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We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 10(5) PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases.

The aim of this review is to answer the question "how to detect the gestational diabetes mellitus (GDM) between 24 and 28 weeks of gestation?". Two approaches are well established: one-step approach (75 g-OGTT) and two-steps approach (50 g followed 100g-OGTT). The analysis of the literature shows that each of these methods has a good reproducibility close to 80 %, without requiring preliminary dietetics. The HAPO study provides consistent data about the 75 g-OGTT materno-fetal morbidity related. Furthermore, the one-step approach, relationship two-steps approach, has several advantages: reduction of time of diagnosis and primary care, better tolerance, simpler memorization. We recommend for the screening and the diagnosis of GDM an 75 g-OGTT with three measures: FPG, 1-h and 2-h. The various alternative methods are discussed. The measure of the fasting blood glucose isolated between 24 and 28 weeks of gestation is not a relevant approach. None of the other alternative methods (HbA1c, fructosamine, glycosuria, random and postprandial plasma glucose) cannot be recommended. Indeed, these methods have been addressed in little numerous studies, among heterogeneous populations, using variable criteria, and variable sensitivity values. Only the HbA1c might be useful to detect a pre-pregnancy diabetes mellitus., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

The aim of this review is to provide answers to the question “How does one screen for and diagnose gestational diabetes mellitus (GDM) between 24 and 28 weeks gestation?” Two methods are currently widely used: a one-step approach (the 75g-Oral Glucose Tolerance Test, OGTT) and a two-step approach (the 50g Glucose Challenge Test, GCT, followed by 100g-OGTT). A review of the literature showed that both methods had good reproducibility (around 80%), whilst neither required preliminary diet changes. The data of the Hyperglycaemia Adverse Pregnancy Outcomes (HAPO) study on materno-foetal morbidity provided consistent support in favour of the 75g-OGTT. In addition, this one-step method presents several advantages over the two-step method, i.e. it provides a faster diagnosis time, better tolerance and it is easier to remember. We thus recommend a 75g-OGTT including three measures of the glycaemia at times 0, 1 and 2 hours for the diagnosis of GDM between 24-28 weeks of pregnancy. A discussion of alternative methods revealed that measuring Fasting Glycaemia (FG) between 24 and 28 weeks of pregnancy was unsuitable, and that measuring HbA1c, fructosamine, glycosuria, or random and postprandial plasma glucose was not advisable. This is based on the fact that too few studies have evaluated these methods, and that the studies usually involved heterogeneous populations in varying numbers, using differing criteria and sensitivity values. However, HbA1c measurements may prove useful in detecting pre-pregnancy diabetes mellitus.

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., (2009 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Objective: Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved., Research Design and Methods: The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR., Results: A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17-36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 beta-cells, and ER exit was inhibited by approximately 50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress., Conclusions: We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the beta-cell.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Insulin secretagogues and insulin sensitizers can be combined with one another as well as with other treatments (described below). Alpha-glucosidase inhibitors delay intestinal absorption of carbohydrates and reduce postprandial glycemia. Orlistat and sibutramine improve insulin sensitivity by helping patients lose weight. Orlistat inhibits hydrolysis of dietary triglycerides. Sibutramine, a noradrenaline and serotonin reuptake inhibitor, reinforces feelings of satiety and increases energy expenditure. After approximately 10 years, insulin therapy is usually required together with oral antidiabetic agents (except glitazones) or alone if HbA(1c) (glycosylated hemoglobin) is>6.5%. New guidelines for management of type 2 diabetes were published in 2006.

Drug treatment of 2 diabetes is intended to normalize glycosylated hemoglobin levels (HbA(1c)<6.5%) and thereby prevent the development of micro- and macrovascular complications. Oral antidiabetic agents target the metabolic abnormalities that cause diabetes. The two principal families of oral antidiabetic agents - insulin sensitizers and insulin secretagogues - can be taken together. Thiazolidinediones or glitazones (insulin sensitizers) improve peripheral tissue sensitivity to insulin. Metformin (an insulin sensitizer) reduces hepatic glucose production. Sulfonylureas and meglitinides (insulin secretagogues) stimulate insulin secretion and can cause hypoglycemia. GLP-1 (Glucagon-Like Peptide-1) analogs and DPP-IV (dipeptidyl-peptidase-IV) inhibitors are new drug classes currently under development.

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.

Significant lower limb arterial obstruction is usually detected by Doppler ankle-brachial pressure index (ABPI) measurement. However, ABPI is non-contributory in cases of diabetic medial sclerosis or calcifications and is unsuitable for the detection of small vessel involvement. Thallium-201, a perfusion agent, is frequently used for the investigation of coronary artery disease, and whole-body (201)Tl scintigraphy (WBS) has also been reported to be useful in the assessment of peripheral artery disease (PAD). Thus, we evaluated the clinical feasibility of simultaneous myocardial and lower limb perfusion assessment. WBS was performed after treadmill exercise and myocardial scintigraphy, and again 4 h later. Calf (201)Tl fractional activities (percentage of whole-body (201)Tl uptake) were calculated. We determined a threshold value of normal post-exercise calf (201)Tl uptake (mean of the (201)Tl fractional uptakes minus 2 SD) in a control group of nine healthy volunteers. We checked its accuracy in a pilot group of 25 diabetic patients with proven PAD. This method permitted the detection of lower limb perfusion abnormalities in 38% of 47 asymptomatic diabetic patients with no evidence of PAD. In conclusion, for asymptomatic diabetic patients, whole-body (201)Tl scintigraphy after a treadmill test seems an efficient method of showing lower limb perfusion abnormalities not detected by ABPI measurement. It allows the evaluation of vascular status with no additional inconvenience for patients when performed after myocardial scintigraphy.

Background: Maternally inherited diabetes and deafness (MIDD), which is seen in 0.5% to 2.8% of patients with type 2 diabetes mellitus, is related to a point mutation at position 3243 of mitochondrial (mt) DNA. Its clinical description is incomplete., Objective: To study the clinical presentation and complications of diabetes in patients with MIDD and to identify clinical characteristics that may help select diabetic patients for mtDNA mutation screening., Design: Multicenter prospective descriptive study., Setting: 16 French departments of internal medicine, diabetes and metabolic diseases, or both., Patients: 54 patients with type 2 diabetes mellitus and the mtDNA 3243 mutation., Measurements: Characteristics of diabetes, metabolic control (glycosylated hemoglobin level), complications of diabetes, and involvement of other organs., Results: On average, patients with MIDD were young at diabetes onset and presented with a normal or low body mass index. None were obese. Seventy-three percent of probands had a maternal family history of diabetes. Diabetes was non-insulin-dependent at onset in 87% of patients; however, 46% of patients had non-insulin-dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. Eighty-six percent of patients who received an ophthalmologic examination had macular pattern dystrophy (a specific retinal lesion). Forty-three percent of patients had myopathy, 15% had cardiomyopathy, and 18% (9 of 51) had neuropsychiatric symptoms. Although the prevalence of diabetic retinopathy was 8% among patients who received an ophthalmologic examination, lower than expected after a mean 12-year duration of diabetes, prevalence of kidney disease was 28%. This suggests that a specific renal involvement was the result of mitochondrial disease., Conclusions: Maternally inherited diabetes and deafness has a specific clinical profile that may help identify diabetic patients for mtDNA testing.

Objective: To evaluate the prevalence of macular pattern dystrophy (MPD) in maternally inherited diabetes and deafness (MIDD), a new subtype of diabetes mellitus that cosegregates with a mutation of mitochondrial DNA (i.e., the substitution of guanine for adenine at position 3243 of leucine transfer RNA) and to report the clinical characteristics of MPD., Design: Prospective cohort study., Participants: Forty-six patients from 29 families with an adenine-to-guanine mutation of mitochondrial DNA were recruited from a French collaborative multicenter study. Thirty-five patients had MIDD, 8 were asymptomatic children of MIDD patients, and 3 had MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). The 33 MIDD patients with diabetes were matched for diabetes duration and gender with 33 patients with "common" type-2 diabetes to compare the prevalence of diabetic retinopathy (DR) in both series., Methods: All patients had a full ophthalmologic examination and fundus photographs., Main Outcome Measures: The presence and severity of MPD and DR were assessed in each patient., Results: Thirty MIDD patients (85.7%) of 35 exhibited bilateral MPD characterized by linear pigmentation surrounding the macula and optic disc. In 24 of these 30 patients, visual acuity was 20/25 or more in both eyes. The prevalence of DR was 6% in MIDD patients with diabetes versus 15% for patients with common type-2 diabetes (a difference that was not significant, P = 0.23). The fundus of each of the eight asymptomatic children was normal. MPD was present in one of the three cases of MELAS., Conclusion: The prevalence of MPD in MIDD is high. Its detection may be helpful for the diagnosis of this new subtype of diabetes, for which specific treatments may be proposed.

The mechanisms of chronic diarrhoea, a frequent symptom in diabetes mellitus, are multifactorial and complex, although small intestinal bacterial overgrowth and autonomic neuropathy seem to play a major role. This study evaluated the prevalence of small intestinal bacterial overgrowth and the effects of antibiotic treatment in a population of diabetic patients with chronic diarrhoea (defined as > 3 stools/24 h, weight > 200 g/24 h, duration > 3 weeks). Small intestinal bacterial overgrowth syndrome was diagnosed by glucose-hydrogen breath testing (sensitivity: 78%, specificity: 89%). The characteristics of diarrhoea (duration, number of stools per day, and gastrointestinal symptoms) were noted. Autonomic neuropathy was assessed by cardiac parasympathetic tests. A total of 35 patients were included, 15 with small intestinal bacterial overgrowth syndrome (43%, group 1) and 20 with no bacterial overgrowth (group 2). Age (52.9 +/- 13.5 vs. 53.9 +/- 11.8 years, NS), duration of diabetes (13.8 +/- 9.1 vs. 10.6 +/- 7.8 years, NS), and HbA1c level (10 +/- 2.9 vs. 10.9 +/- 2.4%, NS) were not different between the two groups. In group 1, duration of diarrhoea was longer (18.1 +/- 18.5 vs. 7.75 +/- 4.02 months, P = 0.05), the number of stools higher (7.1 +/- 5.7 vs. 4.6 +/- 2.6/24 h, P < 0.05), and gastrointestinal symptoms more frequent (13 vs. 10, P < 0.05). The prevalence of small intestinal bacterial overgrowth syndrome and gastrointestinal symptoms was not different in patients with and without autonomic neuropathy (9 vs. 8 and 12 vs. 11 respectively, NS). Eight patients with bacterial overgrowth received antibiotics (amoxicillin-clavulanic acid, 1.5 g/24 h for 10 days). Dramatic clinical improvement was observed in 6 out of 8 of these patients. It is concluded that small intestinal bacterial overgrowth should be considered in case of chronic diabetic diarrhoea because of its frequency (43%), facility of diagnosis, and often successful treatment with antibiotics.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

Relationships between glycaemic control, hypertension, and development of microangiopathy have been well documented in Type 1 (insulin-dependent) but not in Type 2 (non-insulin-dependent) diabetes mellitus. Therefore, we have investigated these relationships in a cohort of 64 Type 2 patients free of retinopathy (by angiofluorography), who were regularly followed until development of retinopathy or for at least 7 years as outpatients. Glycaemic control was assessed by 1 to 4 HbA1 determinations per year. Retinal status was monitored by annual angiofluorography. Nonproliferative retinopathy developed in 14 patients (cumulative incidence at 13 years: 29.8%) after a mean diabetes duration of 14.3+/-8.9 years (range 2-27). In multivariate analysis (Cox model), mean HbA1 during follow-up (p < 0.001), and hypertension at first examination (p = 0.09) were associated with the development of retinopathy, but age, sex, BMI, diabetes duration, smoking, and fasting blood glucose were not. The relative risk for developing retinopathy (RR) was 7.2 (IC 95%: 1.61-32.4) in patients with a mean HbA1 during follow-up above the median value of the cohort (8.3%) compared with patients with HbA1 during follow-up below this value. RR was 2.5 (IC 0.8-8) in patients with HbA1 at first examination above compared to below the median value (8.4%). RR was 3.0 (IC 0.9-10) in patients treated for hypertension at baseline compared to those without treatment. A sixfold increase in retinopathy prevalence was observed between patients with mean HbA1 in the highest or lowest quartile of mean HbA1 distribution during follow-up. This longitudinal study indicates a strong association between long-term glycaemic control and the development of diabetic retinopathy in Type 2 diabetes.

Diabetes mellitus comprises a heterogeneous group of diseases which have chronic hyperglycaemia in common as well as the resulting microvascular, macrovascular and neurological complications of this condition. Familial studies have provided strong evidence for the existence of genetic determinants in the different types of diabetes. In particular, monozygotic twin studies have indicated a higher rate of concordance in non-insulin-dependent (NIDDM) than in insulin-dependent diabetes mellitus (IDDM). In IDDM, 8 susceptibility loci have been identified, notably the HLA complex and insulin promotor gene. Rigorous family studies have identified monogenic subtypes representing 10-15% of all NIDDM: MODY2 related to glucokinase gene mutations, MODY1 and MODY3 secondary to mutation of hepatic nuclear factors, and diabetes resulting from deletion or mutation of mitochondrial DNA. Most NIDDM result from polygenic heredity, and susceptibility genes conducive to increased receptivity to deleterious environmental influences are now under investigation, such as beta 3 adrenergic receptor, FABP2 and OB. Precise analysis of phenotypes in the remaining families or systematic screening of the genome could allow the genes of each subtype to be identified. Finally, susceptibility genes for the increased severity and frequency of vascular complications have been identified, such as angiotensin converting enzyme, aldose reductase and aldehyde dehydrogenase genes. This progress has been facilitated by developments in molecular biology.