Distribution of abdominal adipose tissue as a predictor of hepatic steatosis assessed by MRI.

AIM: To evaluate the relationship between the distribution of visceral and subcutaneous adipose tissue and hepatic steatosis assessed using magnetic resonance imaging (MRI). MATERIALS AND METHODS: One T1-weighted, in-/out-of-phase, single-section sequence at the L3/L4 level and one multi-echo gradient MRI (MGRE) sequence were performed on 65 patients [19 females and 46 males; age 57+/-9.5 years; body mass index (BMI) 31+/-5.1kg/m(2)]. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) surfaces, and hepatic steatosis were automatically calculated using in-house software. Weight, height, BMI, waist circumference, hip circumference, and waist:hip ratio were recorded. The probability of having a steatosis greater than 10% on MRI was evaluated by receiver operating characteristic (ROC) curves. RESULTS: The anthropometric parameter best correlated to hepatic steatosis was the waist-to-hip ratio (r=0.301). VAT and proportion of VAT were correlated to liver fat content (r=0.307 and r=0.249, respectively). No significant correlations were found for BMI, hip circumference, and SAT. The area under the receiver operating characteristics (AUROCs) for the relationship between liver steatosis and BMI, waist circumference, waist:hip ratio, VAT surface, and proportion of VAT, were respectively 0.52, 0.63, 0.71, 0.73 and 0.75. CONCLUSION: Adipose tissue distribution is more relevant than total fat mass when assessing the possibility of liver steatosis in overweight patients.

Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans?

The precise cause of insulin resistance and type 2 diabetes is unknown. However, there is a strong association between insulin resistance and lipid accumulation - and, in particular, lipotoxic fatty acid metabolites - in insulin-target tissues. Such accumulation is known to cause insulin resistance, particularly in skeletal muscle, by reducing insulin-stimulated glucose uptake. Reduced fat-oxidation capacity appears to cause such lipid accumulation and, over the past few years, many studies have concluded that decreased mitochondrial oxidative phosphorylation could be the initiating cause of lipid deposition and the development of insulin resistance. The aim of this review is to summarize the latest findings regarding the link between skeletal muscle mitochondrial dysfunction and insulin resistance in humans. At present, there are too few studies to definitively conclude that, in this context, mitochondria are functionally impaired (dysfunction in the respiratory chain). Indeed, insulin resistance could also be related to a decrease in the number of mitochondria or to a combination of this and mitochondrial dysfunction. Finally, we also consider whether or not these aberrations could be the cause of the development of the disease or whether mitochondrial dysfunction may simply be the consequence of an insulin-resistant state.

A truncated ultrasound screening procedure for atheroma of the cervical arteries in asymptomatic diabetic patients: evidence from a retrospective study.

AIM: To demonstrate that ultrasound screening of diabetic patients presenting with no cerebrovascular symptoms for evaluation of atheroma of the cervical arteries can be limited to the carotid arteries. METHODS: We retrospectively analyzed the results of cervical artery ultrasound imaging of diabetic patients with no cerebrovascular symptoms. This diabetic population was divided into two subpopulations according to whether or not the vertebral and subclavian artery findings were normal or abnormal. RESULTS: Of the 760 patients who fulfilled the criteria for study inclusion, the ultrasound imaging findings of the vertebral and subclavian arteries were normal in 712 cases. Review of the files of the 48 remaining patients showed that findings for either the vertebral or subclavian arteries did not lead to any changes in patient management because of associated risk factors, carotid atheroma or peripheral arterial disease. CONCLUSION: A vascular risk evaluation in diabetic patients could include ultrasound imaging assessment for cervical artery atheroma and our data suggest that such an evaluation could be focused solely on the carotid arteries.

Distribution of adipose tissue: quantification and relationship with hepatic steatosis and vascular profiles of type 2 diabetic patients with metabolic syndrome.

AIM: As the distribution of fat is increasingly related to cardiovascular events, we examined whether or not abdominal-fat quantification using magnetic resonance imaging (MRI) software is reliable, and whether or not it is related to clinical markers of fat distribution as well as to metabolic and vascular status. METHODS: We recorded the anthropometric measurements of 34 obese type 2 diabetic patients with metabolic syndrome. The patients were enrolled to evaluate their abdominal (visceral and subcutaneous) adipose tissue by single-slice L3-L4 MRI. Manual and automated analyses were compared. The relationships between anthropometric measurements, biological markers and intima-media thickness of the common carotid artery were also assessed. RESULTS: We validated the automated software to quantify abdominal-fat deposition with MRI compared with manual measurements (r2=0.95). The waist-to-hip-circumference ratio (WHR) was the only clinical parameter that correlated with the proportion and quantity of visceral and subcutaneous abdominal-adipose tissue evaluated by MRI (r=0.60). In addition, fat repartition as evaluated by WHR was related to hepatic steatosis parameters (ferritin and ALAT) and to intima-media thickness, whereas simple waist circumference was not a determinant in these obese patients. We also showed that the adiponectin-to-leptin ratio was related to adipose tissue distribution. CONCLUSION: Distribution of abdominal fat, as evaluated by MRI, can be reflected by clinical determination of the WHR. Differences in regional accumulations of abdominal fat may be specifically related to variations in the risks of steatosis and vascular rigidity among obese type 2 diabetic patients.

Severe episodes of extra cellular dehydration: an atypical adult presentation of cystic fibrosis.

Cystic fibrosis (CF) is usually diagnosed during childhood by respiratory or gastro-intestinal symptoms. Hyponatremic hypochloremic dehydration with metabolic alkalosis is a rare but typical presentation of CF in infants. In contrast, only 3 cases have been described in adults. We report a case of CF in a 33-year-old Caucasian female presenting with a severe sodium and chloride depletion caused by inappropriate sweating. She experienced three episodes of severe dehydration before the diagnosis was suspected. Sweat chloride test was pathological and mild pulmonary involvement was found on CT scan. Delta F508 mutation and a rare mutation (3849+40 A/G) on the intron 19 of CFTR gene were found. Interestingly, our patient has a heterozygote twin sister, carrier of the same mutations of CFTR gene who also developed CF but with a different phenotype. We suspect modifier genes to be implicated in the differences observed between the two phenotypes. We discuss the physiopathology of electrolyte disturbance and review the other similar adults cases.

Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes.

Microvascular dysfunction may have an early onset in type 1 diabetes (T1D) and can precede major complications. Our objectives were to assess the endothelial-dependent (acetylcholine, ACh; and post-occlusive hyperemia, PORH), non-endothelial-dependent (sodium nitroprusside, SNP) and neurovascular-dependent (local heating, LH and current induced vasodilation, CIV) microcirculatory vasodilation in T1D patients compared with matched control subjects using a laser speckle contrast imager. Seventeen T1D patients - matched with 17 subjects according to age, gender, Body-Mass-Index, and smoking status - underwent macro- and microvascular investigations. The LH early peak assessed the transient receptor potential vanilloid type 1 channels (TRPV1) mediated vasodilation, whereas the plateau assessed the Nitirc-Oxyde (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways. PORH explored sensory nerves and (EDHF), while CIV assessed sensory nerves (C-fibers) and prostaglandin-mediated vasodilation. Using neurological investigations, we observed that C-fiber and A-delta fiber functions in T1D patients were similar to control subjects. PORH, CIV, LH peak and plateau vasodilations were significantly decreased in T1D patients compared to controls, whereas there was no difference between the two groups for ACh and SNP vasodilations. Neurovascular microcirculatory vasodilations (C-fibers and TRPV 1-mediated vasodilations) are impaired in TD1 patients whereas no abnormalities were found using clinical neurological investigations. Clinicaltrials: No. NCT02538120.

Osteoprotegerin levels are associated with liver fat and liver markers in dysmetabolic adults.

AIM: This study aimed to determine the association between visceral adipose tissue (VAT), liver fat (LF) content, and other markers of the metabolic syndrome (MetS) and osteoprotegerin (OPG) in dysmetabolic adults. METHODS: Subjects from the NUMEVOX cohort were included if they fulfilled at least one MetS criterion. They then underwent a thorough metabolic and cardiovascular evaluation, including arterial stiffness, atherosclerotic plaques, homoeostasis model assessment for insulin resistance (HOMA-IR) indices and OPG. VAT and LF content were measured by magnetic resonance imaging (MRI). Ultrasound examination of arteries and arterial stiffness were recorded, and age- and gender-adjusted paired correlations calculated. RESULTS: Body mass index, waist circumference and MRI-derived VAT correlated with OPG, whereas abdominal subcutaneous fat did not. OPG levels were strongly correlated with LF content (r=0.25, P=0.003), liver markers such as alanine aminotransferase (r=0.39, P<0.001) and HOMA-IR index (r=0.39, P<0.0001). Plasma OPG also correlated with arterial stiffness and the number of atherosclerotic sites. CONCLUSION: Plasma OPG levels are positively associated with both liver markers and increased LF content, but not with subcutaneous fat in dysmetabolic men. These findings suggest that elevated OPG levels may play a role in the link between fatty liver disease and enhanced cardiovascular risk.

Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes.

Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = -0.63, P = 0.02). Insulin (+/-1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85alphaPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients.

MRI versus histological methods for time course monitoring of steatosis amount in a murine model of NAFLD.

PURPOSE: Hepatic steatosis is an increasingly frequent disease with potentially severe complications. A simple quantification method is required for pretherapeutic studies to allow steatosis monitoring. This study aimed at evaluating steatosis quantification via a standard 1.5T MRI machine in a murine model. MATERIALS AND METHODS: Eleven groups of two rats received a choline methionine deficient diet. MRI was performed at days 0, 2, 4, 5, 6, 7 and 8, and weeks 2, 3, 4 and 5. A phased array surface coil system was used to acquire a GE T1 in- and out-of-phase multi-echo sequence, with neither cardiac nor respiratory synchronization. Steatosis was calculated with the 3-echoes method. Histological quantifications were performed both by optical analysis (percentage of fatty hepatocytes) and by automated measurement of the area of steatosis (AOS). The reference was total intrahepatic triglycerides (TIT). Protocol was approved by the ethic committee. RESULTS: Steatosis without inflammation, increasing with diet duration, was obtained. MRI provided better agreement (intraclass correlation coefficient) with TIT (0.889, p<0.001) than did AOS (0.629, p=0.001) or optical analysis (0.280, p=0.098). MRI permitted closer monitoring of TIT over time than did AOS or optical analysis. By multivariate analysis, MRI was an independent predictor of TIT on first step and ALT on second step. A model combining these 2 variables provided excellent agreement with TIT (0.953, p<0.001) and permitted excellent monitoring of steatosis over time. CONCLUSION: MRI is reliable, easy, fast and superior to histological techniques for the assessment of hepatic steatosis in a murine model.

Insulin resistance, polycystic ovary syndrome and metformin.

Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.

Molecular mechanisms of insulin-stimulated glucose uptake in adipocytes.

The stimulation of muscle and adipose tissue glucose metabolism, which is ultimately responsible for bringing about post-absorptive blood glucose clearance, is the primary clinically relevant action of insulin. Insulin acts on many steps of glucose metabolism, but one of the most important effects is its ability to increase the rate of cellular glucose transport. This results from the translocation of the insulin-responsive transporter isoform, GLUT4, from intra-cellular vesicular storage sites to the plasma membrane. In adipocytes, a substantial amount of cellular GLUT4 is located in a specific highly insulin-responsive storage pool, termed GLUT4 Storage Vesicles (GSVs). GLUT4 can also translocate to the plasma membrane from the recycling endosomal pool which also additionally contains the GLUT1 isoform of glucose transporter and the transferrin receptor. In this article we review the molecular mechanism by which insulin stimulates GLUT4 translocation in adipose cells, including the nature of the signaling pathways involved and the role of the cytoskeleton.

What kind of simple fasting index should be used to estimate insulin sensitivity in humans?

The hyperinsulinemic euglycemic glucose clamp method is the gold standard for measuring insulin resistance. However it is complex, and simple indexes have been developed. Some of them are based on formulae that calculate the product or the addition of fasting plasma insulin and glucose values whereas others are based on their ratios. We calculated several simple indexes of insulin resistance and compared them to hyperinsulinemic euglycemic clamp data in 111 subjects with a wide range of insulin resistance. We showed that indexes using insulin and glucose ratios in their formulae are poorly correlated with clamp measurements and give false evaluations, particularly in glucose-intolerant and type 2 diabetic subjects. Thus, whatever the glucose profile of study subjects, we suggest the use of a simple index based on the product or the addition of fasting plasma insulin and glucose values instead of their ratios to obtain insulin resistance evaluations close to the hyperinsulinemic euglycemic clamp technique.

[Should silent corticotroph-cell adenoma be classified as a non-functional pituitary adenoma?]. / L'adénome corticotrope silencieux doit-il être classé dans le groupe des adénomes hypophysaires non fonctionnels?

A 45-year-old man underwent surgery for a silent corticotroph-cell pituitary adenoma which developed in 9 months. The tumor was termed silent because it exhibited increased corticotropic secretion without clinical signs of hypercorticism. This classes it as a non-functional adenoma. The non-functional group includes different types of adenomas such as gonadotroph and other silent thyreotroph and somatotroph adenomas with variable proliferative potential. Silent corticotroph-cell adenoma is considered as an aggressive tumor. In contrast, gonadotroph adenomas usually grow slowly and postoperative tumor remnants can remain stable for years. Because of this variability in tumor growth, the therapeutic decision is difficult if there is a postoperative remnant. No precise guidelines can be established. We suggest that non-functional pituitary adenomas should be considered separately, according to the histological type. This classification is essential for improving knowledge and specifying indications for radiotherapy.

[Regional and peripheral arterial stiffness measured by pOpmetre® in patients with Cvx risk factor, link with carotid plaques]. / Rigidité artérielle mesurée par pOpmètre® chez les patients à risque cardiovasculaire, lien aux plaques d'athérome carotidien.

PURPOSE: Aortic stiffness is a functional and structural consequence of ageing and arteriosclerosis. Regional arterial stiffness can be easily evaluated using pOpmetre(®) (Axelife SAS, France). This new technique assesses the pulse wave transit time (TT) between the finger (TTf) and the toe (TTt). Based on height chart, regional pulse wave velocity (PWV) between the toe and the finger can be estimated (PWVtf). pOpscore(®) index is also calculated as the ratio between PWVtoe and PWVfinger and can be considered as a peripheral vascular stiffness index. The aim of the study was to evaluate the relationship between pOpmetre(®) indices and the presence of carotid plaques in a population with cardiovascular risk factors. METHODS: In 77 consecutive patients recruited for a vascular screening for atherosclerosis (46 men aged 54 ± 2 years; 31 women aged 49 ± 3 years; ns), the difference between TTt and TTf (called Dt-f), the regional pulse wave velocity between the toe and the finger (PWVtf = constant × height/Dt-fm/s) and pOpscore(®) were measured by pOpmetre(®). Presence of carotid plaques was assessed using ultrasound imaging. The local aortic stiffness (AoStiff) was evaluated by the Physioflow(®) system. RESULTS: No difference was found between patients with or without carotid plaques (n=25 versus 52) for Ankle-Brachial Pressure Index (ABPI: 1.15 ± 0.04 versus 1.12 ± 0.03), nor for diastolic or systolic blood pressure (87 ± 3 versus 82 ± 2; 137 ± 3 versus 132 ± 2 mmHg). The first group was older than the second (59 ± 2 versus 49 ± 2 years, P<0.002) with a larger intimae media thickness (0.69 ± 0.02 versus 0.63 ± 0.01 mm, P<0.004), a higher AoStiff (10.4 ± 0.7 versus 8.2 ± 0.5m/s, P<0.02), and PWVtf (14.3 ± 1.0 versus 10.7 ± 0.7 m/s, P<0.004) and a shorter Dt-f (57.9 ± 5.1 versus 73.5 ± 3.5 ms, P<0.01). PWVtf (r(2)=0.49, P<0.0001) and Dt-f (r(2)=0.54, P<0.0001) correlated with age. A significant difference in pOpscore(®) index was observed between both groups (1.51 ± 0.3 versus 1.41 ± 0.2, P<0.006). CONCLUSION: Our results show a significant arterial stiffness indices measured by pOpmetre(®) in patients with and without carotid plaques.

MRI measurement of liver fat content predicts the metabolic syndrome.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease among cardiometabolic patients is not completely known because liver biopsy cannot be routinely performed. However, as magnetic resonance imaging (MRI) allows accurate and safe measurement of the hepatic fat fraction (HFF), the aim of this study was to quantify liver fat content in a dysmetabolic adult population. METHODS: A total of 156 adults were included in this cross-sectional study. Liver and visceral fat were assessed by MRI in these subjects, who presented with zero to five metabolic components of the metabolic syndrome (MetS). Arterial stiffness was recorded by ultrasonography, and the maximum Youden index was used to set the optimal HFF cutoff value predictive of the presence of the MetS. RESULTS: Overall, 72% of participants displayed three or more MetS components. HFF ranged from 0.3% to 52% (mean 13.4%). Age- and gender-adjusted HFF was positively correlated with BMI (r=0.44), blood pressure (r=0.19), triglyceridaemia (r=0.22) and glycaemia (r=0.31). MRI-measured visceral adipose tissue did not influence the relationship of steatosis with glycaemia, HOMA-IR and carotid stiffness, but there was a dose-response relationship between the number of MetS components and mean HFF. The optimal HFF for predicting the MetS was found to be 5.2% according to the maximum Youden index point. CONCLUSION: This study highlighted the impact of liver steatosis on cardiometabolic abnormalities with an optimal cutoff value of 5.2% for defining increased metabolic risk.

Clinical and metabolic characteristics of patients with latent autoimmune diabetes in adults (LADA): absence of rapid beta-cell loss in patients with tight metabolic control.

AIM AND METHODS: The present study compared the clinical and metabolic characteristics of latent autoimmune diabetes in adults (LADA) with type 2 diabetes, as well as the residual beta-cell function and progression to insulin treatment, over a 2-year follow-up period, of antibody (Ab)-positive and Ab-negative patients who achieved tight glycaemic control (HbA(1c) 7.0+/-0.8% and 6.5+/-0.9%, respectively, at the time of entry into the study). RESULTS: Glutamic acid decarboxylase antibodies (GADA) and/or islet cell antibodies (ICA) were detected in 10% of patients presenting with non-insulin-dependent diabetes. Around half of Ab-positive patients required insulin treatment during the follow-up. Ab-positive patients displayed lower stimulated C-peptide levels both at entry and during the follow-up compared with Ab-negative patients, although no significant decline in C-peptide levels was observed in either subgroup over two years. Nevertheless, Ab-positive patients progressed more frequently to insulin treatment, and stimulated C-peptide tended to decrease in LADA patients who subsequently required insulin, whereas it remained stable in those who were non-insulin-dependent. In those who progressed, the trend towards C-peptide decline persisted even after starting insulin treatment. CONCLUSION: LADA patients demonstrate lower residual beta-cell function than do type 2 diabetes patients. However, those who achieve tight metabolic control do not present with a rapid decline in beta-cell function. Further studies are needed to determine the optimal treatment strategy in such patients.

[Multifactorial and typological analysis of frailty in uncontrolled hypertensives. The Eclat survey]. / Approche multifactorielle et typologique du concept de fragilité chez les patients hypertendus non contrôlés. Enquête Eclat.

OBJECTIVE: The aim of the Eclat survey was to evaluate the frequency of frailty in uncontrolled hypertensives and to individualize different frailty profiles. PATIENTS AND METHODS: This was an observational, prospective, longitudinal survey conducted in the cohort of uncontrolled hypertensive patients aged 55 years or more. Morbid events having occurred between two visits at a 6-month interval were reported. Patients with at least one event were considered to be frail. Predictive factors of at least one event were identified (logistic regression). The analysis was completed by a typological analysis (principal components analysis and clustering). RESULTS: At least one event occurred in 211 (9%) of 2306 patients (males 55%, 67+/-9 years old, blood pressure [BP]=160+/-11/93+/-8 mmHg, diabetes 23%): cardiovascular (1.7%), gerontological (5.5%), onset of diabetes (1.3%), worsening of renal impact (2%). Three frailty profiles were identified: patients at low risk (n=1507, event rate=6%), with neither cardiovascular risk factors nor target organ damage; patients at moderate risk (n=335, event rate=12%) with numerous risk factors but no target organ damage and patients at high risk (n=243, event rate=23%), the older ones, in bad general condition, with target organ damage, sensorial deficits and cognitive disorders. In a population of uncontrolled hypertensives aged 55 years or more, 9% could be considered as frailty. CONCLUSION: Therapeutic measures might be adapted according to the frailty profile of the patient. With respect to treatment management, healthcare behaviour could differ depending on these frailty profiles.

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.