Glucose tolerance and cardiovascular risk biomarkers in non-diabetic non-obese obstructive sleep apnea patients: Effects of long-term continuous positive airway pressure.

BACKGROUND: Insulin resistance, glucose dyshomeostasis and oxidative stress are associated to the cardiovascular consequences of obstructive sleep apnea (OSA). The effects of a long-term continuous positive airway pressure (LT-CPAP) treatment on such mechanisms still remain conflicting. OBJECTIVE: To investigate the effect of LT-CPAP on glucose tolerance, insulin sensitivity, oxidative stress and cardiovascular biomarkers in non-obese non-diabetic OSA patients. PATIENTS & METHODS: Twenty-eight apneic, otherwise healthy, men suffering from OSA (mean age = 48.9 ± 9.4 years; apnea-hypopnea index = 41.1 ± 16.1 events/h; BMI = 26.6 ± 2.8 kg/m(2); fasting glucose = 4.98 ± 0.37 mmol/L) were evaluated before and after LT-CPAP by an oral glucose tolerance test (OGTT), measuring plasma glucose, insulin and proinsulin. Glycated hemoglobin, homeostasis model assessment resistance insulin, blood lipids, oxidative stress, homocysteine and NT-pro-brain natriuretic peptide (NT-proBNP) were also measured. RESULTS: LT-CPAP treatment lasted 13.9 ± 6.5 months. At baseline, the time spent at SaO2<90%, minimal and mean SaO2 were associated with insulin area under the curve during OGTT (r = 0.448, P = 0.011; r = -0.382; P = 0.047 and r = -0.424; P = 0.028, respectively) and most other glucose/insulin homeostasis biomarkers, as well as with homocysteine (r = 0.531, P = 0.006; r = -0.487; P = 0.011 and r = -0.409; P = 0.034, respectively). LT-CPAP had no effect on all the OGTT-related measurements, but increased plasma total antioxidant status (+7.74%; P = 0.035) in a duration-dependent manner (r = 0.607; P < 0.001), and decreased both homocysteine (-15.2%; P = 0.002) and NT-proBNP levels (-39.3%; P = 0.002). CONCLUSIONS: In non-obese non-diabetic OSA patients, nocturnal oxygen desaturation is strongly associated to insulin resistance. LT-CPAP does not improve glucose homeostasis nor insulin sensitivity but has a favorable effect on antioxidant capacity and cardiovascular risk biomarkers.

Impact of flexible insulin therapy on blood glucose variability, oxidative stress and inflammation in type 1 diabetic patients: the VARIAFIT study.

AIMS: HbA1c only partially predicts vascular risk in patients with type 1 diabetes (T1D), and a role for blood glucose variability (BGV) is a matter of debate. For this reason, this study investigated the impact of an educational programme of flexible insulin therapy (FIT) on BGV and oxidative stress. METHODS: Tests were conducted on 30 adult T1D patients in a prospective, single-centre trial at baseline (M0), and at 3 and 6 months (M3 and M6, respectively) of the FIT programme to determine BGV, as reflected by mean amplitude of glycaemic excursions (MAGE), low blood glucose index (LBGI), lability index (LI), average daily risk range (ADRR), glycaemic lability (scored by two diabetologists), urinary leukotriene E4 (LTE4), 11-dehydro-thromboxane B2 (TXB2) and 8-iso-prostaglandin F2α (PGF2). RESULTS: HbA1c (7.7 ± 0.9%), ADRR, MAGE, LBGI and LI did not change from M0 to M3 and M6, although ADRR and LBGI significantly improved at M3 and M6 in patients with the highest baseline indices (≥ 40 and ≥ 5, respectively). TXB2 declined at M6 (832 ± 625 vs. 633 ± 972 pg/mg; P=0.048), whereas LTE4 and PGF2 remained stable. ADRR showed the strongest correlation with glycaemic lability scores at all visits (r≥0.84, P<0.0001). CONCLUSION: A FIT educational programme improved BGV only in patients with the highest baseline variability, and led to no changes in HbA1c, while ADRR closely correlated with glycaemic lability score. Our data do not support a relationship between BGV and oxidative stress in T1D patients, although the impact of variability on TXB2 deserves further investigation (ClinicalTrials.gov NCT00973492).

Telemedicine and type 1 diabetes: is technology per se sufficient to improve glycaemic control?

AIM: In the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA1c? METHODS: Each patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as "high users" if the proportion of "informed" meals using the IDA exceeded 67% (median) and as "low users" if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA1c levels. RESULTS: Among the high users, the proportion of informed meals remained stable from baseline to the end of the study 6months later (from 78.1±21.5% to 73.8±25.1%; P=0.107), but decreased in the low users (from 36.6±29.4% to 26.7±28.4%; P=0.005). As expected, HbA1c improved in high users from 8.7% [range: 8.3-9.2%] to 8.2% [range: 7.8-8.7%] in patients with (n=26) vs without (n=30) the benefit of telemonitoring/teleconsultation (-0.49±0.60% vs -0.52±0.73%, respectively; P=0.879). However, although HbA1c also improved in low users from 9.0% [8.5-10.1] to 8.5% [7.9-9.6], those receiving support via teleconsultation tended to show greater improvement than the others (-0.93±0.97 vs -0.46±1.05, respectively; P=0.084). CONCLUSION: The Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.

Adverse effects and safety of SGLT-2 inhibitors.

In type 2 diabetes (T2DM), glycaemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM. The available data suggest a good tolerability profile for the three available drugs - canagliflozin, dapagliflozin and empagliflozin - approved by the US Food and Drug Administration (FDA) for the American market as well as in other countries. The most frequently reported adverse events with SGLT-2-i are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to SGLT-2-i declines with increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate-to-severe renal dysfunction. Most patients treated with SGLT-2-i also have a modest reduction in blood pressure and modest effects on serum lipid profiles, some of which are beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others which are not (increased low-density lipoprotein cholesterol, LDL-C). A number of large-scale and longer-term cardiovascular trials are now ongoing. In patients treated with dapagliflozin, a non-significant excess number of breast and bladder cancers has been reported; considered as due to a bias, this is nevertheless being followed in the ongoing trials. No other significant safety issues have been reported so far. Although there is some benefit for several cardiovascular risk factors such as HbA1c, high blood pressure, obesity and increases in LDL-C, adequately powered trials are still required to determine the effects of SGLT-2-i on macrovascular outcomes.

Metabolic disturbances after acute vascular events: a comparative study of acute coronary syndrome and ischaemic atherothrombotic stroke.

OBJECTIVE: This pilot study aimed to compare metabolic disturbances, particularly insulin resistance (IR) and cardiovascular risk factors (CRFs), following two types of acute vascular atherothrombotic disease events: ischaemic atherothrombotic stroke (AS); and acute coronary syndrome (ACS). DESIGN AND METHODS: A total of 110 non-diabetic patients presenting with either AS (n=55) or ACS (n=55) were included in our prospective comparative study, and matched for age and gender. IR was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR) method, and each patient's personal and family history were also recorded. RESULTS: IR was significantly higher in the ACS vs AS group (HOMA-IR index 2.17±1.90 vs 1.50±0.81, respectively; P=0.03). The AS group had a significantly higher prevalence of personal history of hypertension (51% vs 31%; P=0.03), while current smoking was more prevalent in the ACS group (30% vs 18%; P=0.04). There were no significant differences between the two groups as regards any other CRFs. CONCLUSION: The distribution of CRFs varied depending on the vascular event, and metabolic disturbances differed according to the atherothrombotic disease. IR was greater after ACS than AS.

WHO-5, a tool focusing on psychological needs in patients with diabetes: the French contribution to the DAWN study.

AIM: In 2001, the international Diabetes Attitudes, Wishes and Needs (DAWN) programme was launched to evaluate the psychosocial impact of diabetes. In France, DAWN experts carried out an observational study to further understand the impact of diabetes on the psychological well-being of people with diabetes, using the French version of the WHO-5 questionnaire. METHODS: The WHO-5, a unidimensional five-item questionnaire that measures positive psychological well-being, was completed by 2213 patients (1670 with diabetes). A total sum score was calculated, ranging on a scale from 0 to 25. A score less than 13 indicated impaired well-being and a score less than 8 reflected likely depression. RESULTS: The mean total well-being score for the whole study population was 14.1±5.5, and 14.3±5.5 for patients with diabetes and 13.5±5.4 for patients with other chronic diseases. The average score for patients with diabetes only (15.1±5.2) was higher than those for the other subgroups (P=0.005), whereas the average scores for those using insulin (14.8±5.2) and women with diabetes (13.2±5.6) were significantly lower compared with the whole diabetic group (15.6±5.1 [P=0.03] and 15±5.2 [P<0.001], respectively). CONCLUSION: The WHO-5 questionnaire showed satisfactory psychometric properties in a large sample of French diabetic patients. The scale is unidimensional and highlighted differences in well-being, which was lower in diabetic women, in patients with other chronic diseases and in those treated with insulin.

Type 2 diabetes treatment intensification in general practice in France in 2008-2009: the DIAttitude Study.

AIMS: To evaluate the current procedures in French general practice of intensifying hypoglycaemic treatment in orally treated type 2 diabetic patients, according to the French recommendations. METHODS: Type 2 diabetic patient characteristics, HbA(1c) values, hypoglycaemic treatment and physician characteristics were collected from the electronic records of a panel of French general practitioners. Factors associated with the time until intensification of treatment were studied with the Cox model. RESULTS: Among 17 493 orally treated patients with at least two available HbA(1c) values, 3118 patients (18%) required treatment intensification; 65% were on monotherapy, 31% on bitherapy and 4% on tritherapy. These patients were followed for a maximum of 14 months or until treatment was intensified. Treatment was intensified after the second high HbA(1c) value for 1212 patients (39%); this was immediate for 13% of these patients, within 6 months for 39% and within one year for 59%. Treatment intensification was less likely the older the patient, and more likely the higher the first HbA(1c) value, up to an HbA(1c) threshold of 9%. CONCLUSIONS: Therapeutic inertia in caring for type 2 diabetic patients in France is frequent, at least for patients treated in general practice. This inadequate glycaemic control would be expected to have significant patient and public health consequences, with higher rates of associated diabetic complications.

Therapeutic management of orally treated type 2 diabetic patients, by French general practitioners in 2010: the DIAttitude Study.

AIM: To describe the behaviour of French general practitioners (GP) regarding intensification of hypoglycaemic agents in orally treated type 2 diabetic (T2D) patients, according to their HbA(1c) level. METHODS: General practitioners were recruited from a panel of office-based general practitioners. T2D patients who had been orally treated for at least 6 months were included in the study; their characteristics were recorded, and their HbA(1c) values and hypoglycaemic treatments over the previous 24 months extracted from electronic records The major reasons for intensification (or no intensification) of hypoglycaemic agents were recorded at the inclusion visit. RESULTS: A total of 236 general practitioners recruited 2109 T2D patients: 1732 had at least one HbA(1c) value recorded in the previous 6 months, and 52%, 33% and 14% had been treated, with oral hypoglycaemic agents in monotherapy, bitherapy or tri-or quadritherapy, respectively. Of these patients, 702 (41%) remained uncontrolled (47%, 39% and 20% respectively) and according to the current French guidelines needed treatment intensification. Only 46 (7%) had their treatment intensified at inclusion. Of those without intensified treatment, 60% were treated with monotherapy; the main reason given by the general practitioners for not intensifying treatment was a satisfactory HbA(1c) level (53%), although 32% had an HbA(1c)>7%. Other reasons were: lifestyle advice had greater priority (20%); decision was postponed until the next visit (11%); HbA(1c) had decreased since last visit (7%; not confirmed by available data in 58% of cases); a medical priority other than diabetes (6%) and other reasons related to the patient (3%). CONCLUSION: For T2D patients managed by French general practitioners, guidelines are not consistently followed: HbA(1c) should be monitored more frequently and treatment adjusted according to HbA(1c) levels.

A real-life study of the use, effectiveness and tolerability of rosiglitazone in France: the AVANCE study.

AIM: The study aimed to determine the effectiveness and tolerability of rosiglitazone, and its profile in terms of treatment adherence, treated patients and prescribing recommendations under everyday conditions of care. METHODS: This was a "real-life" observational longitudinal study including patients with type 2 diabetes mellitus (T2DM) starting treatment with rosiglitazone and followed for up to 2 years. A questionnaire was completed at the time of inclusion and during routine consultations at around 6, 12, 18 and 24 months following inclusion. Information was collected on sociodemographics, clinical history, treatments, co-morbidities, laboratory data and compliance with treatment. There were three primary outcome measures: treatment response (defined as an HbA1c ≤ 8.0% or a decrease in HbA1c ≥ 0.7%); switch to insulin (as considered necessary by the physician); and occurrence of adverse events requiring a change or discontinuation of treatment. RESULTS: The evaluation included 670 patients (61.1%) treated with rosiglitazone/metformin as fixed-dose combination tablets and 427 (38.9%) with standard rosiglitazone tablets. Rates of HbA1c response, defined as an HbA1c less than or equal to 8.0% or a decrease in HbA1c greater than or equal to 0.7%, ranged from 80.6% to 92.1% depending on the follow-up time. The percentage of patients with an HbA1c less than 7% was 18.4% before rosiglitazone was prescribed, and ranged from 48.2% to 57.8% depending on the follow-up period. Sixty-two patients (6.1%, 95% CI: 4.6-7.6%) switched to insulin therapy during the follow-up period. Spontaneously reported adverse events leading to a change or discontinuation of treatment were seen in 45 patients (4.4%, 95% CI: 3.2-5.6%). CONCLUSION: Rosiglitazone showed sustained efficacy, with around 90% of patients defined as responders to the treatment in terms of reduction in HbA1c, and was relatively well tolerated. The adverse-event profile was consistent with the known effects of rosiglitazone, and no signs of increased cardiovascular ischaemic risk were observed. These results are in agreement with previous studies on rosiglitazone.

Protection of pancreatic INS-1 ß-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin.

Hyperglycemia is detrimental to ß-cell viability, playing a major role in the progression of ß-cell loss in diabetes mellitus. The permeability transition pore (PTP) is a mitochondrial channel involved in cell death. Recent evidence suggests that PTP inhibitors prevent hyperglycemia-induced cell death in human endothelial cells. In this work, we have examined the involvement of PTP opening in INS-1 cell death induced by high levels of glucose or fructose. PTP regulation was studied by measuring the calcium retention capacity in permeabilized INS-1 cells and by confocal microscopy in intact INS-1 cells. Cell death was analyzed by flow cytometry. We first reported that metformin and cyclosporin A (CsA) prevented Ca²+-induced PTP opening in permeabilized and intact INS-1 cells. We then showed that incubation of INS-1 cells in the presence of 30 mM glucose or 2.5 mM fructose induced PTP opening and led to cell death. As both metformin and CsA prevented glucose- and fructose- induced PTP opening, and hampered glucose- and fructose- induced cell death, we conclude that PTP opening is involved in high glucose- and high fructose- induced INS-1 cell death. We therefore suggest that preventing PTP opening might be a new approach to preserve ß-cell viability.

Impact of diabetes mellitus on clinical presentation and prognosis of pancreatic cancer.

INTRODUCTION: The aim of this study was to investigate possible effects of diabetes mellitus on clinical manifestations and prognosis of pancreatic cancer (PC). PATIENTS AND METHODS: We retrospectively reviewed the clinical files of 122 patients with PC, and divided them into two groups: those with diabetes (56 patients) and those without diabetes (66 patients). The two groups were then compared for demographic profiles, clinical manifestations of PC, features of the tumor and fatal outcomes. RESULTS: Mean age, sex distribution, body mass index at cancer diagnosis, prevalence of hypertension, dyslipidemia, weight loss, abdominal pain, lumbar pain, signs of dyspepsia, and size, and histological features of the tumor were similar between the two groups. The cancer was located in the head of the pancreas in 50% of those with diabetes, and 80% of those without diabetes (P=0.04). The median survival time was similar. CONCLUSIONS: Clinical features, tumor size and prognosis of PC are similar in people with and without diabetes. Having diabetes does not seem to contribute to earlier diagnosis of PC.

Basal insulin dose in 40 type 1 diabetic patients remains stable 1 year after educational training in flexible insulin therapy.

AIM: Basal insulin dose (BID) determination is the key to successful flexible insulin therapy (FIT). As our hypothesis was that BID changes over time, the primary objective of the present study was to determine the changes in BID 1 year after a therapeutic educational programme on FIT. METHODS: This single-centre retrospective study recruited the first 40 type 1 adult diabetic patients undergoing an educational FIT programme, which was conducted over a 4-day hospital stay and included a carbohydrate-fasting test. RESULTS: Patients' BIDs decreased between Day 0 and Day 4 after the programme (0.31±0.11IU/kg/day vs 0.27±0.09IU/kg/day; P<0.0001), and was increased at 1 year (0.29±0.09IU/kg/day; P=0.004). There was no significant variation in prandial insulin requirements. A tendency toward a reduction in HbA(1c) was observed at 1 year (8.3±1.4% vs 8.1±1.6%; P=0.075), with a decrease by more than 0.5% in 37.5% of patients. Body weight increased at 1 year (66.9±10.4 kg vs 68.1±10.7 kg; P=0.003), and the gain was greater than 5% in 7.5% of patients. Frequency of mild hypoglycaemia either remained stable (40%) or decreased (30%). Only nine patients (baseline HbA(1c) 8.03±1.7%, baseline BID 0.27±0.09IU/kg/day) had BID increases more than 20%, with no changes in prandial insulin requirements and no distinctive phenotype. Baseline HbA(1c), and BID have an impact on the BID at 1 year of approximately 0.3IU/kg/day in most patients. CONCLUSION: The stability of BID over 1 year, with values close to 0.3IU/kg/day associated with a trend towards improvement in HbA(1c), reduction in the frequency of mild hypoglycaemic episodes and absence of major weight gain, supports the relevance of FIT educational training.

Information and therapeutic education of diabetic patients in French hospitals: the OBSIDIA survey.

AIM: Although several studies have evaluated the efficacy of therapeutic education (TE) programmes in patients with diabetes and demonstrated the benefits of such interventions, operational aspects are rarely described. For this reason, this national survey was conducted to investigate TE in France, and to identify its obstacles and needs. METHODS: A preliminary qualitative phase was extended to include a quantitative survey through face-to-face interviews, followed by a web-based self-administered questionnaire sent out to every healthcare professional dealing with diabetic patients. RESULTS: From the expanded web-based survey, 272 questionnaires were analyzed (39% from academic hospitals, 54% from general hospitals and 7% from private clinics); 85% of these sites provided TE for inpatients. Overall, TE was offered to 66% of patients (84% new patients) and was individualized in 55% of cases, and involved 9.4 healthcare professionals on average, with physicians, nurses and dietitians making up the core team. The TE offered encompassed a wide range of diabetes topics. However, of every 10 healthcare professionals, only 35% received specific training, while 45% received coaching from their colleagues and 10% received no training at all. Evaluation of TE was carried out in 60% of teams by questionnaires or interviews. CONCLUSION: TE is well implemented in French hospitals, but lacks homogeneity and standardization. Training is inadequate from both qualitative and quantitative points of view, and evaluation of TE procedures needs to be developed. There is also a need for more funding and dedicated qualified staff, a lack of which is partly due to the fact that TE is not a recognized medical activity in hospitals.

How patients' attitudes and opinions influence self-care behaviours in type 2 diabetes. Insights from the French DIABASIS Survey.

AIM: This study evaluated the profiles of patients with type 2 diabetes (T2DM) to identify sets of opinions and attitudes towards the disease that might influence self-care behaviours. METHODS: Altogether, 1,092 patients with T2DM, aged 45 or older from a large representative French cohort, completed a self-questionnaire exploring their knowledge and perceptions of diabetes, its impact on various aspects of daily life and self-management practices. Canonical and cluster analyses were used to identify sets of homogeneous 'profiles' of patients linking attitudes and opinions to specific disease-related behaviours (such as changes in lifestyle, drug compliance, treatment satisfaction, impact on everyday life and weight gain). RESULTS: Demographics of the T2DM study population were previously reported along with the main results (60% male; mean age: 66 years; mean age at diagnosis: 55 years; mean BMI: 29kg/m(2)). Five distinct patient types emerged from the typological approach: 'committed' (25%); 'carefree' (23%); 'bitter' (19%); 'disheartened' (19%); and 'overwhelmed' (15%). Each patient type defined a set of attitudes and beliefs towards T2DM that influenced disease-related behaviours, leading to different degrees of diabetes self-management. CONCLUSION: The DIABASIS survey provides important information for diabetes care by identifying distinct patients' profiles that express different degrees of difficulty in implementing self-management. For this reason, patients in each category require different kinds of customized support from their physician to induce behavioural changes that may be key in improving their metabolic control.