Pathophysiological and clinical aspects of the circadian rhythm of arterial stiffness in diabetes mellitus: A minireview.

Several cross-sectional trials have revealed increased arterial stiffness connected with the cardiac autonomic neuropathy in types 2 and 1 diabetic patients. The pathophysiological relationship between arterial stiffness and autonomic dysfunction in diabetes mellitus is still underinvestigated and the question whether the presence of cardiac autonomic neuropathy leads to arterial stiffening or increased arterial stiffness induced autonomic nervous system impairment is still open. Both arterial stiffness and dysfunction of the autonomic nervous system have common pathogenetic pathways, counting state of the chronic hyperinsulinemia and hyperglycemia, increased formation of advanced glycation end products, activation of protein kinase C, development of endothelial dysfunction, and chronic low-grade inflammation. Baroreceptor dysfunction is thought to be one of the possible reasons for the arterial wall stiffening development and progression. On the contrary, violated autonomic nervous system function can affect the vascular tone and by this way alter the large arteries walls elastic properties. Another possible mechanism of attachment and/or development of arterial stiffness is the increased heart rate and autonomic dysfunction corresponding progression. This minireview analyzes the current state of the relationship between the diabetes mellitus and the arterial stiffness. Particular attention is paid to the analysis, interpretation, and application of the results obtained in patients with type 2 diabetes mellitus and diabetic cardiac autonomic neuropathy.

The Role of Biofactors in Diabetic Microvascular Complications.

Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare burden in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies have indicated that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors, like α-lipoic acid and benfotiamine, could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.

Effect of alpha-lipoic acid on arterial stiffness parameters in type 2 diabetes mellitus patients with cardiac autonomic neuropathy.

Objective. Significantly underdiagnosed, diabetes-associated cardiac autonomic neuropathy (CAN) causes a wide range of cardiac disorders that may cause life-threatening outcomes. This study investigated the effects of alpha-lipoic acid (ALA) on arterial stiffness and insulin resistance (IR) parameters in type 2 diabetes mellitus (T2D) patients and definite CAN. Methods. A total of 36 patients with T2D and a definite stage of CAN were recruited. This investigation was carried out on two separate arms: traditional hypoglycemic therapy (n=18, control) and ALA (n=18) 600 mg in film-coated tablets/q.d. in addition to traditional hypoglycemic therapy. The duration of the study was three months. Results. In subjects with T2D and definite stage of СAN, treatment with ALA resulted in a significant decrease of glucose, immunoreactive insulin concentration, and Homeostasis Model Assessment (HOMA)-IR (HOMA-IR) parameters; pulse wave velocity (PWV), aorta augmentation index (AIxao) during the active period of the day and decrease of PWV, AIxao, and brachial augmentation index during the passive period of the day compared with the results, obtained in the control group. Therefore, the administration of ALA to patients with T2D for three months promotes the improvement of glucose metabolism and arterial stiffness parameters. Conclusions. In patients with T2D and definite stage of СAN treatment with ALA improved HOMA-IR and arterial stiffness parameters. These findings can be of clinical significance for the complex treatment of diabetes-associated CAN.

Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment.

Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.

Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives?

Cardiac autonomic neuropathy (CAN) is a serious and common complication of diabetes mellitus (DM). Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of CAN has not been fully appreciated. CAN among DM patients is characterized review the latest evidence and own data regarding the treatment and the treatment perspectives for diabetic CAN. Lifestyle modification, intensive glycemic control might prevent development or progression of CAN. Pathogenetic treatment of CAN includes: balanced diet and physical activity; optimization of glycemic control; treatment of dyslipoproteinemia; correction of metabolic abnormalities in myocardium; prevention and treatment of thrombosis; use of aldose reductase inhibitors; dihomo-γ-linolenic acid (DGLA), acetyl-L-carnitine, antioxidants, first of all α-lipoic acid (α-LA), use of long-chain ω-3 and ω-6 polyunsaturated fatty acids (ω-3 and ω-6 PUFAs), vasodilators, fat-soluble vitamin B1, aminoguanidine; substitutive therapy of growth factors, in severe cases-treatment of orthostatic hypotension. The promising methods include research and use of tools that increase blood flow through the vasa vasorum, including prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na(+), K(+)-ATPase (phosphodiesterase inhibitor), α-LA, DGLA, ω-3 PUFAs, and the simultaneous prescription of α-LA, ω-3 PUFA and DGLA.