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1.
Diabetes Metab ; 47(2): 101167, 2021 03.
Article in English | MEDLINE | ID: mdl-32473964

ABSTRACT

The outbreak of COVID-19 led to an unprecedented inflow of hospitalised patients with severe acute respiratory syndrome (SARS), requiring high-flow non-invasive oxygenation, if not invasive mechanical ventilation. While the best option in terms of non-invasive systems of oxygen delivery is still a matter of debate, it also remains unclear as to whether or not the optimal in-bed positioning of patients might also help to improve their oxygen saturation levels. On the basis of three representative cases, it is possible to propose the following hypotheses: (i) how patients are positioned has a strong influence on their oxygen saturation levels; (ii) saturation-optimalised positions are patient-specific; (iii) prone positions require ergonomic devices; and (iv) saturation-optimalised positions should aim to place the most affected part(s) of the lung(s) on top. Considered together, these hypotheses have led us to recommend that COVID-19 patients should undergo a specific assessment at admission to determine their saturation-optimalised in-bed position. However, further studies are still needed to assess the benefits of such a strategy on clinical outcomes.


Subject(s)
COVID-19/therapy , Lung/diagnostic imaging , Aged , COVID-19/diagnostic imaging , Female , Humans , Male , Middle Aged , Postural Balance , Prone Position , Respiration, Artificial , SARS-CoV-2 , Tomography, X-Ray Computed
2.
Br J Dermatol ; 182(2): 477-480, 2020 02.
Article in English | MEDLINE | ID: mdl-31077337

ABSTRACT

Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune-related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47-year-old patient, treated with the anti-programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti-PD-1-induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow-up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti-programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune-related adverse events (irAEs) are among the most frequent irAEs (14-30% and 30-40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti-PD1 therapy and is associated with severe metabolic complications. With the increase in anti-PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.


Subject(s)
Lipodystrophy, Congenital Generalized , Melanoma , Antibodies, Monoclonal, Humanized , Humans , Immune Checkpoint Inhibitors , Melanoma/drug therapy , Middle Aged , Programmed Cell Death 1 Receptor
3.
Diabetes Metab ; 46(5): 370-376, 2020 10.
Article in English | MEDLINE | ID: mdl-31783142

ABSTRACT

BACKGROUND: Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. METHODS: Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. RESULTS: Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. CONCLUSION: Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.


Subject(s)
Aspirin/therapeutic use , Coronary Artery Disease/diagnostic imaging , Diabetes Mellitus, Type 2/blood , Drug Resistance , Platelet Activation , Platelet Aggregation Inhibitors/therapeutic use , Vascular Calcification/diagnostic imaging , Aged , Arachidonic Acid , C-Reactive Protein/metabolism , Female , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/blood , Inflammation/metabolism , Insulin Resistance , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Platelet Aggregation , Platelet Function Tests , Severity of Illness Index , Thrombopoietin/blood , Thromboxane B2/blood , Tumor Necrosis Factor-alpha/blood
4.
Diabetes Metab ; 44(1): 45-54, 2018 Feb.
Article in English | MEDLINE | ID: mdl-28259539

ABSTRACT

AIM: Alteration of functional beta-cell mass in adults can be programmed by adverse events during fetal life. Previously, it was demonstrated that high glucocorticoid (GC) levels during fetal life participate in this programming by inhibition of beta-cell development. More specifically, GC levels stimulate expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a transcriptional co-regulator of the GC receptor (GR), which per se impairs beta-cell mass and function when overexpressed. As PGC-1α is also a potent inducer of mitochondrial biogenesis, our study aimed to determine how PGC-1α modifies mitochondrial function in beta cells and how it might regulate insulin secretion. METHODS: Beta-cell function was studied in mice overexpressing PGC-1α specifically in beta cells and in MIN6 cells overexpressing PGC-1α in vitro. RESULTS: PGC-1α overexpression in beta cells in vivo leads to a reduced beta-cell mass early in fetal life, whereas PGC-1α overexpression in vitro stimulates mitochondrial biogenesis and respiratory activity without improving ATP production, while increasing oxidative stress and impairing insulin secretion in response to glucose. While oxidative stress with PGC-1α overexpression in beta cells activates AMPK, it has also been revealed that blocking such oxidative stress or AMPK activation restores insulin secretion. CONCLUSION: PGC-1α induces oxidative stress, which disrupts insulin secretion by AMPK activation. Thus, control of oxidative or energetic stress in beta cells may help to restore insulin secretion.


Subject(s)
Insulin-Secreting Cells/metabolism , Oxidative Stress/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Animals , Insulin/metabolism , Mice , Mice, Transgenic , Oxygen Consumption/genetics
7.
Diabetes Metab ; 43(1): 79-82, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27262367

ABSTRACT

BACKGROUND AND OBJECTIVES: Peripheral tissue resistance to insulin action is a characteristic of type 2 diabetes mellitus (T2DM). It has also been reported that some chronic viral infections can contribute to insulin resistance. Human herpesvirus (HHV)-8 infection has been detected in T2DM patients in previous studies. Our study investigated whether the presence of the virus is associated with insulin resistance in patients with ketosis-prone type 2 diabetes (KPD), as reported with other viruses. RESEARCH DESIGN AND METHODS: A total of 11 insulin-free KPD patients positive (+) and seven patients who were negative (-) for HHV-8 infection were recruited; the latter had KPD that was well controlled (HbA1c=6.2±0.7%). A two-step euglycaemic-hyperinsulinaemic clamp test coupled with deuterated [6,6-2H2]glucose was used to assess insulin sensitivity, non-esterified fatty acid (NEFA) suppression and endogenous glucose production. RESULTS: In KPD patients, whether HHV-8+ or HHV-8-, there were no differences in NEFA release, endogenous glucose production or insulin sensitivity (M value). CONCLUSION: Asymptomatic HHV-8 infection does not appear to be associated with decreased insulin sensitivity in diabetic patients. These results should now be confirmed in a larger sample population.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Ketoacidosis , Herpesviridae Infections , Herpesvirus 8, Human , Insulin Resistance , Adult , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/virology , Diabetic Ketoacidosis/epidemiology , Diabetic Ketoacidosis/virology , Female , Glucose Clamp Technique , Herpesviridae Infections/complications , Herpesviridae Infections/epidemiology , Humans , Male , Middle Aged
8.
Diabetes Obes Metab ; 18(7): 693-7, 2016 07.
Article in English | MEDLINE | ID: mdl-26584826

ABSTRACT

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Leptin/analogs & derivatives , Lipodystrophy/genetics , Adult , Diabetes Mellitus, Type 1/metabolism , Female , Glycated Hemoglobin/metabolism , Humans , Hyperglycemia/chemically induced , Hypolipidemic Agents/therapeutic use , Insulin/administration & dosage , Insulin Resistance/physiology , Insulin Secretion , Lamin Type A/genetics , Leptin/deficiency , Leptin/therapeutic use , Lipodystrophy/drug therapy , Male , Mutation/genetics , Syndrome , Triglycerides/metabolism
9.
Diabetes Metab ; 41(4): 326-330, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26337344

ABSTRACT

AIM: Previously, we described patients with ketosis-prone type 2 diabetes (KPD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but no mutation of the G6PD gene. Our present study used two complementary approaches to test whether hyperglycaemia might inhibit G6PD activity: (1) effect of acute hyperglycaemia induced by glucose ramping; and (2) effect of chronic hyperglycaemia using correlation between G6PD activity and HbA1c levels. METHODS: In the first substudy, 16 KPD patients were compared with 11 healthy, non-diabetic control subjects of the same geographical background. Erythrocyte G6PD activity and plasma glucose were assessed at baseline and every 40 min during intravenous glucose ramping that allowed maintaining hyperglycaemia for more than 3h. In the second substudy, erythrocyte G6PD activity and HbA1c levels were evaluated in 108 consecutive African patients with either type 2 diabetes or KPD, and a potential correlation sought between the two variables. RESULTS: The maximum plasma glucose level after 200 min of glucose perfusion was 20.9±3.7 mmol/L for patients and 10.7±2.3mmol/L for controls. There was no difference between baseline and repeated G6PD activity levels during acute hyperglycaemia in either KPD patients (P=0.94) or controls (P=0.57), nor was there any significant correlation between residual erythrocyte G6PD activity and HbA1c levels (r=-0.085, P=0.38). CONCLUSION: Neither acute nor chronic hyperglycaemia affects erythrocyte G6PD activity. Thus, hyperglycaemia alone does not explain cases of G6PD deficiency in the absence of gene mutation as described earlier.


Subject(s)
Diabetic Ketoacidosis/metabolism , Erythrocytes/metabolism , Glucosephosphate Dehydrogenase Deficiency/blood , Glucosephosphate Dehydrogenase/metabolism , Hyperglycemia/complications , Adult , Blood Glucose/metabolism , Case-Control Studies , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/complications , Erythrocytes/enzymology , Female , Glucosephosphate Dehydrogenase/blood , Glucosephosphate Dehydrogenase Deficiency/complications , Humans , Hyperglycemia/blood , Hyperglycemia/metabolism , Male , Middle Aged
10.
Diabetes Metab ; 41(5): 347-57, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25753246

ABSTRACT

PGC-1α is a transcriptional coactivator expressed in brown adipose tissue, liver, pancreas, kidney, skeletal and cardiac muscles, and the brain. This review presents data illustrating how PGC-1α regulates metabolic adaptations and participates in the aetiology of type 2 diabetes (T2D). Studies in mice have shown that increased PGC-1α expression may be beneficial or deleterious, depending on the tissue: in adipose tissue, it promotes thermogenesis and thus protects against energy overload, such as seen in diabetes and obesity; in muscle, PGC-1α induces a change of phenotype towards oxidative metabolism. In contrast, its role is clearly deleterious in the liver and pancreas, where it induces hepatic glucose production and inhibits insulin secretion, changes that promote diabetes. Previous studies by our group have also demonstrated the role of PGC-1α in the fetal origins of T2D. Overexpression of PGC-1α in ß cells during fetal life in mice is sufficient to induce ß-cell dysfunction in adults, leading to glucose intolerance. PGC-1α also is associated with glucocorticoid receptors in repressing expression of Pdx1, a key ß-cell transcription factor. In conclusion, PGC-1α participates in the onset of diabetes through regulation of major metabolic tissues. Yet, it may not represent a useful target for therapeutic strategies against diabetes as it exerts both beneficial and deleterious actions on glucose homoeostasis, and because PGC-1α modulation is involved in neurodegenerative diseases. However, its role in cellular adaptation shows that greater comprehension of PGC-1α actions is needed.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Models, Biological , Transcription Factors/metabolism , Adipose Tissue/metabolism , Animals , Energy Metabolism , Gluconeogenesis , Humans , Insulin Resistance , Insulin Secretion , Liver/metabolism , Muscle, Skeletal/metabolism , Organ Specificity , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Thermogenesis , Transcription Factors/chemistry , Transcription Factors/genetics
11.
Diabetes Metab ; 40(6): 411-22, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25443548

ABSTRACT

Type 2 diabetes (T2D) is a complex, progressive disease with life-threatening complications and one of the most serious public-health problems worldwide. The two main mechanisms of T2D pathogenesis are pancreatic beta cell dysfunction and insulin resistance. It is now recognized that pancreatic beta cell dysfunction is a necessary factor for T2D development. Traditional therapies for controlling blood glucose are suboptimal as they fail to meet target goals for many patients. Glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase-4 inhibitors (DPP4I) are an attractive class of therapy because they reduce blood glucose by targeting the incretin hormone system and, in particular, have the potential to positively affect pancreatic beta cell biology. This review outlines our current understanding of pancreatic beta cell incretin system dysfunction in T2D and summarizes recent evidence of the effect of incretin-based therapies on beta cell function and mass. Incretin-based therapies have shown strong evidence for beneficial effects on beta cell function and mass in animal studies. In humans, incretin-based therapies are effective glucose-lowering agents, but further study is still required to evaluate their long-term effects on beta cell function and safety as well as beta cell mass expansion.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Incretins/administration & dosage , Insulin-Secreting Cells/drug effects , Animals , Diabetes Mellitus, Type 2/physiopathology , Humans , Insulin-Secreting Cells/metabolism
12.
Diabetes Obes Metab ; 16(9): 861-8, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24641271

ABSTRACT

AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. METHODS: Six randomized, placebo-controlled studies of lixisenatide 20 µg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. RESULTS: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9 mmol/l, p < 0.001) and glucose excursion (LS mean difference vs. placebo: -4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0 ng/l, p < 0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p < 0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. CONCLUSIONS: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/agonists , Glucagon/blood , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Peptides/therapeutic use , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Gastric Emptying/drug effects , Glucagon/drug effects , Glucagon/metabolism , Glycated Hemoglobin/metabolism , Humans , Insulin/blood , Insulin Secretion , Postprandial Period , Randomized Controlled Trials as Topic
13.
Diabetes Metab ; 40(1): 56-60, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24076360

ABSTRACT

AIM: This study compared the clinical and biochemical characteristics and microvascular complications found in three groups of type 2 diabetes (T2D) patients: Africans living in Africa; African immigrants living in France; and Caucasians living in France. METHODS: Diagnosed T2D Africans living in Cameroon (n=100) were compared with 98 African migrants diagnosed with T2D after having moved to France, and a group of 199 T2D Caucasian patients living in France. All underwent clinical and biochemical evaluations, and all were assessed for microvascular complications. RESULTS: The median duration of stay of the migrants in France was 15years before being diagnosed with diabetes. Despite similar durations of diagnosis, they were 8.9years younger at the time of diagnosis than Africans living in Cameroon (P<0.001). Caucasians and African immigrants in France had lower HbA1c values than Africans in Cameroon (P<0.001); they were also more aggressively treated for hypertension and dyslipidaemia and, therefore, had significantly lower blood pressure levels and better lipid profiles. Diabetic nephropathy and retinopathy rates were higher in Cameroon than in the two other groups. After adjusting for age, diabetes duration, HbA1c, hypertension and other covariates, only the prevalence of diabetic nephropathy (OR: 5.61, 95% CI: 2.32-13.53; P<0.0001) was higher in Cameroon compared with those living in France. CONCLUSION: Our results suggest that Africans who emigrate to France may develop diabetes earlier than those staying in their home country. However, the latter may be a reflection of late diagnosis of diabetes. Also, the less adequate diabetes and hypertension control in the latter would explain their higher rates of nephropathy. Large-scale cohorts are now warranted to substantiate these observations.


Subject(s)
Black People/statistics & numerical data , Diabetes Mellitus, Type 2/epidemiology , Emigrants and Immigrants/statistics & numerical data , Hypertension/epidemiology , White People/statistics & numerical data , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Cameroon/epidemiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/ethnology , Diabetic Nephropathies/blood , Diabetic Nephropathies/epidemiology , Diabetic Retinopathy/blood , Diabetic Retinopathy/epidemiology , Female , France/epidemiology , Glycated Hemoglobin/metabolism , Humans , Life Style , Male , Middle Aged , Prevalence , Quality of Health Care
14.
Diabetes Metab ; 39(3): 205-16, 2013 May.
Article in English | MEDLINE | ID: mdl-23643351

ABSTRACT

Although regular physical activity is an integral part of T2D management, few diabetic patients have a sufficient level of physical activity. However over the past decade or so, the beneficial effects of regular physical activity have been well demonstrated, both in T2D prevention (50% reduction in the incidence of T2D in subjects with high metabolic risk) as well as T2D management for the improvement of glycaemic control (mean 0.7% improvement of HbA1c) and the reduction of T2D-related comorbidities (improvement in blood pressure values and lipid profile, decrease in insulin resistance). Physical activity has both acute effects (effects of one exercise session) and more prolonged effects of exercise when it is repeated on a regular basis (training effect). In addition, the physical activity recommendations have been extended to a wide range of physical activities (by combining both endurance and muscle strengthening exercises), thus varying the physical activity practiced according to the patient's available time, practice sites, preferences and interests. Following a pathophysiology review, the effects of physical activity will be discussed and presented in terms of evidence-based medicine. The recommendations will be defined and practical prescribing information will be suggested, while taking into account that clinicians are concerned with answering questions regarding how, where and with whom: how can patients be motivated to practice a physical activity over the long-term? And how can qualified exercise trainers and appropriate practice settings be found?


Subject(s)
Diabetes Mellitus, Type 2/therapy , Exercise , Motor Activity , Evidence-Based Medicine , France , Humans
15.
Ann Endocrinol (Paris) ; 72(4): 287-295, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21777901

ABSTRACT

Saxagliptin, a dipeptidyl peptidase-4 inhibitor, has been the focus of a large clinical development programme, including Phase 3 randomized vs placebo-controlled clinical trials as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control using initial monotherapy (metformin, glibenclamide, thiazolidinedione). This clinical programme has shown saxagliptin to be effective in the control of fasting and postprandial glycemic parameters, in addition to a good overall safety profile. The present paper aims at reviewing the overall short-term and long-term efficacy of saxagliptin in its Phase 3 development program and tries to pinpoint some factors that may be more predictive of treatment response in clinical practice. In individual and pooled analyses of the three pivotal add-on to monotherapy trials, saxagliptin (5mg once daily) led to significant reductions in HbA(1c) from baseline to 24 weeks. Additional analyses showed that reductions in HbA(1c) were maintained in the long-term, notably for 102 weeks, in combination with metformin. Data have also shown that the absolute reduction in HbA(1c) seen with saxagliptine from baseline to Week 24 was numerically greater with an elevated baseline HbA(1c). In these recently published pooled analyses, clinically pertinent reductions in HbA(1c) were also obtained with saxagliptin across a wide range of subgroups of T2D patients when examined either by specific baseline demographic characteristics or by ß-cell function indices such as the HOMA-ß.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Adamantane/administration & dosage , Adamantane/therapeutic use , Blood Glucose/analysis , Clinical Trials, Phase III as Topic , Diabetes Mellitus, Type 2/blood , Dipeptides/administration & dosage , Drug Therapy, Combination , Fasting , Food , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/administration & dosage , Randomized Controlled Trials as Topic
16.
Diabetes Metab ; 37(1): 79-82, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21147013

ABSTRACT

AIM: Epidemiological data suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency may be a risk factor for diabetes. Also, the occurrence of haemolysis in the context of diabetes crises has been reported in patients with G6PD deficiency. A unifying hypothesis could explain these associations. METHODS: We report two patients in whom haemolytic crises occurred soon after acute diabetes decompensation, and revealed G6PD deficiency. We have reviewed the mechanisms that may link the two diseases. RESULTS: One patient was admitted for decompensated ketosis-prone type-2 diabetes (KPT2D), but no acidosis, and was treated with insulin, then metformin and glibenclamide. The second patient had type-1 diabetes and ketoacidosis treated with insulin. Haemolytic crises were recognized 8 and 4 days after admission, respectively, and G6PD deficiency was confirmed in both patients. These patients and the other published cases share, as a unique characteristic, the occurrence of haemolysis after diabetes decompensation, whatever the treatment or associated conditions. Experimental data show that hyperglycaemia can reduce expression of the G6PD gene and activity of the enzyme. Conversely, G6PD deficiency can promote oxidative stress and impairment of insulin secretion by beta cells. CONCLUSION: In patients at risk of G6PD deficiency, the possibility of haemolysis should be explored in case of diabetes crisis. In African patients with KPT2D diabetes, potentially oxidative hypoglycaemic agents should be avoided in the remission phase of the disease. G6PD deficiency and diabetes can aggravate each other, and diabetes could be aetiologically associated with G6PD deficiency.


Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Glucosephosphate Dehydrogenase Deficiency/complications , Glucosephosphate Dehydrogenase Deficiency/metabolism , Hemolysis/physiology , Acute Disease , Adult , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Female , Glucosephosphate Dehydrogenase Deficiency/epidemiology , Humans , Male , Oxidative Stress/physiology , Risk Factors
17.
Diabetes Metab ; 37(1): 47-51, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21126899

ABSTRACT

AIM: To describe the clinical presentation and the prognosis of autoimmune type 1 diabetes (T1D) that was first revealed during pregnancy masquerading as gestational diabetes mellitus (GDM). METHODS: We reviewed the files of 21 women in whom diabetes was revealed during a pregnancy ("index pregnancy") and progressed to T1D after delivery, and in whom GAD and/or IA-2 autoantibodies were found. RESULTS: The median age and BMI of the women were 31 years and 19.8 kg/m(2). Eleven women had at least one risk factor for GDM. Eight of the 12 multiparous women had had an abnormal outcome of previous pregnancy, including GDM in five. GDM was diagnosed at week 26 (range: 4-38) of gestation by screening in 18, because of macrosomia in two and during hyperglycaemic crises in three. All were treated with insulin, from the time of diabetes diagnosis in 10 and after 4 weeks (range: 2-15) in 11. Term of delivery was 38 (range: 26-41) weeks. Abnormal outcomes occured in 14 pregnancies, including two fetal deaths, four preterm deliveries and eight macrosomic infants. No congenital malformations were reported. After delivery, insulin therapy was stopped in 18 women for 6 months (range: 2-48). The diagnosis of the autoimmune origin of diabetes was established during the index pregnancy in only eight cases. CONCLUSION: T1D may reveal as GDM in women with or without risk factors for GDM and is associated with a poor prognosis, partly because the correct diagnosis and treatment are delayed. Whether screening for autoimmune markers of T1D should be performed more systematically in women with GDM deserves to be studied.


Subject(s)
Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/epidemiology , Diabetes, Gestational/diagnosis , Diabetes, Gestational/epidemiology , Pregnancy Outcome/epidemiology , Adult , Autoantibodies/blood , Diabetes Mellitus, Type 1/immunology , Diabetes, Gestational/immunology , Diagnosis, Differential , Disease Progression , Female , Fetal Death/epidemiology , Humans , Pregnancy , Prognosis , Risk Factors
18.
Ann Endocrinol (Paris) ; 71(6): 505-10, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21030006

ABSTRACT

Various publications in 2009 showed that the treatment of type 2 diabetic (T2D) patients with macrovascular complications is still a controversial subject, whether with regard to the use of glitazones, to the best management strategy for T2D patients with stable coronary artery disease or to the use of incretin mimetic drugs in patients with heart disease. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes study (RECORD) compared cardiovascular morbidity-mortality outcomes in patients taking rosiglitazone in combination with metformin or sulfonylurea versus metformin with sulfonylurea. The results showed that rosiglitazone was not inferior to the metformin-sulfonylurea combination in terms of mortality and cardiovascular hospitalization, but caution must be used when interpreting the results, as the event rate was low. The BARI 2D study (Bypass Angioplasty Revascularization Investigation 2 Diabetes) is a cardiovascular morbidity-mortality trial with the goal of determining the best strategy for blood glucose control and revascularization in T2D patients with stable coronary artery disease. The results of this trial showed that early revascularization is not clearly beneficial, except in a subgroup of patients in whom surgical revascularization is indicated. The use of GLP-1 analogs (Glucagon-Like Peptide-1) in the acute phase of myocardial ischemia in animal models provided promising results. Some clinical studies also suggest an improvement in cardiovascular risk factors with these treatments. Results from morbidity-mortality studies are needed to better assess the long-term efficiency of these new drugs.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/pathology , Diabetic Angiopathies/drug therapy , Diabetic Angiopathies/pathology , Glucagon-Like Peptide 1/therapeutic use , Animals , Coronary Artery Disease/drug therapy , Coronary Artery Disease/etiology , Heart Diseases/drug therapy , Heart Diseases/etiology , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Risk Factors , Rosiglitazone , Thiazolidinediones/adverse effects , Thiazolidinediones/therapeutic use
19.
Diabetes Metab ; 36(5): 346-51, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20675173

ABSTRACT

The prevalence of type 2 diabetes is rapidly increasing worldwide, yet its primary prevention and treatment are still a challenge. The objectives of this review are to assess the effects of exercise on the prevention of type 2 diabetes in high-risk individuals and on glycaemic control in type 2 diabetic patients. Considering the available reports, there is unequivocal and strong evidence that physical exercise can prevent or delay progression to type 2 diabetes in subjects with impaired glucose tolerance. Also, lifestyle interventions, including diet and physical exercise, can result in a reduction of around 50% in diabetes incidence that persists even after the individual lifestyle counselling has stopped. In addition, short-term randomized studies have confirmed that physical training based on endurance and/or resistance exercises can also improve blood glucose control in type 2 diabetics with a mean glycated haemoglobin decrease of 0.6%. Thus, physical exercise should be part of any therapeutic strategy to slow the development of type 2 diabetes in high-risk individuals and to improve glucose control in type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2/prevention & control , Exercise , Adult , Blood Glucose/analysis , Body Mass Index , Diabetes Mellitus, Type 2/blood , Diet , Female , Glucose Intolerance/therapy , Glycated Hemoglobin/analysis , Humans , Life Style , Lipids/blood , Male , Middle Aged , Physical Endurance , Randomized Controlled Trials as Topic , Risk Factors
20.
Diabet Med ; 27(3): 318-26, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20536495

ABSTRACT

AIM: To demonstrate non-inferiority of vildagliptin compared with gliclazide, as an add-on therapy, in patients with Type 2 diabetes inadequately controlled with metformin in a 52-week, randomized, double-blind, active-controlled study. METHODS: Patients receiving a stable dose of metformin (> or = 1500 mg) were randomized (1 : 1) to receive vildagliptin (50 mg twice daily; n = 513) or gliclazide (up to 320 mg/day; n = 494). RESULTS: Non-inferiority of vildagliptin was demonstrated (95% confidence interval -0.11%, 0.20%) with a mean change (se) from baseline glycated haemoglobin (HbA(1c)) (approximately 8.5% in both groups) to a 52-week endpoint of -0.81% (0.06) with vildagliptin and -0.85% (0.06) with gliclazide. Although a similar proportion of patients reached HbA(1c) < 7.0%, the total number of hypoglycaemic events was lower in the vildagliptin group (6 vs. 11 events). Vildagliptin was non-inferior (margin 0.6 mmol/l) to gliclazide in reducing fasting plasma glucose (1.31 vs. 1.52 mmol/l, P = 0.257). The overall incidence of any adverse events was similar in both groups (approximately 61%), but the number of serious adverse events was higher in the gliclazide group (8.7 vs. 6.7%). The number of patients who discontinued as a result of an unsatisfactory effect was higher in the vildagliptin group (n = 22 vs. 13, respectively) compared with gliclazide, but vildagliptin did not induce weight gain. CONCLUSION: In patients with Type 2 diabetes inadequately controlled with metformin, addition of vildagliptin provided similar HbA(1c)-lowering efficacy compared with gliclazide after 52 weeks of treatment. Although both treatments were well tolerated, vildagliptin-treated patients had fewer hypoglycaemic events and did not gain weight.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Gliclazide/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Adamantane/administration & dosage , Adamantane/adverse effects , Adamantane/therapeutic use , Adolescent , Adult , Aged , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Double-Blind Method , Drug Therapy, Combination , Female , Gliclazide/administration & dosage , Gliclazide/adverse effects , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Male , Metformin/administration & dosage , Metformin/adverse effects , Middle Aged , Nitriles/administration & dosage , Nitriles/adverse effects , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Vildagliptin , Young Adult
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