Louis Monnier

Glycemic Variability Should we and can we prevent it

Diabetes is characterized by glycemic disorders that include both sustained chronic hyperglycemia and acute glucose fluctuations. There is now cogent evidence for the deleterious effects of sustained chronic hyperglycemia that results in excessive protein glycation and generation of oxidative stress. The role of glucose variability from peaks to nadirs is less documented, but there are many reasons to think that both upward (postprandial) and downward (interprandial) acute fluctuations of glucose around a mean value activate the oxidative stress. As a consequence, it is strongly suggested that a global antidiabetic strategy should be aimed at reducing to a minimum the different components of dysglycemia (i.e., A1C, fasting and postprandial glucose, as well as glucose variability). All the therapeutic agents that act on postprandial glucose excursions seem of particular interest for reducing the latter parameter (i.e., the glucose instability). Particular attention should be paid to such emerging therapeutic agents as the glucagon-like peptide 1 agonists and the dipeptidyl peptidase (DPP)-IV inhibitors that act through the incretin pathway.

Enteral absorption in man of eicosapentaenoic acid in different chemical forms

After administering the equivalent of 1 g of eicosapentaenoic acid (EPA) in four different chemical forms, the kinetics of EPA incorporation into plasma triglycerides (TG) were compared by gas liquid chromatography on a capillary column following separation of the lipid fraction by thin layer chromatography.EPA incorporation into plasma TG was markedly smaller and later when EPA was administered as an ethyl ester rather than as EPA free fatty acid, EPA arginine salt or 1,3-dioctanoyl-2-eicosapentaenoyl glycerol (2-EPA). Our results and the data in the literature are compatible with the hypothesis that 2-EPA is absorbed with minimum hydrolysis and escapes random distribution between the other positions of the glycerol molecule during the absorption process.

Glycemic Variability: The Third Component of the Dysglycemia in Diabetes. Is it Important? How to Measure it?:

The dysglycemia of diabetes includes two components: (1) sustained chronic hyperglycemia that exerts its effects through both excessive protein glycation and activation of oxidative stress and (2) acute glucose fluctuations. Glycemic variability seems to have more deleterious effects than sustained hyperglycemia in the development of diabetic complications as both upward (postprandial glucose increments) and downward (interprandial glucose decrements) changes activate the oxidative stress. For instance, the urinary excretion rate of 8-iso-PGF2α, a reliable marker of oxidative stress, was found to be strongly, positively correlated (r = 0.86, p < .001) with glycemic variability assessed from the mean amplitude of glycemic excursions (MAGE) as estimated by continuous glucose monitoring systems (CGMS). These observations therefore raise the question of whether we have the appropriate tools for assessing glycemic variability in clinical practice. From a statistical point of view, the standard deviation (SD) around the mean glucose value appears as the “gold standard.” By contrast, the MAGE index is probably more appropriate for selecting the major glucose swings that are calculated as the arithmetic mean of differences between consecutive peaks and nadirs, provided that the differences be greater than the SD around the mean values. Furthermore, calculating the MAGE index requires continuous glucose monitoring, which has the advantage to detect all isolated upward and downward acute glucose fluctuations. In conclusion, the increasing use of CGMSs will certainly promote better assessment and management of glycemic variability.

Assessment of insulin sensitivity from plasma insulin and glucose in the fasting or post oral glucose-load state.

OBJECTIVE: To compare insulin sensitivity indexes derived from plasma insulin (I) and glucose (G) in the basal state (Sib) and at the second hour (I2h and G2h) of an oral glucose tolerance test (OGTT, Si2h) (i) with measurements of insulin sensitivity using the insulin modified frequently sampled intravenous glucose tolerance test (FSIVGTT) [Si(IVGTT)] and (ii) with modelling of fasting glucose and insulin by the homeostasis model assessment (HOMA).SUBJECTS: 47 subjects entered the study. 31 subjects were classified as having normal glucose tolerance (NGT), 10 as having impaired tolerance to glucose (IGT) and six as type 2 diabetes mellitus according to the World Health Organisation (WHO) criteria.MEASUREMENTS: Sib and Si2h were calculated as follows. Sib=108/(I×G×VD), Si2h=108/(I2hr×G2hr×VD) where VD is an estimate of the apparent glucose distribution volume. A third insulin sensitivity index (SiM) was calculated by averaging Sib and Si2h. HOMA was calculated as follows: I/(22.5×e−lnG)RESULTS: Si(IVGTT), Sib, SI2h and SiM were all significantly higher in subjects with NGT than in those with IGT or type 2 diabetes. Si(IVGTT) was highly correlated (P≤0.0001) with the three insulin sensitivity indexes found in the total population, in subjects with NGT and in those with IGT. In type 2 diabetic patients, a significant correlation was only noted when SiM was tested against Si(IVGTT) (P≤0.05). In most circumstances, the associations of Si(IVGTT) with Sib, SI2h and SiM were stronger than the corresponding associations with Ib, I2h or HOMA. SiM was the index that correlated best with Si(IVGTT) in the whole group (r=0.92, P<0.0001) as well as in NGT (r=0.86, P<0.0001), IGT (r=0.96; P<0.0001) and type 2 diabetes (r=0.83, P≤0.05) subgroups.CONCLUSIONS: Calculations of sensitivity indexes from G and I concentrations in the basal state and during a conventional 2 h OGTT appear to be useful for coupling in the same simple and single test both a determination of glucose tolerance and an estimate of insulin sensitivity.

Supplementation with wine phenolic compounds increases the antioxidant capacity of plasma and vitamin E of low-density lipoprotein without changing the lipoprotein Cu(2+)-oxidizability: possible explanation by phenolic location.

Objectives: To evaluate the effect of the red wine phenolic compound (RWPC) dietary supplementation without alcohol interference on: (1) some of the biochemical characteristics of LDL, (2) the oxidative susceptibility of LDL and (3) the antioxidant capacity of total plasma (Pl-AOC). In order to account for discrepancies between the three series of data, the in vitro stability of the association of phenolic compounds and LDL was tested. Design: An intervention study with 20 volunteers. Each served as his own control. Cu2+-oxidizability of LDL and Pl-AOC were tested on blood samples before and after dietary supplementation. Cu2+-oxidizability of LDL was also tested by co-incubation in the presence of RWPC or phenolic acids with or without extensive dialysis. Setting: The Laboratory of Lipid Biochemistry and Biology, School of Medicine, and the Laboratory of Metabolic Diseases, Lapeyronie Hospital, University of Montpellier, France. Subjects: Healthy males, nonsmokers and moderate drinkers, submitted to a dietary regimen deprived of vitamin E and C for a period of 10 d before supplementation. They also abstained from alcohol, wine, fruit juices, coffee, tea and cola beverages during this period. Intervention: Six 0.33 g capsules/d (namely two capsules at each meal) of a preparation of red wine phenolic compounds in a dry powder form were given to the volunteers over a period of two weeks. Blood samples were drawn in fasting conditions at day 0 and day 14 of the supplementation period. Results: Supplementation led to: (1) in LDL, a significant increase in vitamin E content (n=20, P=0.01) or vitamin E/total fatty acid bis-allylic carbon number ratio (n=20, P=0.006) without modification in the other biochemical characteristics or Cu2+-oxidizability; (2) in plasma, a significant increase in the antioxidant capacity (n=11, P=0.01). In vitro studies showed that RWPC or sinapic, caffeic or ferulic acids incubated in the presence of LDL increased the protection of the lipoparticle against oxidation (caffeic>sinapic>ferulic). This effect, however, was totally lost after extensive dialysis. Conclusions: The enhancing effect of the RWPC supplementation on Pl-AOC may be due to a phenolic-compound action both in the aqueous phase of plasma and at the surface of lipoprotein particles. Surface location possibly explains the enhancing-sparing effect of supplementation on LDL vitamin E and the absence of effect on dialysed-LDL oxidizability. Sponsorship: Supported by a grant from the Scientific Committee ‘Vin et Santé: Pathologies Vasculaires’.

The contribution of glucose variability to asymptomatic hypoglycemia in persons with type 2 diabetes

BACKGROUND The present study was designed to define the relative contributions of glucose variability and ambient glycemia to the incidence of asymptomatic hypoglycemia in type 2 diabetes. METHODS Two hundred twenty-two persons with type 2 diabetes were divided into three groups: Group I (n = 53) on insulin sensitizers alone, Group II (n = 87) on oral hypoglycemic agents (OHAs) to include at least one insulin secretagogue, and Group III (n = 82) on insulin alone or in combination with OHAs. Ambient mean glucose concentration (MG) values (in mmol/L) and glycemic variability (SD around the mean glucose value) (in mmol/L) or mean amplitude of glycemic excursions (in mmol/L) were assessed by a continuous glucose monitoring system. Asymptomatic hypoglycemia was recorded over a 48-h period. Poisson regression analysis was used for assessing the potential predictors of hypoglycaemia. RESULTS The best model fit was obtained with the two following explanatory variables: MG and SD. Hypoglycemia frequency was negatively associated with MG and positively with SD: Log (number of hypoglycemia episodes) = 1.37 - (0.72 × MG) + (1.33 × SD). Odds ratios (95% confidence interval) for hypoglycemic risk were significantly different from 1 for MG at 0.96 (0.95-0.97) (P < 0.0001) and for SD at 1.08 (1.06-1.10) (P < 0.0001). In addition, the risk for hypoglycemia was completely or virtually eliminated when the SD was <1.7 mmol/L irrespective of the ambient glucose level and treatment modality. CONCLUSIONS As the risk of asymptomatic hypoglycemia increases in the presence of increased glucose variability, avoidance of excess glucose fluctuations should be an important consideration for either reducing or preventing the risk of hypoglycemia in type 2 diabetes.

The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach

Recent intervention trials (Veterans Affairs Diabetes Trial, Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease) have underscored problems surrounding the risk‐benefit balance of most therapeutic strategies in type 2 diabetes given, especially the limited cardiovascular advantage of tight glycaemic control when set against the co‐incident risk of severe hypoglycaemia and weight gain. Consequently, therapy should to tailored to the individual. While attractive, such an approach remains highly empiric and to some extent difficult to implement without practical guidance, in particular for the inexperienced physician. To provide a user‐friendly guide for a personalized therapeutic approach to type 2 diabetes, we performed a systematic review of the literature and elaborated a simple rule that was debated at a large independent University Symposium on the occasion of the European Association for the Study of Diabetes held in Vienna 2009. As a result of that process, we now propose an A1C and ABCD of glycaemia management in type 2 diabetes to determine appropriate glycaemic targets based on Age, Body weight, Complications and Disease Duration. ‘A1C and ABCD’ aims to guide clinicians in the use of therapeutic agents more effectively, efficiently and safely. While no regulatory‐approved drug can be excluded, given its proven efficacy, there is a need to better phenotype patients, paying particular attention to ABCD. Based on these parameters, physicians can select the therapeutic strategy with minimum risk and maximum benefit for each individual. Copyright

Contributions of fasting and postprandial glucose to hemoglobin A1c.

OBJECTIVE To define the respective contributions of fasting and postprandial plasma glucose to hemoglobin A1c (HbA1c) in patients with non-insulin-treated type 2 diabetes. METHODS Previous studies of diurnal glycemic profiles are reviewed, and glucose values for predicting successful treatment of diabetes are suggested. RESULTS By analyzing the results from prior studies of diurnal glycemic profiles, we found that the relative contribution of postprandial plasma glucose was high (70%) in patients with fairly good control of diabetes (HbA1c <7.3%) and decreased progressively (30%) with worsening diabetes (HbA1c >10.2%). In contrast, the contribution of fasting plasma glucose showed a gradual increase with increasing levels of HbA1c. By using the same model (the diurnal glycemic profile), we established that post-meal glycemia was a better predictor of good or satisfactory control of diabetes (HbA1c <7%) than was fasting glucose. The best cutoff values that ensured the optimal balance between high sensitivity and specificity were approximately 200 mg/dL at 11 AM and 160 mg/dL at 2 PM. The cut-point values for predicting treatment success (specificity (3) 90%) were 162 mg/dL at 11 AM and 126 mg/dL at 2 PM. CONCLUSION Postprandial plasma glucose is the predominant contributor in patients with satisfactory to good control of diabetes, whereas the contribution of fasting plasma glucose increases with worsening diabetes. Postmeal thresholds for predicting good or satisfactory control of diabetes are dependent on the timing of the meals.

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.

Comparative Effect of Captopril and Nifedipine in Normotensive Patients With Incipient Diabetic Nephropathy

In these studies, the effect of a 6-wk treatment by placebo, the calcium-channel blocker nifedipine, or the converting-enzyme inhibitor captopril was assessed in normotensive patients with insulin-dependent diabetes and incipient nephropathy. In response to captopril and nifedipine, arterial pressure decreased slightly and to a similar extent. These drugs resulted in opposite effects on urinary excretion of albumin [i.e., increase in urinary albumin excretion (UAE) by 40% during nifedipine treatment and decrease by 40% during captopril treatment]. No change in UAE was observed in the p acebo group. This observation of opposite changes in U E i the presence of a similar fall in arterial pressur suggests that the effects of captopril and nifedipine o UAE result from some difference in their intrarenal a ction. The data do not present recommendations for the use or disuse of captopril or nifedipine in such a group of patients and do not allow extrapolation to hypertensive diabetic subjects well controlled by other conventional antihypertensive agents.