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Objective: Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI)., Research Design and Methods: We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI., Results: A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines-osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)-were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events., Conclusions: We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure., (© 2019 by the American Diabetes Association.)

Objective: Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS., Research Design and Methods: Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5)., Results: In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both)., Conclusions: In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.

Objective: Type 1 diabetes is associated with increased platelet reactivity. We investigated whether α-lipoic acid (ALA) has any effect on platelet reactivity in these patients., Research Design and Methods: We randomly assigned 51 type 1 diabetic patients to ALA (600 mg once daily) or placebo for 5 weeks. Platelet reactivity was evaluated by the PFA-100 method and by measuring CD41 and CD62 platelet expression. C-reactive protein (CRP) and 8-iso-prostaglandin F2α serum levels also were measured., Results: Baseline variables were similar in the two groups. After treatment, closure time was longer (P = 0.006) and CD62P platelet expression was lower, both before (P = 0.002) and after (P = 0.009) ADP stimulation in the ALA group compared with the placebo group. CRP and 8-iso-prostaglandin F2α levels showed no differences between the two groups., Conclusions: Our data show that ALA reduces measures of platelet reactivity ex vivo in type 1 diabetic patients, independently of antioxidant or anti-inflammatory effects.

The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity.

Objective: We investigated whether supplementation of the active form of vitamin D (calcitriol) in recent-onset type 1 diabetes can protect beta-cell function evaluated by C-peptide and improve glycemic control assessed by A1C and insulin requirement., Research Design and Methods: Thirty-four subjects (aged 11-35 years, median 18 years) with recent-onset type 1 diabetes and high basal C-peptide >0.25 nmol/l were randomized in a double-blind trial to 0.25 microg/day calcitriol or placebo and followed-up for 2 years., Results: At 6, 12, and 24 months follow-up, A1C and insulin requirement in the calcitriol group did not differ from the placebo group. C-peptide dropped significantly (P < 0.001) but similarly in both groups, with no significant differences at each time point., Conclusions: At the doses used, calcitriol is ineffective in protecting beta-cell function in subjects (including children) with recent-onset type 1 diabetes and high C-peptide at diagnosis.

Objective: Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role., Research Design and Methods: We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy., Results: Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3-4.1], P = 0.006; Ch vs. H, 2.10 [1.3-3.3], P = 0.002; and ND vs. H, 0.90 [0.7-1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2-19.7], P < 0.001; Ch vs. H, 3.56 [1.9-6.7], P = 0.001; and ND vs. H, 0.54 [0.6-5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06-0.5], P = 0.002) and with ND (0.17 [0.05-0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43-2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy., Conclusions: This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy.

Objective: Diabetes increases the risk of coronary heart disease (CHD) to a greater extent in women than in men. We investigated whether type 1 diabetic patients with short duration of disease and without complications have an altered oxidative status and whether there are differences between men and women., Research Design and Methods: We investigated oxidative status in 29 control subjects and 37 patients with uncomplicated type 1 diabetes with duration of 6 +/- 3 years., Results: Compared with control subjects, type 1 diabetic patients had lower total plasma antioxidant capacity (TRAP) (720.3 +/- 111.2 vs. 972.5 +/- 97.7 micromol/l in men, P < 0.001; 579.8 +/- 95.4 vs. 930.1 +/- 84.2 in women, P < 0.001), higher lipid hydroperoxide (ROOH) levels (6.4 +/- 2.2 vs. 2.0 +/- 0.7 micromol/l in men, P < 0.001; 8.1 +/- 1.9 vs. 2.2 +/- 0.6 in women, P < 0.001), higher total conjugated diene (CD) levels (0.037 +/- 0.003 vs. 0.033 +/- 0.002 A.U. in men, P < 0.001), lower 246-nm CD levels (0.0032. +/- 0.0010 vs. 0.0070 +/- 0.0012 A.U. in men, P < 0.001; 0.0022 +/- 0.0011 vs. 0.0072 +/- 0.0014 A.U. in women, P < 0.001), and higher 232-nm CD levels (0.0348 +/- 0.0041 vs. 0.0257 +/- 0.0022 A.U. in men, P < 0.001; 0.0346 +/- 0.0031 vs. 0.0246 +/- 0.0074 A.U. in women, P < 0.001). Compared with diabetic men, diabetic women had lower TRAP (P < 0.01), higher ROOH levels (P < 0.01), and lower 246-nm CD levels (P < 0.05). Plasma concentration of uric acid was significantly lower in patients with type 1 diabetes than in control subjects (3.3 +/- 0.3 vs. 4.3 +/- 0.2 mg/dl; P = 0.009) with a significant difference between women and men with type 1 diabetes (2.6 +/- 0.3 vs. 3.9 +/- 0.3, respectively; P = 0.009)., Conclusions: Our findings suggest that reduced antioxidant activity and increased oxidative stress occur early after the diagnosis of type 1 diabetes, especially in women, and this might explain, at least in part, the increased susceptibility of diabetic women to cardiovascular complications.