Plasminogen activator inhibitor type-1 is an independent marker of metabolic disorders in young adults born small for gestational age.

BACKGROUND: Metabolic syndrome (MS) has been associated with being born small for gestational age (SGA). In epidemiological studies plasminogen activator inhibitor type-1 (PAI-1) levels have been associated with MS. Few studies have examined this association in subjects born SGA. PATIENTS AND METHODS: Five hundred and fifty-seven SGA adults (birth weight < 10th percentile) were compared with 671 subjects with a birth weight between the 25th and 75th percentiles (control group). MS was defined using the World Health Organization (WHO) definition. Active PAI-1 was measured on citrated plasma with bio-immunoassay. RESULTS: MS was more prevalent in the SGA group (8.7%) than in the control group (5.5%; P = 0.03). In both groups, PAI-1 concentrations were significantly correlated with waist circumference, plasma triglycerides, homeostatic model assessment-insulin resistance (HOMA-IR) and associated with male sex and MS. PAI-1 concentrations were significantly increased in the SGA group (12.2 ± 21.2 vs. 10.0 ± 13.5 IU mL⁻¹, P = 0.03) and this remained after adjustment of metabolic variables (P = 0.009). PAI-1 concentrations above 4.9 IU mL⁻¹ (= median of PAI-1 concentration in the control group) were present in 94% of the subjects with MS. Moreover, the adjusted odds ratio (OR) for having elevated PAI-1 was 1.48 (1.08; 1.95) in the SGA group in comparison with the control group (P = 0.005). CONCLUSIONS: PAI-1 plasma concentrations were significantly increased in SGA subjects independently of MS. These data suggest that elevation of PAI-1 concentrations might be an indication of an abnormal secretion at the level of the adipose tissue, endothelial cells or liver and implicated in metabolic disorders reported in SGA subjects.

Fertility is not altered in young adults born small for gestational age.

BACKGROUND: The intrauterine environment may have a lifelong impact on individuals' health. However, results on the relationship between birth size and gonadal function are conflicting, and it remains unknown whether reproductive function is altered in adults born small for gestational age (SGA). The aim of the present study was to compare the fertility of young adults from the general population, born either SGA or appropriate for gestational age (AGA). METHODS: There were 579 adults born SGA (birthweight under the 10th percentile) who were compared with 703 subjects of the same age (age 29.4 +/- 4.1 years) born AGA (birthweight between 25th and 75th percentiles). They fulfilled a questionnaire focusing on the first attempt to give birth, to have a measure of the time to pregnancy and an estimation of the fecundability (the monthly pregnancy probability), two relevant indicators of fertility at the couple level. Ratios of fecundability between AGA and SGA subjects were adjusted for known fertility factors (age, smoking, reproductive history) and for socioeconomic status. RESULTS: Time to pregnancy was comparable in the two groups: 5.7 +/- 8.0 versus 6.6 +/- 10.5 months in AGA and SGA, respectively (P = 0.31), in women and 5.1 +/- 7 versus 6.0 +/- 9 months in AGA and SGA, respectively, in men (P = 0.53). The adjusted ratios of fecundability comparing SGA to AGA subjects were not significant: HR = 0.91 [0.68;1.21] (P = 0.5) in women and HR = 0.95 [0.67;1.74] (P = 0.82) in men. CONCLUSION: When studied in young adults from the general population, fertility is not reduced in those born SGA.

11beta-hydroxysteroid dehydrogenase type 1 of the subcutaneous adipose tissue is dysregulated but not associated with metabolic disorders in adults born small for gestational age.

INTRODUCTION: The mechanisms relating being born small for gestational age (SGA) and the later risk of metabolic disorders are not yet fully understood. Adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity and expression have been positively associated with metabolic syndrome. In humans, no in vivo studies have explored 11beta-HSD1 activity and gene expression in sc adipose tissue of SGA subjects. SUBJECTS AND METHODS: Thirty-nine subjects SGA (birth weight<10th percentile) were matched on gender and age with 36 subjects born appropriate for gestational age (AGA) (25th percentile

Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age.

AIMS/HYPOTHESIS: Insulin resistance (IR) and the metabolic syndrome (MS) have been reported in adults as a consequence of being born small for gestational age (SGA). The process seems to be initiated early in life; however, little is known about the progression of MS and IR in young adults. We hypothesised that being born SGA would promote a greater progression over time of IR and MS, reflecting not only the gain in weight and fat mass but also the extension of the fetal programming process. METHODS: Participants were selected from a community-based cohort and born full-term either SGA (birthweight <10th percentile) or appropriate for gestational age (25th < birthweight < 75th percentile). A total of 1,308 individuals were prospectively followed between the ages of 22 and 30 years. RESULTS: At both ages, individuals born SGA were more insulin-resistant and showed a significantly higher prevalence of MS. Over the 8 year follow-up, the risk of developing MS was twofold higher in those SGA, after adjustment for gain in BMI, whereas the progression of IR was not significantly affected by the birth status. CONCLUSIONS/INTERPRETATION: Our data suggest that metabolic disorders in SGA individuals are amplified by the weight gain with time when adults, both probably resulting from fetal programming. Moreover, the modest increase in IR contrasts with the constant and much higher prevalence of MS.

Fetal origins of insulin resistance and the metabolic syndrome: a key role for adipose tissue?

For several years now, the epidemiological data have shown an inverse relationship between birth-weight and the development in later life of cardiovascular disease and metabolic disorders. The term "small for gestational age" (SGA) describes a neonate whose birth-weight is two standard deviations (SD) below the reference mean, corrected for gestational age and gender. SGA is associated with increased risks of developing hypertension, insulin resistance and type2 diabetes. However, the association with an atherogenic lipid profile is less clear. Nevertheless, all of the components of the metabolic syndrome are present. Yet, in spite of the large body of data in the literature, the biological mechanisms underlying this association are still unclear. To explain the association, various hypotheses have been proposed, pointing to the role of a detrimental fetal environment or genetic susceptibility, or interaction between the two, and to the particular dynamic changes in adiposity that occur during catch-up growth. However, not only quantitative, but also qualitative, abnormalities of adipose tissue have been observed, suggesting a critical role of this organ in the development of metabolic complications.

[Mitochondrial diabetes: clinical features, diagnosis and management]. / Diagnostic clinique et biologique du diabète mitochondrial et particularités de sa prise en charge.

Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognised by the physicians. Maternally inherited diabetes and deafness (MIDD) resulting from the mutation 3243A>G of the mitochondrial DNA is the most frequent mutation associated with mitochondrial diabetes. This review summarizes the range of clinical phenotypes associated with MIDD and outlines the advances in genetic diagnosis, pathogenesis and management of these patients.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

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.

Switching fibrate to statin in type 2 diabetic patients: consequences on lipid profile.

UNLABELLED: Interest of statins in terms of morbid-mortality reduction in primary and secondary prevention in type 2 diabetic patients has broadly been proven in recent studies, while evidence for fibrates preventive effect is considerably weaker. HMGCoA reductase inhibitors are known to decrease low density lipoprotein cholesterol (LDL C) in a greater extension than triglycerides (TG). In type 2 diabetic patients, the dyslipidemic profile is commonly associated with reduced high-density lipoproteins (HDL C), increased TG and normal or mildly elevated LDL C. PATIENTS AND METHODS: Type 2 diabetic outpatients (n=45) treated with fibrate with or without history of cardiovascular disease were included. Mean age was 57.7+/-13.2 yr, sex ratio was 16/39 (F/M), and BMI was 29.3+/-4.4 kg/m(2). Non-inclusion criteria were TG>or=3.5 g/L and intolerance to statins or a combined lowering lipid therapy. Serum lipid profile, HbA(1c) and creatin kinase (CK) were assessed under treatment with fibrate, then after a 3-month wash-out period, and after a 6-month treatment with a low dose of atorvastatin (10 mg/day). RESULTS: After a 3-month wash-out period, total cholesterol (TC) was 1.98+/-0.31 g/L (m+/-SD), TG 1.63+/-1.09 g/L, HDL C 0.46+/-0.12 g/L, and LDL C 1.22+/-0.31 g/L. Comparing lipid profile with atorvastatin vs fibrate, we observed a significant decrease in TC and LDL C (1.56 vs 1.79 g/L P=0.001, and 0.84 vs 1.09 g/L, P=0.001, respectively). No significant difference between treatments was observed for TG (1.35 vs 1.17 g/L, P=0.06), and HDL C (0.44 vs 0.48 g/L, P=0.15). When treated with atorvastatin, 90% of patients achieved a LDL C<1 g/L, compared to 51% when treated with fibrate (P=0.001). HbA(1c) remained about 7.6+/-1.5%, and CK in the normal range. CONCLUSION: In well-controlled type 2 diabetic patients previously treated with fibrate, short-term (6 months) treatment with low-dose atorvastatin (10 mg/day) improves TC and LDL C levels, without any alteration in TG and HDL C levels.

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.

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.

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study.

AIMS/HYPOTHESIS: We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD). METHODS: This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension. RESULTS: In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p < 0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p < 0.007) and prevalence of hypertension (33.8 vs 64.2%, p < 0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p < 0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR <60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p < 0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results. CONCLUSIONS/INTERPRETATION: This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.

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.

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.

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.

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.

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.

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.