Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice.

The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic 'swings'. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named 'V') and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named 'S') for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.

Estrogen-progestin therapy in women after stem cell transplant: our experience and literature review.

Women undergoing stem cell transplantation (SCT) are mostly young and have more than 90% probability of ovarian failure, which is often permanent. A woman's age, use of radiotherapy and alkylating chemotherapy, and the allogeneic type of transplant are associated with a higher rate of premature ovarian failure and worse residual ovarian function. Premature ovarian failure has serious systemic and psychological effects that may need treatment and should be managed by practitioners trained to treat this particular population of women. Ultrasonographic evidence of ovarian follicles is often associated with a future resumption of cycles, but there are no serum markers to predict the return of ovarian function in these patients. In our center, the rate of ovarian function recovery was 7% after allogeneic SCT and 25% after autologous SCT (P<0.05). There are no guidelines on how to manage premature ovarian failure induced by myeloablative treatments followed by SCT. Because of the likelihood of the need for long-lasting estrogen plus progestin therapy (EPT) and the increased risk of secondary neoplasia after SCT, the EPT should be as physiological as possible. In our experience, the cyclical sequential combination of estradiol (2 mg daily) plus dydrogesterone (10 mg for 14 d/mo) was associated with excellent compliance because of its simple administration and few adverse effects. Such a treatment led to a dramatic improvement in vasomotor, urogenital, and psychological symptoms related to estrogen deficiency. However, in the allogeneic transplantation setting, up to 25% of women may suffer from gynecological chronic graft-versus-host disease, which may become apparent as hematocolpometra after introduction of EPT. Thus, accurate pretreatment evaluation and frequent monitoring during treatment are required. Moreover, EPT absorption may be reduced in patients who received allotransplants and have gastrointestinal or skin chronic graft-versus-host disease.

Severe leucopenia associated with Sitagliptin use.

We report the case of a type 2 diabetes subject who developed severe leucopenia associated with treatment with the dipeptidil-peptidase 4 enzyme inhibitor Sitagliptin and highlights DPP4 inhibitors as a possible cause of unexplained hematolgical abnormalities in patients receiving DPP4-inhibitor treatment.

Association between osteoprotegerin G1181C and T245G polymorphisms and diabetic charcot neuroarthropathy: a case-control study.

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.

Hypouricemia linked to an overproduction of nitric oxide is an early marker of oxidative stress in female subjects with type 1 diabetes.

OBJECTIVE: The aim of this study is to verify whether, early in the course of type 1 diabetes and assuming hyperglycemia as the only risk factor, women demonstrate a change in oxidative status due to an interaction between nitric oxide (NO) and uric acid production. METHODS: Thirty-eight women with type 1 diabetes of less than 10 years' duration and with no diabetic complications were compared with 25 matched healthy female controls. Insulin, C-peptide, NO, HbA(1c) and oxidative stress metabolites were determined from venous blood samples taken from all patients after a 12 h overnight fast. Urine samples were used for urinary uric acid determination. RESULTS: Most oxidative stress metabolites were significantly increased (p < 0.0001), while plasmatic and urinary uric acid levels were significantly lower (p < 0.0001) in patients with type 1 diabetes compared with controls. Mean NO levels were inversely related to uricemia. Bivariate regression analysis showed a significant correlation between plasmatic uric acid and NO (p = 0.004), ascorbic acid (p = 0.042), triglycerides (p = 0.014) and HbA(1c) (p < 0.0001). Linear multivariate regression analysis showed a significant relationship between HbA(1c) and plasmatic uric acid (beta = - 0.465, p = 0.0004). CONCLUSIONS: Oxidative stress is already present in the early stages of type 1 diabetes. We conclude that the initial increase in oxidative stress could be linked to a reduction in plasmatic levels of uric acid, which is probably directly caused by an overproduction of NO.

Association between cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: effect of beta-blockade.

AIMS: To assess the relationship between cardiac autonomic dysfunction and inflammation in patients with type 1 diabetes and whether beta-blocker therapy might improve both abnormalities in these patients. METHODS AND RESULTS: We studied 49 patients with type 1 diabetes (age 50.5 +/- 11 years, 33 men). Serum levels of high-sensitivity C-reactive protein, as a marker of inflammation, and frequency-domain heart rate variability (HRV) on 24 h Holter monitoring, as a measure of cardiac autonomic function, were assessed in all patients. Twenty-one patients with depressed HRV were subsequently randomized to receive atenolol (50 mg daily) or no-beta-blockade. HRV and C-reactive protein were re-assessed after 3-4 weeks from randomization. An inverse correlation was found between C-reactive protein levels and HRV parameters, with the highest r coefficient shown with low-frequency (LF) power (r = -0.38; P = 0.007). Furthermore, C-reactive protein serum levels were significantly higher in patients with bottom quartile values of LF power compared with patients with values in the three top quartiles (4.64 +/- 2.8 vs.1.79 +/- 1.6 mg/L, respectively; P = 0.003), also after adjustment for potential confounding variables (P = 0.013). HRV parameters improved significantly in patients treated with atenolol, but not in the no-atenolol group. Furthermore, C-reactive protein levels decreased in the beta-blockade group, but not in the no-beta-blockade group (P = 0.04 for changes between groups). CONCLUSION: In type 1 diabetic patients, serum C-reactive protein levels are significantly associated with depressed HRV; the favourable effects of beta-blockade on both HRV parameters and C-reactive protein serum levels suggest that autonomic nervous system may have significant modulator effects on inflammation.