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.

Difficulties of smoking cessation in diabetic inpatients benefiting from a systematic consultation to help them to give up smoking.

AIM: To assess the value of systematic smoking cessation consultations for diabetic smokers admitted to hospital. METHODS: All diabetic smokers admitted to the Diabetes Department of Georges Pompidou European Hospital between February 2003 and February 2004 were systematically offered a consultation with a physician specialised in tobacco cessation. Follow-up visits at three, six and nine months were planned. RESULTS: Of the 306 diabetic patients admitted, 38 (12.4%) were smokers. There were more men than women in the group of smokers and the diabetic smokers were younger than the non-smokers. The smokers had fewer micro-angiopathic complications than the non-smokers, but there was no difference in the frequency of macro-angiopathic complications. The level of nicotine physical dependence was moderate or high for 60% of the smokers. Although all the smokers agreed to the consultation, less than half agreed to drug-based treatments to help them to give up smoking and only 15% returned for the six-month visit. Only one patient had stopped smoking at the six-month visit. CONCLUSION: This study demonstrates the difficulties in systematic interventions to help diabetic patients to stop smoking. Diabetic smokers probably constitute a specific population for which the barriers to giving up smoking should be explored.

When should ultrasonography be used to detect asymptomatic carotid atheroma in diabetic patients?

INTRODUCTION: While guidelines for detection of silent myocardial and lower limb ischemia are established, data on screening asymptomatic carotid lesions remain scarce. However, such screening would be costly. Since the prevalence of diabetes increases constantly, it is necessary to keep screening costs low by setting up criteria for the selection of patients at risk of ischemic cerebral attack and those who will need medical or surgical attention. Diabetic patients, particularly type 2, often have many reasons to take anti-platelet agents and lipid-lowering therapy. Therefore, carotid ultrasonography screening would have little effect on treatment modification or on glycaemia and blood pressure objectives, but could improve the prognosis of operable lesions. IN THE GENERAL POPULATION: A one-time screening program was considered worthwhile if the prevalence of severe asymptomatic stenosis was over 20%. The presence of another arterial occlusive disease or other cardio-vascular risk factors could be a major argument for screening. IN DIABETIC PATIENTS: Carotid intima-media thickness (IMT) was recognized as a reliable prognostic indicator of heart attack and stroke. It worsens with duration of diabetes, renal failure, cardiac neuropathy and poor long term glycaemic control. CONCLUSION: Our review suggests that a one-time carotid ultrasonography screening could be recommended for diabetic patients with coronary disease or lower limb atherosclerosis (secondary prevention), all diabetic patients above 60 years of age, smokers, hypertensive and with hypercholesterolemia; type 1 diabetic patients with poor long term glycaemic control; all type 2 diabetic patients with renal failure, a long duration of ill-controlled diabetes or with a carotid bruit. This literature review should be analyzed with caution. It would be helpful to organize a prospective long term study on all types of diabetic patients, including a carotid ultrasonography screening program by experienced radiologists.

Prolonged improvement of total pancreatic allograft function by previous intrathymic bone marrow cell injection in rats.

Donor-specific induction of tolerance was previously achieved in the diabetic rat by intrathymic injection of pancreatic islets. It allowed a secondary islet graft in any site without immunosuppression. Since total pancreatic graft in man is metabolically more proficient than islet graft, we attempted tolerance induction for total vascularized pancreas transplantation in diabetic BN recipient rats by an intrathymic bone marrow cell (BMC) injection from Lewis donor rats, associated to an antilymphocyte antibody (ALS) administration. Control groups consisted of isogenic grafts, allogenic grafts without tolerance induction and allogenic grafts with ALS alone. In all grafted groups, mean blood glucose and plasma insulin were normalised within 24 h. Graft rejection (clinically suggested by diabetes recurrence and later confirmed by histology) appeared at 18 +/- 2 postoperative days in the absence of intrathymic BMC injection and at 36 +/- 8 days in the group with BMC injection (p < 0.05). Intrathymic bone marrow graft was successful in delaying rejection in our study.

Adjustable gastric banding in a public university hospital: prospective analysis of 400 patients.

BACKGROUND: Laparoscopic application of an adjustable gastric band (LAGB) is considered the least invasive surgical option for morbid obesity. It has the advantage of being potentially reversible and can improve quality of life. METHOD: Between April 1997 and January 2001, 400 patients underwent LAGB. There were 352 women and 48 men with mean age 40.2 years (16-66). Preoperative mean body weight was 119 kg (85-195) and mean body mass index (BMI) was 43.8 kg/m2 (35.1-65.8). RESULTS: Mean operative time was 116 minutes (30-380), and mean hospital stay was 4.55 days (3-42). There was no death. There were 12 conversions (3%). 40 complications required an abdominal reoperation (10%), for perforation (n = 2), gastric necrosis (n = 1), slippage (n = 31), incisional hernia (n = 2) and reconnection of the tube (n = 4). We noticed 7 pulmonary complications (2 ARDS, 5 atelectasis) and 30 minor problems related to the access port. At 2 years, mean BMI had fallen from 43.8 to 32.7 kg/m2 and mean excess weight loss (EWL) was 52.7% (12-94). CONCLUSION: LAGB is a very beneficial operation with an acceptable complication rate. EWL is 50% at 2 years if multidisciplinary follow-up remains assiduous. Surveillance for late anterior stomach slippage within the band is essential.

Predictors of response to glimepiride in patients with type 2 diabetes mellitus.

OBJECTIVE: The purpose of DIAMETRE (DIabète et Amarel en Monothérapie. Etude de Titration pour la définition des Répondeurs) was to identify factors predictive of response to glimepiride monotherapy in type 2 diabetic patients in the setting of a prospective multicentre open study. MATERIAL AND METHODS: Patients aged 35-70 years with poorly controlled diabetes [fasting plasma glucose (FPG) > or =1,40 g/l and < 3 g/l at baseline] were treated with glimepiride for 6 months, with dosage titrated from 1-6 mg daily, depending on the monthly FPG measurement. Responders were defined as patients with a) FPG < 7.78 mmol/l (1.40 g/l) and HbA(1c) < 7.5% at endpoint, or b) decrease in FPG > or = 20% and/or HbA1c > or = 10%. Stepwise logistic regression analysis was used to identify factors predictive of response. RESULTS: Of 849 patients evaluable for efficacy, 483 (56.9%) were responders. The response was independently influenced by prior treatment with OADs [OR: 0.399 (0.290-0.549), p=0.0001] and diabetes duration [OR: 0.912 (0.877-0.948), p=0.0001]. Ninety patients (9.2%) experienced 124 episodes of symptomatic hypoglycaemia. Multivariate analysis revealed that a high level of HbA(1c) decreased the risk of symptomatic hypoglycaemia [OR: 0.734 (0.628; 0.858), p=0.0001] whereas a family history of type 2 diabetes doubled this risk [OR: 1.956 (1.246; 3.072), p=0.003]. CONCLUSION: This large-scale study, conducted under conditions approximating to current medical practice, confirms that glimepiride has a favourable risk-benefit ratio in type 2 diabetes mellitus. Diabetes duration and previous treatment with OADs reduced the likelihood of being a responder to treatment.

Type 1 diabetes with no diabetic complications, 62 years later.

We report a type 1 diabetes in an 88-year-old female patient discovered in 1938 at the age of 26. She was promptly put on insulin, which lasted 62 years so far. This patient was highly remarkable because she portrayed a historical case of insulin-treated diabetes diagnosed in 1938. The absence of microangiopathy and specially retinopathy was quite singular, all the more reason that her diabetes was ill-controlled. Environmental or genetic factors may, one day, explain this unusual favourable outcome.

[Laparoscopic gastroplasty for morbid obesity: prospective study of 300 cases]. / Gastroplastie laparoscopique pour obésité morbide: étude prospective de 300 cas.

STUDY AIM: Laparoscopic gastric banding for morbid obesity is noninvasive and reversible. The aim of this prospective study was to report the preliminary results of this procedure in the first 300 patients. PATIENTS AND METHODS: From April 1997 to January 2000, 300 patients were laparoscopically operated for severe obesity: 266 women, 34 men, with a mean age of 40.1 years (range: 16-66). The mean preoperative weight was 118 kg (range: 85-195) and the mean body mass index (BMI) was 43.6 kg/m2 (range: 35.1-65.8). This is a recent and complete series with a mean follow-up of 10 months (range: 3-31). The primary endpoint was excessive weight loss (EWL) and the secondary endpoints were tolerance and morbidity. RESULTS: There were no postoperative deaths. The mean operating time was 129 minutes (range: 50-380). A conversion to laparotomy was necessary in 11 patients. The mean hospital stay was 4.76 days (range: 3-42). There were 29 complications (9.6%), 16 among the first 50 procedures: 14 patients underwent an abdominal reoperation (2 perforations, 3 early slippages, 7 late slippages, 2 incisional hernias); 6 had respiratory complications with 2 ARDS and 9 developed a complication related to the port. At one year, BMI decreased from 43.6 to 33.7 kg/m2 and EWL reached 44.2%; 80% of the patients lost 60% of their excess weight. CONCLUSION: Our experience is encouraging with an acceptable complication rate (5%) after 50 procedures. Slippage remains the main reason for close surveillance. Half of the excess weight can be comfortably lost in one year when the whole medical and surgical staff provide close support for each patient.

Total pancreatico-duodenal transplantation with portal venous drainage: metabolic assessments in diabetic rats.

A perfect metabolic correction of diabetes is essential to completely eradicate long-term chronic complications. Only a total pancreatic graft with portal venous drainage enables such an achievement. Isogenic Lewis rats were used for donors, recipients and controls. Pancreatico-duodenal transplantation was either heterotopic with systemic venous drainage (n = 12) or paratopic with portal drainage (n = 11). All animals were regularly monitored for non-fasting plasma glucose and insulin. Both techniques promptly restored the non-fasting plasma glucose to normal values (p<0.003). Normo-insulinemia (47.4+/-6.4 microU/ml) was obtained in the paratopic group, while the heterotopic group showed hyperinsulinism (132.0+/-15.2 microU/ml). Perfect metabolic control justifies the additional technical difficulties of total paratopic pancreatic transplantation with portal venous drainage.

[Laparoscopic gastroplasty for severe obesity. 300 cases, evaluation of the first 150]. / La gastroplastie par laparoscopie pour grands obèses. 300 cas, évaluation des 150 premiers.

OBJECTIVES: The laparoscopic approach for gastroplasty is gaining widespread acceptance for morbid obesity. Less invasive and potentially reversible, this gastroplasty guarantees better quality of life. We thus evaluated perioperative complications in our consecutive series of 300 patients and followed the excessive weight loss (EWL) for the first 150. PATIENTS AND METHODS: Between April 1997 and January 2000, 300 patients underwent laparoscopic gastroplasty for severe obesity according to the NIH criteria: 266 women, 34 men, mean age 40.1 years (16-66 years). Mean preoperative weight was 118 kg (85-195 kg) and mean body mass index (BMI) was 43.4 kg/m2 (31.5-65.8). Two hundred one patients had 1.3 comorbidity due to excess weight. The first 150 patients were followed 15.5 months (12-31) without any lost to follow-up. Medical, dietary and psychological data were recorded every 3 months for 18 months. The main evaluation criteria was EWL; others were tolerance and morbidity. RESULTS: There was no death. Mean operative time was 129 minutes (50-380), mean hospital stay was 4.76 days (3-42). There were 11 conversions (3.6%). There were 29 complications (9.6%): 11 were postoperative (5 underwent an abdominal operation for 2 perforations, 3 early slippages; and 6 respiratory problems with 2 ARDS) and 18 were late complications (7 late slippages, 2 incisional hernias and 9 port problems). Follow-up of the first 150 patients was complete: at one year, BMI fell from 43.6 to 33.8 kg/m2 and EWL reached 50.5% at 18 months. CONCLUSION: Our experience is recent, but in light of the danger of the spontaneous course of morbid obesity, the results are encouraging due to the absence of mortality and the low rate of complications after the first 50 procedures. Half of the excess weight can be lost in one and a half years. Patient comfort remains quite acceptable with the active support of the surgery and medical teams.

The outcome of advanced chronic nephropathy in type 1 and type 2 diabetic and non-diabetic patients: a prospective study.

To compare end-stage progression of nephropathy in type 1 and type 2 diabetic patients and non-diabetic subjects, we prospectively studied 92 patients with advanced uraemia not yet on dialysis (mean age 57.2 +/- 15.0 years), with a serum creatinine level above 200 mumol/L. The study included monthly serum creatinine (SC) measurements and quarterly outpatient follow-up (mean 10.8 +/- 7.1 months, range 1-21). Sixty subjects (65.2%) were diabetic (28 type 1 and 32 type 2). At inclusion, 95.6% of patients had anti-hypertensive medications. Drug category, dosage and combination were similar for both groups. Blood pressure (< or = 130/85 mmHg) and glucose level targets (fasting < or = 7.5 mmol/L and postprandial < or = 10 mmol/L) were obtained in all patients. Initial SC was not significantly different between diabetic and non-diabetic patients (426.5 +/- 189.4 mumol/L vs. 405.1 +/- 201.9 mumol/L). SC increased significantly faster in diabetic than non-diabetic patients (respectively 3.9 +/- 6.1% and 1.5 +/- 4.6% monthly, p < 0.05), with no difference between type 1 and type 2 diabetes. One-third (33.7%) of all patients started dialysis during follow-up (40% diabetic and 22% non-diabetic). Their weight, body mass index, age, sex ratio, treatment and aetiology were similar. During follow-up, the patients (29.4%) who sustained a major vascular event differed only in age (62.1 years vs. 55.2 years; p < 0.001). In this study, diabetic renal disease worsened significantly faster than other nephropathies, in spite of proper normalisation of blood pressure and glucose level. Therefore, it is essential to diagnose and manage Type 2 diabetes early to avoid encumbering dialysis centres with older patients.

No increase of hypoglycaemia upon transfer of aged longstanding type 1 diabetic patients to human insulin: a prospective randomized study. The Investigators of the Transfert Study.

To assess the frequency and severity of hypoglycaemia following transfer to human insulin, 94 aged Type 1 diabetic patients on animal insulin were randomly assigned either to continue their usual insulin (group A, n = 48) or convert to equivalent preparations of human insulin (group B, n = 46). At inclusion, the two groups showed no differences in age (58.1 +/- 2.2 vs. 54.4 +/- 2.3 years), duration of diabetes (20.8 +/- 1.4 vs. 19.6 +/- 1.6 years) (mean +/- SEM), and glycosylated haemoglobin (HbA1c) values (9.1 +/- 0.2% vs. 8.9 +/- 0.2%). There were 43 eligible patients in group A and 41 in group B. After three months of treatment, HbA1c values were not significantly different between the two groups (8.6 +/- 0.2% vs. 8.5 +/- 0.2%), and there was no difference in the frequency and intensity of hypoglycaemic episodes. Quality of life, as assessed by a questionnaire, was similar at inclusion and after three months. However, the anxiety level was significantly lower in group B. Type 1 diabetic patients were efficiently and safely switched from animal to human insulin without aggravating the incidence of hypoglycaemia, in spite of two major risk factors, i.e. advanced age and diabetes of long duration.

Grafted immunoisolated human benign insulinoma reduces the incidence of diabetes in young NOD mice without abolishing the auto-immunity.

Exogenous insulin may prevent the auto-immunity of diabetes in rodents. We studied the preventive effect of a safe endogenous insulin delivery in the diabetes-prone NOD mouse by immuno-protected human insulinoma grafts. Perm-selective macrocapsules seeded with human insulinoma were implanted in 34 young NOD mice, 4 and 8 weeks old. The animals were observed 18 months and compared to 34 NOD mice grafted with empty fibers and 25 simply observed. Before grafting, the capacity of the macrocapsules to release insulin was assessed in vitro by perifusion studies and by implantation to 12 diabetic NOD mice. At perifusion, the insulin release of the macrocapsules responded to step changes in glucose. During the in vivo study, the capsules reduced the glycemia of diabetic mice from 18+/-3.5 to 7.3+/-2.1 mmol/L. In the study groups, the survival rate without diabetes (50-70%) was statistically different from controls (10-20%). Recipient's splenocytes transplanted to irradiated male NOD mice transferred the autoimmunity in 75-83% of grafted mice and 86-100% of controls. Insulitis was persistent in all, although milder in the grafted mice. Encapsulated insulinoma prevents diabetes in the NOD mouse without abolishing the auto-immunity. The quantity and quality of the tissues needed and the best moment to graft them have to be determined. The prevention of diabetes by encapsulated pancreatic tissue is appealing because of its simplicity and safety.

Pancreatic transplantation in experimental non-insulin-dependent diabetic rats.

The effect of pancreatic transplantation on noninsulin -dependent diabetes mellitus (NIDDM) had not been evaluated in animal models. We assessed its impact by the insulin-glucose clamp study in experimental diabetic rats. NIDDM was induced in Lewis female rats by streptozocin at the age of 5 days (n5-STZ). To determine its effect on insulin sensitivity, we measured the glucose turnover rate and performed euglycemic hyperinsulinemic clamp studies, evaluating hepatic glucose production (HGP) and glucose uptake. This assessment was conducted on 5 groups of 6 female Lewis rats: 2 groups n5-STZ tested at the age of 10 and 14 weeks, respectively; 2 normal age-matched groups; and a fifth group (n5-STZ) transplanted at 10 weeks of age and tested at 14 weeks. Heterotopic pancreaticoduodenal transplantation was performed, using an end-to-side anastomosis between the donor celiac artery and portal vein to the recipient infrarenal aorta and vena cava, respectively. Pancreatic drainage was achieved by an end-to-side duodenojejunostomy. At 10 weeks of age, diabetic n5-STZ rats showed decreased body weight, hyperglycemia, moderate insulinopenia, a significantly higher basal HGP as compared with normal controls (28.5 +/- 10 vs. 10.7 +/- 4 mg/kg/minute, P<0.05), and ineffective suppression of the HGP by the insulin infusion. Glycemia, body weight, and basal HGP were normalized in the transplanted group and were statistically similar to age-matched normal controls. HGP was totally suppressed by the insulin infusion. However, the blood insulin level remained significantly higher than in the normal groups (P<0.05). We conclude that n5-STZ is a reliable model of NIDDM and that pancreatic transplantation, without immunosuppressive drugs in this isogenic line, corrects all tested parameters of glucose homeostasis and improves insulin sensitivity.

[Is there a role for pancreas transplantation in the treatment of type II diabetes mellitus? Experimental study]. / Y a-t-il une place pour la transplantation pancréatique dans le traitement du diabète du type II? Etude expérimentale.

There is no experimental basis for transplantation of the pancreas in patients with non-insulin-dependent diabetes mellitus. We compared results in normal and grafted non-insulino-dependent Lewis rats. A heterotopic pancreatico-duodenal graft was implanted with end-to-side anastomosis of the coeliac artery and the portal vein of the donner on the infrarenal aorta and inferior vena cava of the recipient. The diabetic rats showed weight loss, high blood glucose levels (3.30 +/- 1.25 milligrams), moderate insulinopenia and significantly elevated liver production of glucose. Glycaemia, weight and liver production of glucose were the same as those in the group of normal animals. We concluded that transplantation of the pancreas in an isogenic model without immunosuppression can correct glucose levels and insulino-resistance. It could be suggested in man.

[Demography and effects of chronic renal insufficiency in Ile-de-France]. / Démographie et incidence de l'insuffisance rénale chronique en Ile-de-France.

In order to assess the incidence of chronic renal failure (CRF) and the demographic characteristics of affected patients, a prospective, multicenter epidemiologic study was conducted with the cooperation of all nephrology and dialysis units in the Ile-de-France district, the total population of which is 10660000 inhabitants (source: national census, march 1990). Included were patients with a plasma creatinine (Pcr) concentration > or = 200 mumol/l referred during the one-year period from July 1, 1991 until June 30, 1992. The overall response rate was 98.5%. A total of 2775 adult patients were recorded, including 1780 males (64%) with a mean (+/- SD) age of 58.1 +/- 16.3 years and a mean Pcr of 447 +/- 214 mumol/l, and 995 females (36%) with a mean age of 59.2 +/- 16.4 years and a mean Pcr of 425 +/- 185 mumol/l. Age of patients was < 40 in 16%, 40-59 in 31%, 60-74 in 34% and > or = 75 years in 19%. Pcr was 200-399 mumol/l in 54%, 400-599 mumol/l in 25%, 600-799 mumol/l in 12% and > or = 800 mumol/l in 9%. The overall incidence of CRF was 260/million population/year, twice higher in males than in females (348 vs 179/10(6)/year, p < 0.001). Incidence of CRF dramatically rose with age in both genders, with figures as high as 1124 and 356/10(6)/year respectively in male and female patients aged > or = 75 years, vs 288 and 151/10(6)/year in patients aged < 40 years. A sequential evaluation was performed in a representative sample of 251 patients with initial Pcr > or = 300 mumol/l. End-stage renal failure (ESRF) was reached within one year in 99% of patients with PCr > 600, 49% with Pcr 500-599, 24% with PCr 400-499 and 11% with PCr 300-399 mumol/l. Based on these figures, the predicted incidence of ESRF within one year of referral was 864 out of the 2775 patients, an estimated annual incidence of 81 patients per million population. In conclusion, this prospective study affords the first direct information on the incidence of chronic renal failure and the demographic characteristics of patients with CRF in the Ile-de-France district. Due to the design of the study conducted only in nephrology units, the estimated figure of 81 new patients per million population per year reaching ESRF is a minimal evaluation. In view of the relentless aging of population in France, an incidence of at least 100 ESRF patients per million population per year is to be expected in the next future.