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.

Key priorities in managing glucose control in older people with diabetes.

Older people with diabetes represent a major and increasing proportion of our elderly population and their care requires better organisation. Targets for risk factor control and pathways of care must be adjusted to the subject's general health status. It is thus advisable to screen for frailty. We have carried out a detailed literature review of the studies published on diabetes in older people since 1990. Studies were considered if they included groups or subgroups of diabetic patients > 65 years old. This review discusses the elaboration of general targets for care, the approach to risk factor control, the screening and the specific prevention or management of complications, the integration of geriatric concepts in diabetes care and the specificity of education with respect to frailty status.

A call to incorporate the prevention and treatment of geriatric disorders in the management of diabetes in the elderly.

The prevalence of type 2 diabetes increases with age. However, the management of diabetes in the elderly has received surprisingly little attention. Diabetes in the elderly is associated with a high risk of geriatric syndromes including malnutrition and sarcopenia, functional impairments, falls and fractures, incontinence, depression and dementia. Tight glycaemic control for the prevention of vascular complications is often of limited value in the elderly. However, glycaemic control and non-pharmacological therapy may prevent diabetes symptoms and delay geriatric syndromes. The prevention, screening and treatment of both conventional diabetic complications and geriatric syndromes should be integrated in a management plan to optimize the patients' overall health status and quality of life.

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.

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.

The elderly diabetic's eyes.

This review article attempts to clarify current and future issues concerning diabetic retinopathy in the elderly. This retinopathy is often part of multiple geriatric ophthalmological diseases (cataract, glaucoma, age-related macular degeneration [ARMD]). Current management is insufficient. A variety of factors come together to aggravate the situation: the increase in the number of elderly diabetic patients and the decrease in the number of ophthalmologists. Through a review of the literature, seriously lacking in prospective studies specific to the geriatric population, we discuss the epidemiology, the screening problems, and the various issues concerning the overall ophthalmologic and diabetologic management inherent to these patients' age and condition. We stress the seriousness of the visual disability of the older subject, but also the overall morbidity and mortality. We observe that recommendations can only be based on expert opinion. Each section includes a warning on the high iatrogenic risk in this area. The caregiver should avoid two pitfalls: a lax attitude related to fear or defeatism and excessive interventionism that may be inappropriate to the patient's condition.

Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD).

OBJECTIVE: In patients with maternally inherited diabetes and deafness (MIDD), due to 3 243 A > G mutation of mitochondrial DNA (mtDNA), diabetes may present with variable phenotypes. OBJECTIVE: To ascertain the existence of two distinct phenotypes, MIDD1 and MIDD2, in a series of patients with MIDD. DESIGN: Multicenter prospective study. PATIENTS: 77 patients with diabetes and the mtDNA 3243 mutation and 139 control patients with type 1 (T1D) or type 2 (T2D) diabetes, matched according to initial presentation of diabetes, age at onset, sex, and duration of diabetes (24 T1D and 115 T2D, including 55 treated with insulin). MEASUREMENTS: Anthropometric characteristics (height, body weight, body mass index [BMI], sex), family history of diabetes, and characteristics of diabetes (age at onset, treatment, hemoglobin A1c [HbA1c]), extrapancreatic manifestations. RESULTS: In 13 cases (17%, MIDD1), diabetes presented as insulin-dependent from the onset, with ketoacidosis in 6 cases. In 64 cases (83%, MIDD2), diabetes resembled T2D, and was treated with diet in 12 cases, oral hypoglycemic agents in 21 cases, or insulin in 31 cases. Compared with patients with MIDD2, patients with MIDD1 were characterized by lower age at onset of first manifestation of MIDD (25.4 +/- 9.6 vs 33.7 +/- 13.2 Years, P<0.0005), lower body weight (49.1 +/- 7.4 vs 56.3 +/- 10.9 kg, P<0.0025), lower BMI (18.2 +/- 2.3 vs 20.9 +/- 3.6 kg/m2, P<0.0005), and higher HbA1c levels (9.5 +/- 2.0 vs 7.5 +/- 1.6%, P<0.0005). Frequency of family history of diabetes and of extrapancreatic manifestations was the same in both MIDD subtypes. No difference was found within the MIDD2 subtype when comparing patients treated with or without insulin. Compared with matched controls, patients with MIDD had a lower BMI (MIDD1/T1D 18.2 +/- 2.3 vs 24.0 +/- 3.6 kg/m2 and MIDD2/T2D 20.9 +/- 3.6 vs 30.2 +/- 5.9 kg/m2, P<0.0025). Lastly, male patients with MIDD had a shorter height than controls (MIDD1/T1D: 166.1 +/- 3.2 vs 177.3 +/- 6.6 cm and MIDD2/T2D: 168.4 +/- 7.2 vs 173.6 +/- 6.6 cm P<0.025). CONCLUSIONS: These results confirm the existence of two different phenotypes in MIDD, MIDD1 and MIDD2, which may be related to the severity of the mitochondrial disease. The role of other genetic and/or environmental factors in the variable phenotype of MIDD remains to be elucidated.

Hyperhomocysteinemia and arterial aneurysm.

Hyperhomocysteinemia (HCY) is an independent risk factor for atherosclerosis. Arterial aneurysm has rarely been described in association with heterozygous HCY. Here we report two cases of this association. Case 1 was 32-Year-old man who presented with distal trophic manifestations of the lower extremities. Upon investigation, occlusive arterial disease with fusiform aneurysm of both popliteal arteries and occlusion of the left cubital artery were found. Laboratory findings indicated HCY due to homozygous methylene tetrahydrofolate reductase (MTHFR) deficiency. Case 2 was 38-year-old man with no history of trauma who presented with repeated ischemic events involving the right hand in association with isolated aneurysm of the right cubital artery. Histological study demonstrated extensive dystrophic changes in the aneurysmal vessel wall, including sclerohyalin deposits. The only abnormality was homozygous MTHFR deficiency. Pathologic changes induced by HCY in vessel walls may be implicated in early arterial aneurysm. The association of anatomic lesions, young age, and absence of other causes suggests that the relationship between HCY and arterial aneurysm observed in these two patients was not coincidental.

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.

[Treatment of metastatic malignant insulinomas. 2 cases]. / Traitement des insulinomes malins métastatiques. Deux observations.

Malignant insulinomas are slow growing tumours for which the prognosis is worsened by metastatic disease and sequellae of excess hormone secretion. Management of unresectable tumours includes intravenous chemotherapy and local treatments such as palliative surgery and transcatheter arterial embolization of liver metastases. Long-term survival can also be improved by inhibition of secretory products of the tumour with either octreotide, a somatostatin analogue, or diazoxide. We report two cases of malignant insulinomas with liver metastases for which objective responses were obtained with combination of local treatment and intravenous chemotherapy.

Safety of pentamidine prophylaxis for Pneumocystis carinii pneumonia on the endocrine pancreatic function in HIV patients.

We assessed the pancreatic beta cells function of HIV patients receiving either 300 mg per month of aerosolized pentamidine (n = 12) or oral trimethoprim-sulfamethoxazole (TMP-SMX), twice a day three times per week (TMP: 160 mg, SMX: 800 mg) (n = 10). Intravenous (i.v.) glucose tolerance tests were performed after i.v. injection of 0.5 glucose by kg of body weight in 30 seconds. Plasma insulin levels were assessed at baseline, 1, 2, 3 and 5 min. Moreover, in patients receiving inhaled pentamidine, plasma glucose amylase and insulin levels were measured every 30 min for 2 hours after the end of the aerosol. Plasma pentamidine levels were measured 30 min after the end of the aerosol. Those tests were performed every 2-3 months for one year. In most patients taking aerosol treatment, pentamidine levels were detectable, remaining under levels of 50 ng/ml. Pentamidine plasma levels increased in a time dependent manner. Baseline plasma glucose, amylase and insulin levels were in normal range and remained stable during the therapy. For 7 out of 12 patients, glucose tolerance tests showed an adequate insulin secretion: the addition of the two best insulin levels were higher than 70 IU/ml. When this criteria was not found (n = 5), a glucagon stimulation test allowed to exclude an endocrine pancreatic dysfunction. Due to its apparent short half-life, increased pentamidine levels could be related to an improvement of spray techniques as well as to a cumulative effect. Pancreatic function was preserved in pentamidine-treated patients compared to TMP-SMX-treated patients.

[Hepatic involvement associated with ingestion of metapramine]. / Atteinte hépatique associée à la prise de métapramine.

The authors report the cases of 3 women who developed hepatic injury during administration of metapramine, a tricyclic antidepressant introduced in France in 1984. One patient had jaundice and pruritus; the 2 others had loss of weight. Serum alkaline phosphatase and serum transaminase activities were increased in 3 and 2 patients, respectively. Blood hypereosinophilia was found in one patient; erythrocyte sedimentation rate was elevated in 2 patients. The outcome was favorable after drug withdrawal in the 3 patients. Liver biopsy showed centrolobular cholestasis in the 3 patients. There was no rechallenge; in 2 patients, other drugs than metapramine might be implicated in hepatic injury; however, the similarity of these 3 cases suggests that metapramine, like other tricyclic antidepressants, may be responsible for hepatic injury.

Androgen producing adrenal adenoma. Report on a case associated with hyperparathyroidism.

In a 41-year-old hirsute woman, severe hypercalcemia led to the discovery of hyperparathyroidism related to the involvement (hyperplasia/or adenoma) of the 4 parathyroid glands. Plasma and urinary DHA, plasma DHA-sulfate and delta 5 steroid precursors were elevated. Steroid hormone hypersecretion was stimulated by hCG and ACTH, and exhibited a paradoxical rise during dexamethasone administration. Computerized tomography scanning as well as arteriography disclosed bilateral adrenal hyperplasia and left adrenal adenoma. Bilateral adrenal vein catheterization indicated a left/right gradient for delta 5 steroids and delta 5 steroid sulfates. At surgery a left brown adrenal encapsulated adenoma was removed with a hyperplastic adrenal gland. Results of in vitro studies (adrenal steroid content and incubation) together with postadrenalectomy hormonal results suggest that the left brown adrenal adenoma was the main source of excessive androgen production. The infrequent association of an androgen-producing adrenal adenoma with hyperparathyroidism raises the hypothesis of multiple endocrine neoplasia syndrome. However, evidence for this diagnosis is lacking in the absence of other glandular involvement and of family history.