One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN),1–3 which encompasses damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics.4

The present report discusses the clinical manifestations (eg, resting tachycardia, orthostasis, exercise intolerance, intraoperative cardiovascular liability, silent myocardial infarction [MI], and increased risk of mortality) in the presence of CAN. It also demonstrates that autonomic dysfunction can affect daily activities of individuals with diabetes and may invoke potentially life-threatening outcomes. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of autonomic function and to provide therapeutic choices that are based on symptom control and that might abrogate the underlying disorder.

Little information exists as to frequency of CAN in representative diabetic populations. This is further complicated by the differences in the methodology used and the lack of standardization. Fifteen studies using different end points report prevalence rates of 1% to 90%.1 The heterogenous methodology makes it difficult to compare epidemiology across different studies. CAN may be present at diagnosis, and prevalence increases with age, duration of diabetes, and poor glycemic control. CAN also cosegregates with distal symmetric polyneuropathy, microangiopathy, and macroangiopathy. Age, diabetes, obesity, and smoking are risk factors for reduced heart rate variability (HRV)5 in type 2 diabetes. Thus, there may be selectivity and sex-related differences among the various cardiovascular risk factors as to their influence on autonomic dysfunction.6 HbA1c, hypertension, distal symmetrical polyneuropathy, retinopathy, and exposure to hyperglycemia were shown to be risk factors for developing CAN in type 1 diabetes.7

### Resting Tachycardia

Whereas abnormalities in HRV are early findings of CAN, resting tachycardia …

Diabetic Cardiovascular Autonomic Neuropathy

It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.

https://diabetes.diabetesjournals.org/content/diabetes/57/6/1446.full.pdf

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

Context: Diabetic complications appear to be multifactorial in origin, but in particular, the biochemical process of advanced glycation, which is accelerated in diabetes as a result of chronic hyperglycemia and increased oxidative stress, has been postulated to play a central role in these disorders. Advanced glycation involves the generation of a heterogenous group of chemical moieties known as advanced glycated end products (AGEs), this reaction occurring as a result of a nonenzymatic reaction with glucose interacting with proteins, lipids, and nucleic acids, and involves key intermediates such as methylglyoxal. Evidence Synthesis: In this review we report on how these AGEs may exert deleterious effects in diabetes, as well as address current strategies to interrupt the formation or action of AGEs. First, AGEs act directly to induce cross-linking of long-lived proteins such as collagen to promote vascular stiffness, and, thus, alter vascular structure and function. Second, AGEs can interact with certain...

/pdf/the-role-of-advanced-glycation-end-products-in-progression-ez2bybickx.pdf

The role of advanced glycation end products in progression and complications of diabetes

It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes. Diabetes 57:1446‐1454, 2008

Oxidative Stress as a Major Culprit in Kidney Disease in

Diabetic neuropathy: mechanisms to management.

In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.

A. Lindemann

Papers

A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.