Lactic acidosis: relationship between metformin levels, lactate concentration and mortality.

AIM: The role of metformin in lactic acidosis is regularly questioned. Arguments against a causal role for metformin in lactic acidosis occurrence are the lack of correlation between plasma metformin and lactate levels, as well as between metformin plasma levels and mortality. We aim to analyse these correlations in a large series of lactic acidosis cases recorded in the French nationwide pharmacovigilance database. METHODS: All cases of lactic acidosis spontaneously reported between 1985 and October 2013 associated with metformin exposure were extracted from the pharmacovigilance database. We assessed the statistical correlations between prescribed daily doses of metformin, plasma concentrations of metformin and lactate, pH and plasma creatinine, as well as the relationship between mortality and these variables. RESULTS: Seven hundred and twenty-seven cases of lactic acidosis were reported during the period. Metformin plasma concentration was documented for 260 patients, lactate plasma concentration for 556 patients, pH for 502 patients, creatinine for 397 patients and the vital outcome for 713 patients. Metformin plasma concentration, lactate concentration, pH and plasma creatinine were all correlated (P < 0.001). There were significant differences between surviving and deceased patients in terms of metformin plasma levels (25.2 vs. 37.4 mg/l, P = 0.002) and lactate concentrations (10.8 vs. 16.3 mmol/l, P < 0.001). Thirty per cent of patients died when metformin concentration was > 5 mg/l compared with 11% for patients with concentration < 5 mg/l (P = 0.003). CONCLUSIONS: Our data suggest that metformin accumulation contributes to the pathogenesis and prognosis of lactic acidosis.

Increased levels of soluble Fas in serum from diabetic patients with neuropathy.

OBJECTIVE: The aim of this study was to investigate circulating soluble Fas (sFas) and Fas ligand (sFasL), two transmembrane glycoproteins involved in apoptosis, in the serum of diabetic patients. MATERIAL AND METHODS: We assessed sFas and sFasL serum levels in normal controls (n=15), and in both 42 diabetic patients without complications, or with predominant retinopathy or neuropathy, using sFas and sFasL specific ELISA method. RESULTS: sFasL serum levels were less than 0.1 ng/ml in normal controls and in each group of diabetic patients. In diabetic patients with a predominant neuropathy, sFas serum levels were significantly increased not only when compared with normal controls (13.5 +/- 3.6 ng/ml vs 7.1 +/- 1.1 ng/ml, p<0.001), but also when compared with patients without complications (vs 9.1 +/- 1.8 ng/ml, p<0.001) or with a predominant retinopathy (vs 8.7 +/- 1.9 ng/ml, p<0.001). CONCLUSIONS: These preliminary data suggest that a dysregulation of the Fas system in peripheral neuronal cells may be involved in the increase of sFas observed in diabetic patients with neuropathy.

Maternally inherited diabetes and deafness: a multicenter study.

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.

[High carcinoembryonic antigen level following cancer surgery: another way to detect thyroid medullary carcinoma]. / Taux élevés d'antigène carcinoembryonnaire après exérèse d'un cancer: un autre mode de révélation du carcinome médullaire thyroïdien.

INTRODUCTION: Thyroid medullary carcinoma is usually detected in the presence of an isolated thyroid nodule or in the context of a family disease: familial thyroid medullary carcinoma or multiple endocrine neoplasia type 2A. EXEGESIS: Here we report a third means of detection: an unexplained rise in carcinoembryonic antigen levels after cancer surgery. In each case, the carcinoembryonic antigen increase led to the assessment of the caicitonin plasma level and to a thyroid echography being performed. Thyroid medullary carcinoma was confirmed in every case after surgery. CONCLUSION: Even though the association of thyroid follicular carcinoma with familial adenomatous polyposis is common, the association of thyroid medullary carcinoma with breast or colonic carcinoma remains exceptional and probably accidental. Due to the seriousness of the thyroid medullary carcinoma, it is mandatory to look for it in the event of an unexplained rise in the carcinoembryonic antigen level, by assessing the calcitonin plasma level.

Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.

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.

Expression and coupling of somatostatin receptors in rat adrenal (PC12) and pituitary (GC) cell lines.

Somatostatin (somatotropin release-inhibiting factor, SRIF) interacts with G-protein coupled receptors (sst) designated sst1 through sst5. In PC12 and GC cells, SRIF binding sites were identified and mRNA receptor expression was evaluated. SRIF binding sites were expressed at a much lower density in PC12 (Kd = 21.2 +/- 3.9 nM; Bmax = 31 +/- 8 fmol/mg protein) than in GC cells (Kd = 6.4 +/- 1.6 nM; Bmax = 643 +/- 29 fmol/mg protein). sst3 receptor mRNA (81% of the total) was mainly expressed in PC12 cells, while sst1/2 receptor mRNAs were mostly expressed in GC cells (64 and 29%, respectively). In PC12 cells, adenylyl cyclase (AC) activity was unaffected by SRIF-14 (binding all SRIF receptors), octreotide (specific for sst2/3/5 receptors), BIM 23056 (binding sst3/5 receptors) or CH275 (specific for sst1 receptors), 1 microM each. In GC cells, SRIF-14 or octreotide, but not the two other peptides, significantly inhibited AC activity.

Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth.

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.

Alterations in composition and concentration of lipoproteins and elevated cholesteryl ester transfer in non-insulin-dependent diabetes mellitus (NIDDM).

Cholesteryl esters (CE) exchange between lipoproteins through the action of cholesteryl ester transfer protein (CETP). Situations at high risk for atherosclerosis are often accompanied by an accelerated net mass CE transfer (CET) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). However, the question as to whether the net mass CET is increased or decreased in non-insulin-dependent diabetes mellitus (NIDDM) has led to controversial data. To clarify this point, we have undertaken a detailed study of CET in 105 NIDDM patients by comparison with 17 control subjects. Net mass CET was approximately doubled in NIDDM. Plasma CETP activity and unidirectional CET from HDL to VLDL + LDL (CETHDL-->VLDL + LDL) or from VLDL + LDL to HDL (CETVLDL + LDL-->HDL) were measured under controlled lipoprotein concentrations using radioisotopic assays. No difference was observed in plasma CETP activity between NIDDM and controls. In NIDDM, CETHDL-->VLDL + LDL and CETVLDL + LDL-->HDL were decreased by 25% and 20%, respectively, as a consequence of alterations in lipoprotein compositions. Net mass CET was highly correlated with plasma triglyceride (TG) concentration (r = 0.66, P < 0.001) but not with that of LDL-cholesterol (r = 0.06, P > 0.6). When TG levels were decreased following dietetic recommendations or insulinotherapy, the net mass CET was lowered accordingly. We conclude that net mass CET is accelerated in NIDDM in spite of a decreased unidirectional CETHDL-->VLDL + LDL. This results from a lowered CETVLDL + LDL-->HDL and from elevated TG concentration, and the latter probably reflects a concentration effect of VLDL.

Multiple abnormalities in the transfer of phospholipids from VLDL and LDL to HDL in non-insulin-dependent diabetes.

Transfers or exchanges of cholesterol esters and triglycerides between lipoproteins are mediated by a specialized protein referred to as cholesteryl ester transfer protein (CETP), whereas those of phospholipids (PLs) are facilitated by both CETP and a specific phospholipid transfer protein (PLTP). In the present study, the authors compared phospholipid transfer (PLT) in normal subjects and in patients with non-insulin-dependent diabetes (NIDD), which is associated with an increased risk of atherosclerosis. PLT was measured in different recombination experiments using an isotopic assay in which the transfer of labelled PLs from very low-density lipoprotein (VLDLs) and low-density lipoproteins (LDLs) to high-density lipoproteins (HDLs) was determined. This allowed discrimination between the roles of VLDLs + LDLs, HDLs, and plasma PLT activity (PLTA). VLDL + LDL-dependent PLT, HDL-dependent PLT and PLTA were decreased in NIDD. VLDL + LDL-dependent PLT was found to be negatively correlated with the PL/apolipoprotein B ratio, whereas HDL-dependent PLT was positively correlated with the HDL2/HDL3 and PL/apolipoprotein A-I ratios and negatively correlated with the flow activation energy at the HDL surface. The HDL2/HDL3 ratio was positively correlated with PLTA but not with CETP, which confirms previous reports suggesting that PLTP might act as an HDL conversion factor. These data show that several abnormalities in PLT occur in NIDD and raise the question as to whether a lowered PLT might be a new characteristic of dis factors associated with an increased risk of atherosclerosis.