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).

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.

[Study of a detection strategy for silent ischemia in diabetic patients: 18 month follow-up of the ARCADIA register]. / Etude d'une stratégie de détection de l'ischémie silencieuse chez les patients diabétiques: suivi à 18 mois du registre ARCADIA.

BACKGROUND: The prognostic impact of a myocardial ischemia-based therapeutic program in asymptomatic diabetic patients remains controversial. We prospectively assessed the benefit of a stratification algorithm based upon clinical and myocardial perfusion imaging (MPI) data on cardiovascular events in such patients in a non-randomized register. METHOD: 701 consecutive asymptomatic diabetic patients were classified to be at low or intermediate-to-high cardiac risk according to 13 simple boil-clinical parameters. Intermediate-to-high risk patients were scheduled for MPI and underwent either a conventional (Group 1, n=180) or an intensive multifactorial (Group 2, n=245) therapeutic program. Low risk patients (Group 3, n=276) underwent no specific management. RESULTS: At the end of the survey and as a consequence of intensive management, lipid lowering therapy, antiplatelet drugs, and beta-blockers were more often prescribed in Group 2 than in Group 1 (55, 31 and 17% versus 36, 23, and 8% respectively, p<0.01). Planned coronary angiography in case of severe ischemia on MPI and revascularization were more frequent in Group 2 (16.2 and 8.9%) than in Group 1 (8.0 and 2.8% - p<0.01). At 19-month follow-up (96.7% completed), major event rate in Group 2 was significantly lower than in Group 1 (3.9 versus 9.8%, p<0.01) and similar to that of Group 3 (2.2%, NS). CONCLUSION: Easy-to-perform risk stratification is able to select diabetic patients with good medium-term prognosis. In clinically selected higher risk patients, an intensive medical therapy combined with coronary angiography +/- revascularization in case of large ischemia on MPI is effective to improve prognosis.

Effects of a myocardial ischaemia-guided therapeutic program on survival and incidence of coronary events in asymptomatic patients with diabetes: the ARCADIA study.

AIM: To assess the prognostic impact of a therapeutic program based on bioclinical risk-stratification and myocardial-perfusion-imaging (MPI) data on survival and the occurrence of coronary events (CE=death+myocardial infarction) in asymptomatic patients with diabetes. METHOD: Five hundred twenty one consecutive asymptomatic diabetic outpatients were prospectively enrolled and clinically classified as being at either low or high cardiac risk. All high-risk patients (n=245, age 61+/-9 years) underwent MPI and an intensive multifactorial medical therapeutic program, including anti-ischaemic agents in cases of moderate ischemia; a coronary angiography was performed in all high-risk patients with severe ischaemia (n=38), followed by immediate revascularization if necessary (n=21). Low-risk patients (n=276, age 57+/-9 years) underwent medical management of their risk factors. RESULTS: At the 19-month (median) follow-up (range, 12-36 months), both high- and low-risk patients showed similarly low CE rates (2.3% and 1.5% per year, respectively; age- and gender-adjusted log-rank P=NS). None of the patients who underwent myocardial revascularization experienced any CEs, and none of the low-risk patients died during follow-up. The negative predictive value of first-line bioclinical stratification was 0.98 for the occurrence of CEs, and 0.95 when low-risk patients were combined with high-risk patients who had normal MPI findings. CONCLUSIONS: Bioclinical first-line stratification allows identification of diabetic patients who have a good medium-term cardiac prognosis. The CE rate is similar in selected high-risk asymptomatic patients with diabetes using an intensive MPI-guided program that combines medical therapy, coronary angiography in the 16% of cases with severe ischemia and, if appropriate, revascularization.

One-year efficacy and safety of Web-based follow-up using cellular phone in type 1 diabetic patients under insulin pump therapy: the PumpNet study.

AIM: Conventional follow-up of type 1 diabetic patients treated with continuous subcutaneous insulin infusion (CSII) was compared with intensive coaching using the Web and the cellular phone network for retrospective data transmission and short message service (SMS). METHODS: Thirty poorly controlled patients (HbA1c 7.5-10%) were enrolled in a bicenter, open-label, randomized, 12-month, two-period, crossover study. After a 1-month run-in period, 15 patients were randomly assigned to receive weekly medical support through SMS based upon weekly review of glucose values, while 15 patients continued to download self-monitored blood glucose (SMBG) values on a weekly basis without receiving SMS. After 6 months, patients crossed over to the alternate sequence for 6 additional months. Visits at the clinic were maintained every 3 months. RESULTS: Patients with long-standing inadequately controlled diabetes (24 +/- 13 years) were included. A non-significant trend to reduction in HbA(1c) (-0.25+/-0.94%, P<0.10) and mean glucose values (-9.2+/-25 mg/dl, P=0.06) during the 6-month SMS sequence was observed as compared with the no-SMS period. No safety issue (hypoglycemia, glucose variability) was reported. Adherence to SMBG was not affected by the trial. Quality of life analysis suggests a significant improvement in DQOL global score, as well as the DQOL satisfaction with life subscale, during the SMS sequence. CONCLUSIONS: Long-term telemedical follow-up of insulin pump-treated patients using a cellular phone-, SMS- and Web-based platform is feasible, safe, does not alter quality of life and associated with a trend toward improved metabolic control.

Variations of ambulatory blood pressure with position in patients with type 1 diabetes: influence of disease duration and microangiopathy in a pilot study.

OBJECTIVE: To study the influence of position changes on 24-h ambulatory blood pressure (ABP) in normotensive or mildly hypertensive normoalbuminuric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A cross-sectional evaluation of patients was staged according to the duration of diabetes (DD) and the presence of microangiopathy. We recruited 37 patients (30 men and 7 women), aged 38 +/- 12 years, who were normotensive or mildly hypertensive (diastolic blood pressure [DBP] <105 mmHg) and free of antihypertensive treatment and microalbuminuria. They were included according to DD (group 1, <5 years; group 2, > or =10 years). An additional group of seven diabetic patients with microalbuminuria and mild untreated hypertension was also investigated. We recorded 24-h ambulatory blood pressure every 15 min with a position sensor, which allowed for the discrimination between standing or supine/sitting position in the patient. RESULTS: Mean daytime (10:00 A.M. to 8:00 P.M.) ABP in supine/sitting position did not significantly differ between groups 1 and 2. However, standing ambulatory systolic blood pressure (ASBP) and ambulatory DBP (ADBP) were significantly higher than supine/sitting ASBP and ADBP in group 1 (DeltaSBP 4 +/- 5, DeltaDPB 4 +/- 6 mmHg, P < 0.01) but not in group 2 (DeltaSBP 2 +/- 8, DeltaDBP 2 +/- 4 mmHg, P = NS). Patients free of microangiopathy presented with significantly higher ABP in standing position than in sitting/lying position, whereas patients with retinopathy and/or nephropathy exhibited no significant increase of ABP during standing. CONCLUSION: The monitoring of position during ambulatory measurement of blood pressure in type 1 diabetic patients shows different patterns in relation to disease duration and the presence of microangiopathy.

Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels.

OBJECTIVE: In patients with type 2 diabetes, a normal HDL cholesterol level does not rule out that LDL particles may be small. Although techniques for analyzing LDL subfractions are not likely to be used in clinical practice, a prediction of LDL size based on a regular lipid profile may be useful for assessment of cardiovascular risk. RESEARCH DESIGN AND METHODS: Sixty patients with type 2 diabetes with acceptable glycemic control and an HDL cholesterol level > or = 1 mmol/l were recruited after cessation of lipid-altering treatments. LDL size was determined by 2-20% PAGE; patients having small LDL (n = 30) were compared with those having intermediate or large LDL (n = 30). RESULTS: Clinical characteristics, pharmacological therapies, lifestyle, and prevalence of diabetes-related complications were similar in both patient groups. LDL size correlated negatively with plasma triglycerides (TGs) (R2 = 0.52) and positively with HDL cholesterol (R2 = 0.14). However, an inverse correlation between the TG-to-HDL cholesterol molar ratio and LDL size was even stronger (R2 = 0.59). The ratio was > 1.33 in 90% of the patients with small LDL particles (95% CI 79.3-100) and 16.5% of those with larger LDL particles. A cutoff point of 1.33 for the TG-to-HDL cholesterol ratio distinguishes between patients having small LDL values better than TG cutoff of 1.70 and 1.45 mmol/l. CONCLUSIONS: The TG-to-HDL cholesterol ratio may be related to the processes involved in LDL size pathophysiology and relevant with regard to the risk of clinical vascular disease. It may be suitable for the selection of patients needing an earlier and aggressive treatment of lipid abnormalities.

[Atherosclerosis and arteriosclerosis of the small vessels in chronic renal insufficiency and after transplantation: lipid factors]. / Athérosclérose et artériosclérose des petits vaisseaux chez l'insuffisant rénal chronique et après transplantation: facteurs lipidiques.

The prevalence of lipid abnormalities is very high in patients with impaired renal function and after transplantation. Coronary heart disease (CHD) morbidity and mortality are impressive in these patients. No prevention study using lipid lowering agents is available in this population. Thus recommendations are still based on pathophysiological data or extrapolated from the results reported in prevention studies from kidney disease-free subjects. The treatment of hyperlipidemia can be recommended considering the expected reduction of events due to CHD. The lipid targets may be those recommended in other high risk patients: LDL-cholesterol < 120 mg/dl and triglycerides < 150 mg/dl. Unfortunately, the use of both statins and fibrates noteworthy is under restraint in case of renal failure and immunosuppressive therapy. Prospective clinical trials are needed to demonstrate the effect of lipid lowering on the course of chronic renal failure and graft dysfunction.

ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM?

BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients.

Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.

OBJECTIVE: To compare 24-h ABP in normotensive type 1 diabetic patients with and without microalbuminuria. RESEARCH DESIGN AND METHODS: The study was a retrospective comparison of cases and matched control subjects. The first phase included 35 type 1 diabetic patients, normotensive by OMS criteria. The 23 patients with normoalbuminuria (< 15 micrograms/min) were compared with 12 patients with microalbuminuria (> or = 15 micrograms/min). In the second phase, the 12 microalbuminuric patients were paired by sex- and age-matched with 12 normoalbuminuric patients and 12 nondiabetic healthy control subjects. We measured casual systolic and diastolic BP and HR, 24-h ABP and AHR (recorded with a Spacelabs automatic recorder), and microalbuminuria. RESULTS: No correlation between microalbuminuria and casual BP was observed. Microalbuminuria was correlated significantly with diastolic 24-h APR and nocturnal systolic and diastolic ABP (r = 0.35, 0.38, and 0.33, respectively; P < 0.05) and with AHR during all time periods (24-h, r = 0.46; day, r = 0.39; night, r = 0.39; P < 0.05). Normo- and microalbuminuric patients did not differ in casual BP and HR. However, microalbuminuric patients had a significant increase in systolic 24-h ABP (119.1 +/- 8.2 vs. 113.1 +/- 8.1, P = 0.05), diastolic 24-h ABP (74.9 +/- 7.5 vs. 70.2 +/- 5.7, P = 0.04), nocturnal systolic ABP (112.8 +/- 7.1 vs. 105.8 +/- 7.9, P = 0.01), and AHR during all time periods. The same results were observed when patients were paired by age and sex. CONCLUSIONS: Normotensive microalbuminuric type 1 patients, although strictly comparable with normoalbuminuric patients for casual BP and HR, have an increased ABP and HR, especially during the night. This difference might reflect dysautonomia. Ambulatory measurement of BP and HR is more appropriate than casual measurements in hemodynamic studies of incipient diabetic nephropathies and could be proposed as an interesting tool for an early prediction of diabetic nephropathy.

Acromegaly due to a growth hormone-releasing hormone-secreting bronchial carcinoid tumor: further information on the abnormal responsiveness of the somatotroph cells and their recovery after successful treatment.

UNLABELLED: We studied GH secretion in a patient with acromegaly and a bronchial carcinoid tumor before and again after surgical removal of this tumor. Before removal of the carcinoid tumor, plasma GH increased slightly after glucose loading (OGTT) and markedly after TRH (650%) and insulin (440%) treatment. Plasma GH did not change after GH-releasing hormone (GHRH), LHRH, or L-dopa administration. Somatostatin (SRIH) infusion lowered plasma GH. No change in plasma immunoreactive GHRH (IR-GHRH) occurred after TRH, glucose, insulin, or SRIH administration. Two weeks after removal of the carcinoid tumor, TRH induced GH secretion (250%) when the IR-GHRH level was undetectable and somatomedin-C was within normal limits. Fifteen weeks after surgery, the patient had normal GH secretion. IN CONCLUSION: no pattern of GH secretion is diagnostic of acromegaly due to ectopic GHRH secretion, but the lack of GH response to exogenous GHRH and a large response during hypoglycemia may be features of this condition. When acromegaly and abnormal GH responsiveness are induced by a GHRH-secreting tumor, the increases in plasma GH after TRH, glucose, and insulin administration are not mediated by GHRH. After removal of the GHRH-secreting tumor, persistent paradoxical GH response to TRH does not require abnormally high IR-GHRH levels and does not preclude complete recovery.

Pattern of plasma levels of cortisol, dehydroepiandrosterone and pregnenolone sulphate in normal subjects and in patients with homozygous familial hypercholesterolaemia during ACTH infusion.

The aim of this study was to determine whether patients with homozygous familial hypercholesterolaemia (FH) have impaired adrenal cortical function. Plasma levels of cortisol, dehydroepiandrosterone (DHA), pregnenolone sulphate (PS) and DHA sulphate (DHAS) were measured during and 8 h ACTH infusion in six controls and two patients with homozygous FH. The basal PS levels of both patients and the basal DHA level of one were abnormally low for age and pubertal stage. During ACTH infusion we observed in both patients: (1) a mild impairment of control response after sustained stimulation (P less than 0.002); (2) a clear impairment of PS response (values less than 2 SD of those in controls); (3) a clear impairment of DHA response (values less than 2 SD) until 4 h in the boy who was at pubertal stage 4 and whose response could be compared to controls; no increase at all in the affected girl (pubertal stage 2) at a stage where normal subjects respond with significant increase. These results suggest that patients with FH lack cholesterol for corticosteroid biosynthesis under maximal ACTH stimulation and that mild chronic ACTH stimulation due to a deficit in the cholesterol supply to adrenal cells might increase the conversion of delta 5 to delta 4-steroids. They provide further evidence to support the primordial role of low density lipoprotein (LDL)-cholesterol in adrenal steroidogenesis in vivo.