MRI assessment of regional differences in phosphorus-31 metabolism and morphological abnormalities of the foot muscles in diabetes.

PURPOSE: To assess differences in the phosphorus-31 (31 P) metabolism and morphology in multiple muscle regions in the forefoot of diabetic patients and normal subjects. MATERIALS AND METHODS: Fifteen diabetic patients and 15 normal subjects were assessed for muscle atrophy by 1 H magnetic resonance imaging (MRI) at 3T to grade the flexor hallucis, adductor hallucis, interosseous regions, and entire foot cross-section. Each region and the entire foot were also quantitatively evaluated for metabolic function using 31 P imaging for spatial mapping of the inorganic phosphate (Pi) to phosphocreatine (PCr) ratio (Pi/PCr). The ratio of viable muscle area to the predefined region areas (31 P/1 H) was calculated. The variability of each method was assessed by its coefficient of variation (CV). RESULTS: Muscle atrophy was significantly more severe in diabetic compared to normal subjects in all regions (P < 0.01). The 31 P/1 H area ratio was significantly larger in the adductor hallucis than in the other two regions (P < 0.05). The Pi/PCr ratio was significantly different between the two groups in the flexor hallucis and interosseous regions (P < 0.05) but not adductor hallucis region. The CV for Pi/PCr ranged from 10.13 to 55.84, while it ranged from 73.40 to 263.90 for qualitative grading. CONCLUSION: Changes in atrophy and metabolism appear to occur unequally between different regions of the forefoot in diabetes. The adductor hallucis region appears more capable of maintaining structural and metabolic integrity than the flexor hallucis or interosseous regions. The CV analysis suggests that the quantitative 31 P methods have less variability than the qualitative grading. J. Magn. Reson. Imaging 2016;44:1132-1142.

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

OBJECTIVES: In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. BACKGROUND: Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. METHODS: Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. RESULTS: Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-ß, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes. CONCLUSIONS: Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.

Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options.

OBJECTIVE: To facilitate the clinician's understanding of the basis and treatment of painful diabetic neuropathy (PDN). BACKGROUND: PDN is one of several clinical syndromes in patients with diabetic peripheral neuropathy (DPN) and presents a major challenge for optimal management. METHODS: A systematic review of the literature was undertaken for articles specific to PDN, using Medline databases between 1966 and 2007. RESULTS: The epidemiology of PDN has not been well established and on the basis of available data the prevalence of pain is 10% to 20% in patients with diabetes and from 40% to 50% in those with diabetic neuropathy. It has a significant impact on the quality of life and health care costs. Pathophysiologic mechanisms underlying PDN are similar to other neuropathic pain disorders and are broadly characterized as peripheral and central sensitization. The natural course of PDN is variable, with many patients experiencing spontaneous improvement and resolution of pain. Hyperglycemia-induced pathways result in nerve dysfunction and damage, which lead to hyperexcitable peripheral and central pathways of pain. Glycemic control may prevent or partially reverse DPN and modulate PDN. Quantifying neuropathic pain is difficult, especially for clinical trials, although this has improved recently with the development of neuropathic pain-specific tools, such as the Neuropathic Pain Questionnaire and the Neuropathic Pain Symptom Inventory. Current therapeutic options are limited to symptomatic treatment and are similar to other types of neuropathic pain. CONCLUSIONS: A better understanding of the peripheral and central mechanisms resulting in PDN is likely to promote the development of more targeted and effective treatment.

The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients.

We examined the effects of high-dosage vitamin E treatment over a 12-month period on the vascular reactivity of micro- and macrocirculation and left ventricular function in diabetic patients. Subjects (n = 89) were randomized to vitamin E (1,800 IU daily) or placebo and were followed for 12 months. High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (NID; endothelium independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure vascular reactivity in the forearm skin. Left ventricular function was evaluated using transthoracic echocardiogram. At the end of the 6-month period, a worsening in endothelium-dependent skin vasodilation (P = 0.02) and rise in endothelin levels (P = 0.01) were found in the vitamin E compared with the placebo group. At the end of the 12-month period, a worsening was observed in NID (P = 0.02) and a marginal worsening was seen in systolic blood pressure (P = 0.04) and FMD (P = 0.04) in the vitamin E compared with the placebo group. In addition C-reactive protein levels decreased marginally in the vitamin E compared with the placebo group (P = 0.05). No changes were observed in left ventricular function. We concluded that long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients. Because vitamin E-treated patients had a worsening in some vascular reactivity measurements when compared with control subjects, the use of high dosages of vitamin E cannot be recommended.