmembran.

Metabolism of proteins which compose capillary basement membrane is altered in diabetic patients. In the kidney, this leads to an impaired permselectivity of glomerular basement membrane and consequently to onset of proteinuria. Proteinuria which is often increased by hemodynamic factors, initiates and promotes the development of diabetic glomerusclerosis. Aside from near-normal metabolic control, special antihypertensive treatment can reduce proteinuria and retard loss of kidney function in proteinuric diabetic patients. The beneficial effect of ACE-inhibitors on course of diabetic nephropathy is generally thought to be a consequence of decreased systemic and intraglomerular pressure. However, recent longterm studies in Type I and Type II diabetic patients with nephropathy showed that ACE-inhibition can reduce proteinuria independent from their hemodynamic effects and, thus, improves the filtration properties of glomerular basement membrane. This may be due to an influence of ACE-inhibition on metabolism of basement membrane proteins.

The association of HLA antigens A3, B7, and DW2 with 330 multiple sclerosis patients in the United States.

Reported associations of HLA antigens with MS have varied considerably. In this study we have examined 330 clinically definite MS patients from the United States. The frequency of DW2 (52%) was highly statistically significant in MS patients as compared to controls (p less than 0.00001). Neither A3 nor B7 was significantly increased in MS; however, the joint occurrences of A3-DW2 (20% vs 7%, p less than 0.001) and B7-DW2 (30% vs 13%, p less than 0.0002) are highly associated with MS.