How do patients with type 2 diabetes perceive their disease? Insights from the French DIABASIS survey.

AIM: The main purpose of this survey was to describe type 2 diabetes (T2DM) from the patient's standpoint in a representative French panel in 2008. METHODS: Fourteen thousand two hundred and one individuals from the general population aged 45 or older completed a self-questionnaire exploring knowledge about diabetes; 1092 replies were from patients with T2DM. RESULTS: The prevalence of T2DM in this population was 7.7%, with demographics as follows: 60% men; mean age: 66 years; mean age at diagnosis: 55 years; mean BMI: 29 kg/m(2). Eighty-five percent of T2DM patients reported that they wanted more information about at least one aspect of the disease at diagnosis; they reported feeling anxious (30%), frightened (13%), angry (4%) or that the disease was unfair (12%). Half of the patients had modified their dietary habits but 71% found it difficult to engage in regular physical activity. Most patients (90%) were treated with drugs: 81% with oral antidiabetic drugs (OAD) (44% in monotherapy) while 19% received insulin (alone or in combination with OAD). Twenty-three percent complained of weight gain since start of current therapy (average gain of 7.3 kg). Insulin initiation represented a turning point for patients who became more aware of the disease severity, more willing to follow advice and to take greater control over their disease management. The mean time from diagnosis to insulin initiation was 13.8 years. Half of the patients perceived their disease as severe especially women, patients who initially reacted with anxiety, insulin-treated patients and those actively involved in their disease management. Some gender differences emerged: women took the disease more seriously, were more engaged in self-management, and reported a higher impact on daily life. CONCLUSIONS: DIABASIS provides important information for diabetes care by highlighting patients' views of the disease, such as distress at diagnosis, lack of adequate information to cope with this distress and the important supportive role played by the family. A deeper understanding of patients' perception of the disease would help optimize customized care.

Benefits of Ophdiat, a telemedical network to screen for diabetic retinopathy: a retrospective study in five reference hospital centres.

AIM: One objective of Ophdiat, a telemedical network using digital non-mydriatic cameras in Ile-de-France, is to develop a comprehensive screening programme that provides access to annual fundus examinations to all diabetic patients. The aim of this study was to evaluate the benefits of this programme in a hospital setting. METHODS: A retrospective analysis of 500 case reports of diabetic patients hospitalized before and after Ophdiat setup was performed in five reference hospital centres. At each centre, 100 case reports (50 before, 50 after) of patients aged greater than 18 years, hospitalized for their annual check-up, with no known diabetic retinopathy (DR) before hospitalization and with the last fundus examination performed greater than 11 months previously, were randomly selected. The primary endpoint was the proportion of patients whose fundus examinations were performed during hospitalization; secondary endpoints were the number of cases of DR found and the time taken by ophthalmologists to make the diagnosis. RESULTS: The mean proportion of patients with fundus examinations was 50.4% and 72.4% before and after, respectively, Ophdiat (P<0.01). The prevalence of DR was 11.1% before and 12.7% after (not significant). The mean time taken by an ophthalmologist per diagnosis of DR was 0.90 half-day before and 0.32 half-day after Ophdiat. CONCLUSION: This evaluation shows that Ophdiat, combined with the availability of modern and effective devices, has improved DR screening in diabetology departments in hospitals. Additional human resources would certainly ensure more effective use of the system.

Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

Severity of diabetic microvascular complications is associated with a low soluble RAGE level.

AIMS: The receptor for advanced glycation end-products (RAGE) has been implicated in diabetic microvascular complications, but several lines of evidence suggest that the soluble isoform of RAGE (sRAGE) may protect against AGE-mediated vessel damage. The characterized AGE Nepsilon-carboxymethyllysine (CML) is associated with diabetic microvascular complications. In the present study, we measured blood levels of sRAGE and CML-protein in diabetic patients with and without microvascular complications. METHODS: Thirty patients with type-2 diabetes were recruited into the study, comprising 20 who had no microvascular complications, and 10 who had both retinal and renal complications. sRAGE was measured in serum by ELISA, and CML by competitive ELISA. RESULTS: sRAGE blood levels were similar in both the controls and diabetic patients without microvascular complications. In patients with complications, the mean sRAGE blood level was significantly decreased (1068+/-231pg/mL) compared with diabetic patients without complications (P=0.028). CML-protein was increased in all diabetic patients, but to a higher extent in those who had microvascular complications. CONCLUSION: The association of low sRAGE with high CML-protein levels in diabetic patients who developed severe diabetic complications supports the hypothesis that sRAGE protects vessels against AGE-mediated diabetic microvascular damage.

Abnormalities in insulin secretion in type 2 diabetes mellitus.

Type 2 diabetes mellitus is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. beta-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal beta-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. When permanent hyperglycaemia is present, progressive severe insulin secretory failure with time ensues, due to glucotoxicity and lipotoxicity, and oxidative stress. A marked reduction in beta-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in beta-cell apoptosis non-compensated by neogenesis.

OPHDIAT: a telemedical network screening system for diabetic retinopathy in the Ile-de-France.

OBJECTIVE: International and national guidelines recommend an annual funduscopic examination for all diabetic patients, but such annual fundus examinations are not sufficiently performed in France. Non-mydriatic fundus photography is a valid method of evaluation for diabetic retinopathy (DR) and a viable alternative to ophthalmoscopy. After two pilot studies demonstrated the feasibility of telemedical screening for diabetic retinopathy in both hospital and primary-care settings, we developed a regional telemedical network, OPHDIAT, designed to facilitate access to regular annual evaluations of patients with diabetes while saving medical time. MATERIALS AND METHODS: OPHDIAT comprises peripheral screening centres equipped with non-mydriatic cameras, where fundus photographs are taken by technicians linked by telemedicine to a reference centre, where ophthalmologists grade the images. Currently in the Ile-de-France region, 16 screening centres are linked through a central server to an ophthalmologic reading centre and includes 11 centres located in the diabetes departments of 11 hospitals, one diabetic retinopathy screening centre located in northern Paris, three in healthcare centres and one in a prison. RESULTS: During the 28-month evaluation period, 15,307 DR screening examinations were performed. Retinal photographs of at least one eye could not be graded in 1332 patients (9.7%) and diabetic retinopathy was detected in 3350 patients (23.4%). After the screening examination, 3478 patients (25.2%) were referred to an ophthalmologist for either DR, cataract and/or non-gradable photographs. CONCLUSION: Fundus photography combined with telemedicine has the potential to improve the regular annual evaluation for diabetic retinopathy. The organization of the network around a central reading centre serves to guarantee quality control.

Macular pattern dystrophy in MIDD: long-term follow-up.

A case of maternally inherited diabetes and deafness (MIDD)-associated macular pattern dystrophy with a 15-year follow-up is reported. On initial examination at age 37, visual acuity was normal, but chorioretinal atrophy at the posterior pole was already present in both eyes. At age 52, visual acuity remained normal in the right eye and was only slightly decreased in the left eye despite notable extension of the areas of chorioretinal atrophy in that eye. No evidence of diabetic retinopathy was present at any time. This case shows that visual acuity can remain stable in the long term despite extensive lesions of macular pattern dystrophy.

Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.

Dysfunctional endothelium is associated with and, likely, predates clinical complications of diabetes mellitus, by promoting increased vascular permeability and thrombogenicity. Irreversible advanced glycation end products (AGEs), resulting from nonenzymatic glycation and oxidation of proteins or lipids, are found in plasma, vessel wall, and tissues and have been linked to the development of diabetic complications. The principal means through which AGEs exert their cellular effects is via specific cellular receptors, one of which, receptor for AGE (RAGE), is expressed by endothelium. We report that blockade of RAGE inhibits AGE-induced impairment of endothelial barrier function, and reverse, in large part, the early vascular hyperpermeability observed in diabetic rats. Inhibition of AGE- and diabetes-mediated hyperpermeability by antioxidants, both in vitro and in vivo, suggested the central role of AGE-RAGE-induced oxidant stress in the development of hyperpermeability. Taken together, these data support the concept that ligation of AGEs by endothelial RAGE induces cellular dysfunction, at least in part by an oxidant-sensitive mechanism, contributing to vascular hyperpermeability in diabetes, and that RAGE is central to this pathologic process.

Type 2 diabetes mellitus: epidemiology, pathophysiology, unmet needs and therapeutical perspectives.

In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this "diabetes epidemic". Type 2 diabetes is a multifactorial disease, defined as resulting from defects in insulin secretion (including abnormalities in pulsatility and kinetics, quantitative and qualitative abnormalities of insulin, beta-cell loss progressing with time) associated with insulin resistance (affecting liver, and skeletal muscle) and increased glucagon secretion. The lack of compensation of insulin resistance by augmented insulin secretion results in rise in blood glucose. To achieve satisfactory glycaemic control in order to prevent diabetes related complications, drug therapy is generally required in addition to life style changes. Currently available oral therapies offer a large panel of complementary drugs, but they have several contraindications and side effects. In spite of major advances in the management of type 2 diabetes, and the strictness of new guidelines, some goals remain unachieved and the new family of insulin-secretors (DPP-IV inhibitors, GLP-1 analogues) should enrich therapeutic approaches.

Acute lower limb ischemia is a frequent complication of severe diabetic hyperosmolarity.

AIM: To describe the outcome of intensive care unit (ICU) patients admitted with a hyperglycaemic hyperosmolar non-ketotic syndrome (HHNS), with a specific analysis of precipitating conditions and complications including lower limb ischemia. METHODS: Retrospective review of patients admitted in a university-hospital ICU for HHNS. RESULTS: Seventeen consecutive patients (9F/8M, age: 75 years [57-81] (median [25-75% percentiles], Glasgow Coma score: 13 [12-14]) were admitted for HHNS over an 8-year period (1998-2005). On admission, the blood glucose level was 40.0 mmol/l [26.3-60.8], the corrected serum sodium concentration 167 mmol/l [158-174], and the calculated plasma osmolarity 384 mosmol/l [365-405]. All the patients presented with renal failure due to severe dehydration. An infection was identified as the precipitating factor in 8/17 cases. Three (18%) patients died in the ICU. Non-survivors were significantly older than survivors (P=0.02). Using univariate analysis, no other parameter measured on admission was related to mortality. Four patients (24%) presented with lower limb ischemia. They had a significantly more elevated blood urea nitrogen (P=0.03), creatinine phosphokinase level (P=0.04), and leukocyte count (P=0.02). The bilateral, symmetrical, and distal extremity involvement suggested diminished blood flow due to hyperviscosity, hypotension, vasoconstrictors, or cholesterol emboli rather than a proximal arterial obstruction as causative mechanisms. No patient was treated surgically. Ischemia reversed with fluid loading and resulted in toe dry digital necrosis. CONCLUSION: HHNS is a rare but life-threatening cause of ICU admission. There is a high incidence of lower limb ischemia in HHNS patients, which may be related to dehydration and blood hyperviscosity.

Muscle infarction in a young woman with brittle type 1 diabetes.

We present the first case of muscle infarction in a 30-year-old woman who had a 5-year history of type 1 diabetes mellitus that was not complicated by nephropathy, retinopathy or neuropathy. All common causes of muscle infarction were excluded, particularly microangiopathy and a hypercoagulable state. The differential diagnosis included infection (pyomyositis, necrotic fasciitis), focal inflammatory myositis, vascular events, trauma, tumor and diabetic amyotrophy, all of which were excluded. In spite of good glycaemic control, her diabetes remained brittle; alternating states of transient acute hypoglycaemia and hyperglycaemia may have been responsible for the infarction. Brittleness resumed after treatment with subcutaneous insulin infusion using a portable pump. No recurrence of muscle infarction was observed during a 18-month follow-up.

No evidence for left ventricular diastolic dysfunction in asymptomatic normotensive type 2 diabetic patients: a case-control study with new echocardiographic techniques.

OBJECTIVE: We sought to determine whether abnormalities of left ventricular structure and function could be detected in asymptomatic type 2 diabetic patients free of cardiovascular complications. RESEARCH DESIGN AND METHODS: We compared 48 subjects with type 2 diabetes (34 men, 50+/-6 years) without hypertension, coronary artery disease and microangiopathic complications with 30 age-matched healthy controls. Left ventricular diastolic function was assessed by conventional Doppler echocardiography and new echocardiographic techniques (tissue Doppler imaging, color M-mode propagation velocity). A pseudonormal (PN) pattern of left ventricular filling was screened by several methods including Valsalva maneuver. RESULTS: Systolic function was normal in all patients. There was no significant difference in conventional and new echocardiographic Doppler indices of diastolic function between patients and control subjects. A PN diastolic function frequently suggested by the Valsalva maneuver (20 patients) was excluded using the new parameters. CONCLUSIONS: Diastolic dysfunction is not as frequent as previously described in selected patients with type 2 diabetes free of microangiopathic complications. New Doppler echocardiographic methods provide, in contrast with the Valsalva maneuver, a reliable estimate of diastolic function and should be incorporated in the non-invasive screening for diabetic cardiomyopathy.

Zygomycosis: an uncommon cause for peripheral facial palsy in diabetes.

Mucormycosis is an emerging fungal infection with a high rate of mortality. Diabetic and immuno-compromised patients are the most frequent hosts. We report a case of rhino-orbito-cerebral mucormycosis revealed by facial palsy in a diabetic, immuno-compromised patient with difficult life conditions. He received intravenous antifungal treatment (amphotericin B) and early surgical debridement and completely recovered with no recurrence after 3 months of follow-up. Physicians should be aware of such atypical clinical presentations due to the need for early appropriate combined medical and surgical management to improve disease recovery and prognosis.

Occurrence of gestational diabetes mellitus, maternal and fetal outcomes beyond the 28th week of gestation in women at high risk of gestational diabetes. A prospective study.

AIM: Among the numerous guidelines defining the diagnostic strategy of gestational diabetes mellitus (GDM), none of them suggest a follow-up in women with risk factors beyond the 28th week of gestation (WG). The primary objective of this study was to assess the incidence of GDM beyond 28 WG in a group of women at high risk. The secondary objectives were to evaluate maternal and fetal outcomes in early and late GDM (between 24-28 WG, and beyond 28 WG), as well as to compare them to a normal glucose tolerance (NGT) group. METHODS: A prospective study conducted in 191 consecutive women. Between 24-28 WG, the diagnosis of GDM was performed in a two-step approach (50 then 75 g). Beyond the 28 WG, the diagnosis of GDM was based on self-monitoring blood glucose (SMBG). All women were educated about an individualized diabetic diet and to perform SMBG daily glucose profiles. RESULTS: Seventy-two percent of the women at risk had developed GDM. Among these, 54% had developed early GDM, between 24-28 WG, and 18% had developed late GDM, beyond the 28th WG. Gestational age of late GDM was estimated 30 WG. In late GDM, onset of diabetes seems to be predicted by an increase in capillary glucose value determined at 22:00 hours, but this needs to be confirmed. Women who develop GDM2 have a significantly higher rate of macrosomia and more important pre-pregnancy overweight, underlining this impact in the occurrence of macrosomia. Finally maternal outcomes were not different in the 3 groups with intensive intervention.

Elevation of CKP induced by ezetimibe in monotherapy: report on two cases.

Few cases of myopathy have been reported in patients treated with ezetimibe as monotherapy or in association with a statin. We report on two cases of elevation of CKP that occurred upon monotherapy with ezetimibe, which were reversible after discontinuation of the drug. In both cases, patients previously experienced intolerance with other lipid-lowering agents. The pathogenesis of muscle toxicity associated with ezetimibe is not known yet. An interaction with statin or a toxicity mechanism common to several lipid-lowering drugs have been suggested. A potential role of induction of glucuronidation by numerous associated drugs can also be involved Although association of ezetimibe with myopathy seems to be uncommon, special attention should be given to patients treated with ezetimibe who had a previous intolerance to other lipid-lowering drugs and who received several drugs.

Kearns Sayre syndrome: an unusual form of mitochondrial diabetes.

Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the emergence before age 20 of progressive external ophthalmoplegia, pigmentary retinopathy, together with other heterogeneous clinical manifestations, including cardiac conduction defects, muscle abnormalities and endocrinopathies. KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We report the case of a 43-year-old woman, with diabetes mellitus as a first manifestation at age 19. Later, she exhibited bilateral ptosis and external ophthalmoplegia with progressive worsening. DNA analysis identified a large mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By reporting this case with diabetes mellitus as first manifestation, we aim at emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.

[Diabetes and mitochondrial cytopathies: pathological studies]. / Diabète et cytopathies mitochondriales: données anatomo-pathologiques.

Maternal diabetes associated with neural deafness is designated as MIDD (maternal inherited diabetes and deafness); it is linked to a A3243G tRNA leucine gene mutation. The disease course is progressive and involvement of other systems is frequent. In most cases, macular pattern dystrophy is present. Muscular lesions are characteristic of mitochondrial myopathies. Mitochondrial abnormalities have also been observed in pancreas, heart, kidney, smooth muscle of the digestive tract with variable heteroplasmy levels. MIDD may present as a single syndrome or is part of MELAS or Kearns-Sayre syndrome.

Remission of proteinuria following correction of hyperlipidemia in NIDDM patients with nondiabetic glomerulopathy.

OBJECTIVE: Animal studies suggest that hyperlipidemia may play a direct role in glomerular damage. In patients with non-insulin-dependent diabetes mellitus (NIDDM), dyslipidemia occurs early in the course of nephropathy and may be involved in the progression of renal disease. CASES: We report on two young NIDDM patients with marked hyperlipidemia and proteinuria, in whom renal biopsy demonstrated nondiabetic glomerulopathy. In both cases, the decrease in blood lipid levels was associated with a major decrease in proteinuria. Episodes of hyperlipidemia were associated with a resumption of heavy proteinuria in one patient with serum triglyceride levels and proteinuria being closely correlated. CONCLUSIONS: These two cases suggest that hyperlipidemia has an important role in the pathogenesis of glomerular disease.

Extra-pancreatic manifestations in diabetes secondary to mitochondrial DNA point mutation within the tRNALeu(UUR) gene.

OBJECTIVE: A point mutation in the mitochondrial genome has been identified as a cause of diabetes and deafness. We report two pedigrees with and A-to-G transition at nucleotide 3243 of mtDNA within the tRNALeu(UUR) gene and focus our investigations on other localizations of the anomaly, particularly muscle and retina. RESEARCH DESIGN AND METHODS: Muscular localization has been studied in probands by invasive and noninvasive methods, including muscle biopsy (evaluation of the proportion of mutated mtDNA in comparison to blood cells, measurement of respiratory chain complex activities and histological and histochemical aspects) and 31P-nuclear magnetic resonance (NMR) spectroscopy. Ophthalmic and angiographic examination of retina, electroretinography, and visual evoked potentials were performed in five subjects. RESULTS: This mutation, previously described in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), was expressed more abundantly in muscle than in nucleated blood cells. This low expression in blood cells could hamper the diagnosis for some patients. In addition, despite poor clinical expression, muscle was found to be highly affected. Ragged red fibers and dystrophic mitochondria were observed in muscle biopsy. Histochemical assays showed decreased activity of respiratory chain complexes, and 31P-NMR in vivo data further confirmed the defect of muscle oxidative processes. Exercise-induced lactate production was increased. Finally, in both families, an atypical "salt and pepper" pigmentary retinopathy was observed without consequences on visual acuity. CONCLUSIONS: In diabetes secondary to 3243 mtDNA mutation, infraclinical muscular and ocular lesions are frequent. These two locations of the disease, which are easily investigated by simple methods, can help in the diagnosis of this new type of diabetes.