Metformin as a protective agent against natural or chemical toxicities: a comprehensive review on drug repositioning.

BACKGROUND: Metformin is the first prescribed drug for hyperglycemia in type 2 diabetes mellitus. Mainly by activating AMPK pathway, this drug exerts various functions that among them protective effects are of the interest. PURPOSE: Herein, we aimed to gather data about the protective impacts of metformin against various natural or chemical toxicities. RESULTS: An extensive search among PubMed, Scopus, and Google Scholar was conducted by keywords related to protection, toxicity, natural and chemical toxins and, metformin. Our literature review showed metformin alongside its anti-hyperglycemic effect has a wide range of anti-toxic effects against anti-tumour and routine drugs, natural and chemical toxins, herbicides and, heavy metals. CONCLUSION: It is evident that metformin is a potent drug against the toxicity of a broad spectrum of natural, chemical toxic agents which is proved by a vast number of studies. Metformin mainly through AMPK axis can protect different organs against toxicities. Moreover, metformin preserves DNA integrity and can be an option for adjuvant therapy to ameliorate side effect of other therapeutics.

Unexpectedly long half-life of metformin elimination in cases of metformin accumulation.

INTRODUCTION: In a study of the oral administration of a single dose of metformin to healthy participants, the estimated half-life (t½ ) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation. METHODS: We systematically reviewed all the data on plasma and erythrocyte metformin assays available in our centre. We then selected patients with a plasma metformin concentration ≥ 5 mg/l and in whom the metformin concentration had been remeasured once or more at least 5 days after admission. RESULTS: Twelve patients met the aforementioned criteria. All but one of these patients displayed generally severe lactic acidosis on admission (mean ± sd pH and lactate: 6.88 ± 0.35 and 14.8 ± 6.56 mmol/l, respectively) and 11 were treated with dialysis. The mean ± sd time interval between the first and last blood sample collections for metformin measurement was 8.3 ± 3.2 days (range 5-14 days). Five days after the first sample had been collected, metformin was still detectable in plasma and in erythrocytes in all patients. Metformin remained detectable for up to 13 days (both in plasma and in erythrocytes). The estimated mean terminal t½ for metformin in plasma and erythrocytes was 51.9 and 43.4 h, respectively. CONCLUSIONS: The prolonged elimination of accumulated metformin (even after dialysis therapy) challenges the traditional view that the drug clears rapidly because of a short half-life in plasma.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Metformin accumulation without hyperlactataemia and metformin-induced hyperlactataemia without metformin accumulation.

AIM: These case reports demonstrate that, at the individual level, blood metformin concentrations and metformin effects on lactate do not always correlate. METHODS: We report here on two unusual cases: metformin accumulation in the absence of hyperlactataemia; and metformin-induced hyperlactataemia with no metformin accumulation. RESULTS: Patient #1 presented with severe kidney failure, severe acidosis (pH: 7.04), normal lactataemia (0.90 mmol/L) and marked metformin accumulation. Patient #2 presented with hyperlactataemia, even after dose reduction, during otherwise well-tolerated metformin treatment. Arterial lactate levels were 8.8, 8.2 and 4.7 mmol/L during metformin therapy with daily doses of 2550, 1700 and 850 mg, respectively. After withdrawal, metformin was reintroduced for 5-day periods at 500 mg/day up to 2000 mg/day with washout intervals. Lactate concentration, normal at baseline, rapidly exceeded 2 mmol/L after metformin administration. CONCLUSION: These clinical data suggest a new concept for metformin therapy: there may be either resistance or, conversely, hypersensitivity to metformin effects on lactate generation according to the individual patient.

The relationship between metformin therapy and sleep quantity and quality in patients with Type 2 diabetes referred for potential sleep disorders.

AIMS: Given that sleep disorders are known to be related to insulin resistance, and metformin has favourable effects on insulin resistance and on ventilatory drive, we sought to determine whether metformin therapy was related to sleep variables in a group of patients with Type 2 diabetes. METHODS: We performed a retrospective, observational study of our centre's database for patients referred for potential sleep disorders and then compared metformin-treated patients with those not treated with the drug. All study patients had undergone the same standard polysomnographic procedure. A multivariate analysis was performed to establish whether or not there was an independent relationship between metformin use and sleep variables (after adjusting for age, gender, BMI, neck circumference, cumulated risk factors and insulin use). RESULTS: We studied 387 patients (mean ± sd age: 58.4 ± 10.8 years), of whom 314 had been treated with metformin. Total sleep time and sleep efficiency were higher in metformin-treated patients than in patients not treated with metformin [total sleep time: 6 h 39 min vs. 6 h 3 min, respectively (P = 0.002); sleep efficiency: 77.9 ± 12.3 vs. 71.5 ± 17.2%, respectively (P = 0.003)]. These differences persisted after adjustment for covariates and were observed even although metformin users had a higher BMI than did non-users (median 37.5 vs. 34.8 kg/m(2) ; P = 0.045). CONCLUSION: We showed that metformin therapy is associated with a longer sleep duration and better sleep efficiency. Randomized clinical trials are needed to confirm metformin's favourable effect on sleep quality and quantity.

The criteria for metformin-associated lactic acidosis: the quality of reporting in a large pharmacovigilance database.

AIMS: To study the quality of pharmacovigilance reporting in cases of so-called 'metformin-associated lactic acidosis' and, ultimately, whether or not the criteria for this condition are indeed met. METHODS: We searched for cases meeting the criteria for metformin-associated lactic acidosis [arterial pH < 7.35, blood lactate > 5 mmol/l (45 mg/dl) and detectable plasma metformin concentration] in a 15-year period (1995-2010) in a pharmacovigilance database of the license holder for metformin (Merck Serono, Lyon, France). RESULTS: We found 869 reports stated as 'metformin-associated lactic acidosis' from 32 countries. The respective criteria for pH, lactate concentration and metformin concentration were met in 51.2, 53.3 and 13.9% of cases. All three criteria were met in just 10.4% of cases. By year, each of the percentages remained roughly stable throughout the study period. CONCLUSIONS: The role of metformin in triggering metformin-associated lactic acidosis was assessed incorrectly in most patients and the quality of reporting did not improve over time.

Efficiency of laparoscopic sleeve gastrectomy on metabolic syndrome disorders: two years results.

OBJECTIVES: There are very few studies evaluating the efficacy of sleeve gastrectomy on the metabolic syndrome, truly a worldwide pandemic. The main objective of this study was to retrospectively determine the evolution of the metabolic syndrome and its associated comorbidities (type 2 diabetes, arterial hypertension, and dyslipidemia) at 24 months after sleeve gastrectomy. The secondary objective was to determine the predictive factors for resolution of this syndrome. MATERIAL AND METHODS: Between July 2004 and February 2008, 241 patients with morbid obesity (males: 17%) underwent sleeve gastrectomy in our center. Patients were seen in combined medical and surgical outpatient postoperative follow-up consultation at 3, 6, 12 and 24 months. Patients were classed as responders or not, according to whether or not the metabolic syndrome (as defined according to the National Cholesterol Education Program-Adult Treatment Panel III [NCEP-ATPIII]) disappeared at 24 months follow-up. RESULTS: Thirty-six patients (15% of all patients, 30% of males) presented initially with metabolic syndrome. Twenty-six patients (72%) still had metabolic syndrome at 6 months, 17 patients (47%) at 12 months, and 13 patients (36%) at 24 months. The main parameters that regressed after sleeve gastrectomy were type 2 diabetes and hypertriglyceridemia. In univariate analysis, only one parameter (systolic blood pressure) appeared to be a factor of non-resolution of the metabolic syndrome at 24 months. CONCLUSION: Our study showed that sleeve gastrectomy reduced the incidence of the metabolic syndrome and several of its components.

Autoimmune polyendocrine syndrome type 1 in north-western France: AIRE gene mutation specificities and severe forms needing immunosuppressive therapies.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS1) has been poorly evaluated in France. We focused on the north-western part of the country to describe clinical phenotypes, especially severe forms of the disease, and AIRE gene mutations. METHODS: Clinical and immunological data were collected, and pathological mutations were identified by DNA sequencing. RESULTS: Nineteen patients were identified with APS1. Clinical manifestations varied greatly, showing 1-10 components. Mucocutaneous candidiasis, adrenal failure, hypoparathyroidism, alopecia and other severe infections were the most frequent components. Four patients had severe forms, needing immunosuppressive therapy: 2 for hepatitis; 1 for severe malabsorption, and 1 for a T cell large granular lymphocytic leukemia. These therapies were very effective but caused general discomfort. One patient died of septicemia. Four different AIRE gene mutations were identified, and a 13-bp deletion in exon 8 (c.967-979del13) was the most prevalent. There was at least one allele correlating with this mutation and alopecia occurrence (p = 0.003). No novel mutation was detected. CONCLUSION: APS1 appears to be rare in north-western France. We identified 4 cases with a severe form needing immunosuppressive therapy. The AIRE gene mutations are more like those found in north-western Europe than those found in Finland.

[The eye and anorexia nervosa. A case report]. / Oeil et anorexie mentale. A propos d'un cas.

INTRODUCTION: Vitamin A deficiency occurs in the poor in developing countries and is one of the main causes of blindness by perforative corneal complications. It is a rare pathology in industrialized countries and it is associated with an absorption syndrome. The authors report the first case of hypovitaminosis A in a patient suffering from chronic and severe anorexia nervosa. CASE REPORT: The patient suffered from epiphora, photophobia, and hesperanopia. The ophthalmologic findings were keratoconjunctival xerosis with bilateral corneal ulcerations. The visual field showed a concentric bilateral restriction of isopters with tubular central vision, a similar aspect to retinitis pigmentosa. The ERG was modified with a b2 reduction and normal photopic and impaired scotopic responses. The fluorescein angiography was normal. The serum concentration of retinol confirmed the diagnosis of hypovitaminosis A. Corneoconjunctival improvement was obtained with vitamin supplementation, but no campimetric improvement was observed. DISCUSSION: The corneoconjunctival signs result from direct destruction of goblet cells, whereas the campimetric deficit is explained by a dysfunction of rod cells. Rhodopsin, necessary to the survival of the cell, cannot be renewed if retinol is not present, which causes a permanent bright light stimulation that is lethal for the photoreceptor. CONCLUSION: Vitamin A deficiency is rarely caused by psychiatric disease. Even if the main clinical finding is xerophthalmia with a high risk of keratomalacia, the visual prognosis can also be engaged by dysfunction of photoreceptors.

Effect of metformin on survival rate in experimental sepsis.

AIM: Because "metformin-associated lactic acidosis" refers to metformin and concurrent pathologies as co-precipitating factors, the respective impact in the outcome of metformin therapy, metformin accumulation, and general diseases should be determined. We therefore constructed a model of sepsis in mice treated with metformin at a dose corresponding to clinical practice, or to accumulation. METHODS: 460 mice were separated in 3 groups: no metformin therapy, a 7-day metformin therapy at 50 mg.kg(-1).day(-1) (MET50) or 500 mg.kg(-1).day(-1) (MET500). Blood was drawn on day 7 in 40 metformin-treated animals for determining metformin concentrations. The 420 other mice were divided in 14 subgroups according to the amount of an intra-peritoneal inoculum of E. coli ranging from 5.103 to 1010 CFU/ml in order to construct a lethal dose curve. The survival rate was assessed at 7, 13, 24, 36, 60 and 120 hours thereafter. RESULTS: Plasma metformin concentrations were 0.26 +/- 0.13 mg/l in MET50, and 4.63 +/- 1.92 mg/l in MET500. The comparative analysis of the survival rates at 120 hours showed no difference of mortality, always occurring for an inoculum amount > 10(8) CFU/ml. Comparing the survival rates from time 0 to 120 hours using Kaplan-Meyer curves and the Logrank test, there was no difference between the different groups. CONCLUSION: Metformin, even at a dose mimicking accumulation, does not aggravate the mortality rate in this model of sepsis. Consequently, metformin can not be considered as toxic in such a condition.

Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.

OBJECTIVES: Although the existence of a deep compartment for metformin has long been hypothesized, there is still little direct information concerning metformin distribution in individual tissues in man. The only available study involves chronic metformin therapy. In that study, the measurement of metformin in erythrocytes provided a reliable indicator of metformin distribution and of potential accumulation. To determine the kinetics of metformin in plasma and in erythrocytes after acute oral administration, we performed the present study in healthy subjects after a single oral dose of metformin and compared the pharmacokinetics parameters in erythrocytes to those in plasma. METHODS: Six nondiabetic participants took the study dose of 850 mg metformin at 8: 00 AM after a non-standardized breakfast (i.e., as recommended in clinical practice). Blood samples were collected for metformin measurement in plasma and in erythrocytes at 0, 1, 2, 3, 4, 6, 9, 24, 33, 48, 57, and 72 h. RESULTS: Maximum metformin concentration was attained at 3.0 +/- 0.3 h in plasma and 4.7 +/- 0.5 h in erythrocytes. This difference was not significant. Metformin concentrations peaked at a maximum almost 6 times higher in plasma than in erythrocytes (1.7 +/- 0.1 and 0.3 +/- 0.0 mg/l, respectively). However, because the elimination half-life of metformin was much longer in erythrocytes (23.4 +/- 1.9 h vs. 2.7 +/- 1.2 h), there was no difference in area under the curve between plasma and erythrocytes. The distribution volume (plasma) was calculated to be 146 +/- 11 l. Plasma and erythrocytes concentration-time curves showed that metformin was not detectable in plasma 24 hours after the oral administration, while it remained detectable in erythrocytes up to 48 hours. Metformin concentrations crossed approximately 13 hours after having reached their maximum values in plasma, approximately 16 h after metformin intake. CONCLUSION: Having demonstrated the rapid elimination of metformin from plasma and its slow disappearance from erythrocytes, the presents results should contribute to adjustment of metformin dosage to renal function, assessment of drug compliance, and retrospective analysis (when blood samples are drawn with delay) of the link between metformin and development of lactic acidosis. Most importantly, the present findings should help to ascertain the optimal dosage of metformin, particularly in elderly patients.

Measurement of metformin concentration in erythrocytes: clinical implications.

AIMS: Although pharmacokinetics studies have long suggested a deep compartment for the antidiabetic drug metformin, there is still little information concerning metformin accumulation by individual tissues in man. In the present study, the erythrocyte was chosen to represent this putative deep compartment and metformin concentration in erythrocytes (EM) was compared with that in plasma (PM) to delineate clinical implications. METHODS: A reference group of 58 patients with well-tolerated metformin treatment was studied to provide standard mean metformin concentrations in the fasting state. Secondly, to provide transverse data reflecting clinical practice, the authors reviewed an investigation group of 93 metformin-treated patients with available PM and EM, which had been requested either to adjust metformin dosage to renal function, or to screen for potential metformin accumulation following renal failure, metformin overdose or lactic acidosis. Thirdly, the case of an individual with major metformin accumulation was studied to provide information about metformin elimination. RESULTS: From the bulk of data, we performed three types of analyses: (1) PM and EM were compared. In the investigation group, this comparison was extended to subgroups separated according to low-to-normal, moderately increased or highly increased metformin concentration. (2) Correlative analyses of PM, EM and serum creatinine were performed. (3) A kinetic study of the spontaneous decline of PM and EM was conducted. PM and EM were, respectively, 0.5 +/- 0.4 mg/l and 0.8 +/- 0.4 mg/l in the reference group, and 11.7 +/- 17.8 mg/l (mean +/- SD, range 0.0-71.9 mg/l) and 7.5 +/- 9.4 mg/l (0.0-34 mg/l) in the investigation group, mean serum creatinine of which was 290 +/- 258 micro mol/l. In the low-to-normal PM subgroup (n = 28), PM and EM were, respectively, 0.39 +/- 0.38 mg/l and 0.84 +/- 0.68 mg/l (p < 0.001). In the moderately increased PM subgroup (from therapeutic concentrations +2 SD to 5 mg/l, n = 24), PM and EM were 2.82 +/- 1.13 mg/l and 2.72 +/- 2.03 mg/l (NS). In the sharply increased PM subgroup (> 5 mg/l, n = 41), PM and EM were 27.6 +/- 23.2 mg/l and 17.0 +/- 11.4 mg/l (p = < 0.001). PM and EM were tightly correlated (r = 0.72 in the reference group and r = 0.90 in the investigation group, p < 0.001 for both). Metformin concentrations were also correlated with those of serum creatinine, but more so in the investigation group; in subgroups, a positive correlation was found only at high metformin concentrations and in erythrocytes. The kinetic study performed in the patient with major metformin accumulation showed that PM and EM dropped within less than 3 days from a maximum concentration of 80.0 mg/l and 20.4 mg/l, respectively, to 0.67 mg/l and 6.52 mg/l. CONCLUSIONS: In conclusion, metformin appears to accumulate in erythrocytes and, consequently, may be part of a deep compartment for the drug. This evidence of slow decline in erythrocyte metformin concentration may contribute to retrospective diagnosis of metformin accumulation and to refinements in adjusting metformin dosage to renal function.

Efficacy and tolerance of calcium alginate versus vaseline gauze dressings in the treatment of diabetic foot lesions.

BACKGROUND: The study aimed at comparing the efficacy and tolerance of an alginate wound dressing with a vaseline gauze dressing in the treatment of diabetic foot lesions. METHODS: This open-label randomized multicenter controlled study was designed to assess the effect of an up to 6-week treatment with either calcium alginate or vaseline gauze dressings. Lesions were either acute or chronic, under cleansing, and with a surface area of 1-50 cm(2); osteomyelitis and severe hypovascularization were non-inclusion criteria. Dressings were changed every day then, once granulation had occurred, every 2 to 3 days. Primary outcome was the proportion of patients with granulation tissue over 75% of the wound area and having a 40% decrease in wound surface area; secondary outcomes were pain on dressing changes, the number of dressing changes, and adverse events. RESULTS: Seventy-seven patients were enrolled. Due to the premature cessation of treatment in 13 patients, it was decided to reduce the period of the efficacy analysis to 4 weeks (without revising the criteria of efficacy). The success rate was of 42.8% in the calcium alginate group and of 28.5% in the vaseline gauze group (not significant difference). A subsequent analysis of granulation tissue surfaces covering the wounds at week 4 (all surfaces taken together) showed a superiority of calcium alginate (p=0.04). Pain on dressing change was lower in the calcium alginate group (p=0.047) and the total number of dressing changes tended also to be lower (p=0.07). Adverse events, which occurred 4 times in the calcium alginate group and 6 times in the other, were judged independent of the treatments. CONCLUSIONS: As compared with vaseline gauze, calcium alginate appears to be more appropriate for topical treatment of diabetic foot lesions in terms of both healing and tolerance.

Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis'.

OBJECTIVE: The link between metformin and lactic acidosis in metformin therapy may be causal, associated or coincidental. Our objective was to investigate this link by studying and analysing published reports of so-called 'metformin-associated lactic acidosis'. RESEARCH DESIGN AND METHODS: systematically searched in the BIOSIS, DERWENT, EMBASE, MEDLINE, and PASCAL databases of the English language and non-English language literature for all reports of so-called 'metformin-associated lactic acidosis' published from May 1995 through January 2000. We did not include reports related to metformin overdose or contrast media-induced renal failure. Metformin accumulation and concurrent pathologies were critically reviewed as precipitating factors for metformin-associated lactic acidosis. Metformin accumulation was assessed in terms of the recorded measurement of metformin concentration in plasma or, if not available, by the presence of primary renal failure, i.e. renal failure that was not secondary to a shock syndrome. RESULTS: We found 21 reports describing a total of 26 patients. Criteria of lactic acidosis (lactate > 5 mmol/l, pH

Metformin retention independent of renal failure in intestinal occlusion.

Metformin is eliminated by the kidneys, and metformin accumulation has always been noticed in oligo-anuric patients. We have reported an exception to the rule with the case of a metformin-treated patient having metformin accumulation contrasting with a mild increase in serum creatinine in the context of a volvulus of the sigmoid colon. This case prompted us to examine the association between intestinal occlusion and plasma metformin concentrations. For this purpose, we developed an experimental animal model of mechanical obstruction of the intestine. Rats were pre-treated during 3 weeks via drinking solution at a dose of approximately 100 mg/kg/day of metformin. They underwent at day 0 either sham-operation (n=7) or operation (n=8) to place a plastic tube around the ileum near the ileocaecal valve. Metformin administration was pursued on days 1, 2, and 3 giving a single dose of 100 mg/kg by intragastric gavage. Four days after the surgery, i.e. 24 h after the last metformin administration, the surviving intestinal obstructed rats (n=8) developed overt intestinal dilation but no biochemical abnormality compared to sham-operated animals (n=7; arterial lactate concentrations respectively 4.87 +/- 0.63 mmol/l and 3.97 +/- 0.30 mmol/l, NS, and serum creatinine concentrations 69.0 +/- 1.7 micromol/l and 68.7 +/- 1.9 micromol/l, NS). By contrast, there was a striking difference with regard to metformin concentrations, decreasing from 2.95 +/- 0.94 mg/l at day 0 to 0.12 +/- 0.03 mg/l at day 4 (p<0.001) in the sham-operated group but remaining unchanged (1.65 +/- 0.76 mg/l and 1.61 +/- 0.51 mg/l) in the operation group. In conclusion, this is the first experiment showing that intestinal occlusion may be responsible for metformin retention in the absence of renal failure. Whether this observation may be relevant to other drugs remains to be established.

Lactic acidosis in metformin therapy.

The biguanide drugs metformin and phenformin have been linked in the past to lactic acidosis, a metabolic condition associated with high rates of mortality. Although concern over the hyperlactataemic effect of phenformin led to the withdrawal of this drug from clinical practice in the 1970s, the situation with metformin has been less clear. Retrospective data indicate that, in metformin-treated patients with lactic acidosis, neither the degree of hyperlactataemia nor accumulation of metformin is of prognostic significance. Furthermore, the lowest rates of mortality were seen in patients with high plasma concentrations of metformin, which has led to the hypothesis that the drug may confer some benefit, linked to an increase in vasomotility, in such cases. Overall, it appears that mortality in patients receiving metformin who develop lactic acidosis is linked to underlying disease rather than to metformin accumulation, and that metformin can no longer be considered a toxic drug in this respect. These findings are likely to be of considerable relevance to the management of patients with type 2 (non-insulin-dependent) diabetes mellitus, especially where such patients are elderly.

Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations.

OBJECTIVE: The antidiabetic drug metformin has been associated in a small number of patients with lactic acidosis, a serious condition with a poor prognosis. However, because of lack of data, the prognostic significance of hyperlactataemia in metformin-treated patients is not known. METHODS: Data were collected from 49 metformin-treated patients with lactic acidosis (arterial lactate level > or = 5 mmol/L and blood pH < or = 7.35) and available plasma metformin concentration data to investigate the association of arterial lactate levels and plasma metformin concentrations with mortality. RESULTS: The overall mortality rate in this patients sample was 45% and the median arterial lactate level was 13.1 mmol/L. Median lactate levels were similar in patients who survived (13 mmol/L) and those who died (14.3 mmol/L), whereas the median plasma metformin concentration was 3 times higher in patients who survived (20.6 mg/L versus 6.3 mg/L). CONCLUSION: In this, the largest series of metformin-treated patients with lactic acidosis yet reported, 55% of patients survived and these patients had a median arterial lactate level of 13.1 mmol/L. Neither arterial lactate levels nor plasma metformin concentrations were of prognostic significance in relation to mortality in this sample of metformin-treated patients with lactic acidosis. Death in these patients appeared instead to be associated with other hypoxic disease or underlying ill health. These observations suggest that accumulation of metformin may not be as significant with respect to high arterial levels of lactate and their effects as has been traditionally thought.

Insulin sensitivity, insulin action, and fibrinolysis activity in nondiabetic and diabetic obese subjects.

Because inconsistencies occur with regard to the relative contribution of insulin to the hypofibrinolysis characteristic of obesity and diabetes, we explored the relationship between insulin and fibrinolysis, assessing both insulin sensitivity and insulin action. Seventeen markedly obese subjects (body mass index [BMI], 34.0+/-1.6 kg/m2; 12 nondiabetic and five diabetic) were studied using the three-step euglycemic-hyperinsulinemic clamp technique. Since the circadian rhythm of the fibrinolytic system may obscure a true effect of insulin, variations in fibrinolysis parameters observed during the glucose clamp were compared with those occurring spontaneously because of the circadian rhythm. Compared with six normal-weight subjects (BMI, 21.0+/-0.9 kg/m2), all obese subjects exhibited basal hyperinsulinism (fasting plasma insulin, 16.0+/-1.4 v 9.8+/-1.3 microU/microL, P < .001; fasting plasma C-peptide, 1.4+/-0.2 v 0.5+/-0.2 ng/mL, P < .001), hypofibrinolysis (euglobulin lysis time [ELT], 378+/-29 v 222+/-31 minutes, P=.01; tissue plasminogen activator [tPA] antigen, 7.8+/-0.9 v 4.2+/-0.5 ng/mL, P=.04; plasminogen activator inhibitor type 1 [PAI-1] activity, 22.2+/-2.5 v3.9+/-0.6 AU/mL, P=.004), and marked insulin resistance (M value, ie, the maximal glucose disposal rate, 9.1+/-0.6 v 18.6+/-0.8 mg/(kg x min), P < .001). The M value correlated inversely with tPA antigen (r=-.46, P=.05). During insulin infusion, values for fibrinolysis parameters decreased, but were not different compared with variations due to the circadian rhythm. In conclusion, our findings together with previously reported data reinforce the idea that chronic hyperinsulinism is linked to hypofibrinolysis, but insulin does not seem to acutely regulate the fibrinolysis system.