Metformin. Anti-Aging-Guide -- Your plan to stay young

Metabolism. 2005 Mar;54(3):314-20.
The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus.
Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, Shin CS, Kim SY, Lee HK, Park KS.

Abstract Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 mu g/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.

Obstet Gynecol Surv. 2005 Mar;60(3):178-9
Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity.
Baillargeon JP, Jakubowicz DJ, Iuomo MJ, Jakubowicz S, Nestler JE.
Hospital de Clinicas Caracas, Caracas, Venezuela; and the Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
The goal of this randomized, controlled, double-blind trial was to learn whether insulin-sensitizing drugs can improve ovulation frequency and serum-free testosterone (T) in nonobese women with polycystic ovary syndrome (PCOS) whose insulin sensitivity was normal. The 100 women enrolled in the study, 17 to 40 years of age, had normal glucose tolerance, fasting insulin, and peak insulin levels during oral glucose tolerance testing (OGTT). The fasting glucose-to-insulin ratio also was normal. Criteria for PCOS were 8 or fewer menstrual periods in the past year and a serum total T exceeding 70 ng/dL. Participants received 850 mg metformin, 4 mg rosiglitazone, a combination of both treatments, or at least 1 placebo twice a day for 6 months. Treatment began when the women were in the equivalent of the follicular phase of the cycle.Only women given rosiglitazone gained significant body weight (1.1 kg), and the posttreatment body mass index was significantly greater in this group. All actively treated women had a significant decline in their waist-to-hip ratio. Systolic blood pressure fell significantly in all actively treated groups but not in placebo recipients. Diastolic pressure decreased and was similar in all groups at the end of the study. Ovulatory cycles were 6- to 8-fold more frequent with treatment and were highest in women given metformin or combination therapy. Ovulation rates at 6 months were markedly increased except in the placebo group. Menstrual bleeding also was greater in treated women. Combination treatment did not yield additive results for either ovulation or menstrual bleeding. Serum total and free T levels decreased significantly with active treatment. Compared with placebo, fasting insulin levels, the area under the insulin curve during an OGTT, and the OGTT-based insulin sensitivity index improved significantly after metformin or combination therapy, but not after rosiglitazone.The investigators concluded that insulin-sensitizing drugs are effective in nonobese women with PCOS even if baseline insulin sensitivity is normal.

Ann Intern Med. 2005 Mar 1;142(5):323-32.
The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance.
Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, Hamman RF, Ackermann RT, Engelgau MM, Ratner RE; Diabetes Prevention Program Research Group.
University of Michigan Health System, Ann Arbor, Michigan, USA.
BACKGROUND: The Diabetes Prevention Program (DPP) demonstrated that interventions can delay or prevent the development of type 2 diabetes. OBJECTIVE: To estimate the lifetime cost-utility of the DPP interventions. DESIGN: Markov simulation model to estimate progression of disease, costs, and quality of life. DATA SOURCES: The DPP and published reports. TARGET POPULATION: Members of the DPP cohort 25 years of age or older with impaired glucose tolerance. TIME HORIZON: Lifetime. PERSPECTIVES: Health system and societal. INTERVENTIONS: Intensive lifestyle, metformin, and placebo interventions as implemented in the DPP. OUTCOME MEASURES: Cumulative incidence of diabetes, microvascular and neuropathic complications, cardiovascular complications, survival, direct medical and direct nonmedical costs, quality-adjusted life-years (QALYs), and cost per QALY. RESULTS OF BASE-CASE ANALYSIS: Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively. The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately 1100 dollars for the lifestyle intervention and $31 300 for the metformin intervention. From a societal perspective, the interventions cost approximately 8800 dollars and 29,900 dollars per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness improved when the interventions were implemented as they might be in routine clinical practice. The lifestyle intervention was cost-effective in all age groups. The metformin intervention did not represent good use of resources for persons older than 65 years of age. LIMITATIONS: Simulation results depend on the accuracy of the underlying assumptions, including participant adherence. CONCLUSIONS: Health policy should promote diabetes prevention in high-risk individuals.

An Med Interna. 2004 Jun;21(6):288-90.
Lactic acidosis in diabetic patient treated with metformin.
Solano Remirez M, Gonzalez Arencibia C, Alvarez Frias M, Llorente Diaz B, Echegaray Agara M.
Servicio de Medicina Interna. Hospital de Navarra. Pamplona, Spain.
We present a case of metabolic acidosis ina man, recently diagnosed with type 2 Diabetes Mellitus under treatment with metformin. Metformin (along with Fenformin and Butformin) is an oral antihyperglycemic agent belonging to the biguanide group employed in the treatment of non insulin dependent diabetes (NIDDM). Its main use is in associattion with other oral agents in obese diabetic patients with difficult metabolic control. In some of these patients, clearly beneficial developed lactic acidosis, specially in those who have predisposing factors (respiratry failure, liver disease or cardiovascular disease) and/or those who require high dosis. For this reason we describe itacute;s pharmacokinetics, therapeutic indications and its correct use in this type of diabetic patient.

Diabet Med. 2004 Aug;21(8):829-36.
Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome.
Glueck CJ, Bornovali S, Pranikoff J, Goldenberg N, Dharashivkar S, Wang P.
Cholesterol Center, Jewish Hospital, Cincinnati, OH, USA.
Abstract Aims Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre-eclampsia, and was it safe for mother and neonate? Methods In the current study, pre-eclampsia and other pregnancy outcomes were prospectively studied in 90 women with PCOS who conceived on metformin 1.5-2.55 g/day, and had >/= 1 live birth (97 pregnancies, 100 live births) compared with 252 healthy women (not known to have PCOS) with >/= 1 live birth, consecutively delivered in a community obstetrics practice. Results Women with PCOS were older than controls (33 +/- 5 vs. 29 +/- 6 years, P < 0.0001), more likely to be > 35 years old at conception (23 vs. 13%, P = 0.028), much heavier (93 +/- 23 vs. 72 +/- 18 kg, P < 0.0001, BMI 33.8 +/- 7.8 kg/m(2) vs. 25.6 +/- 5.9, P < 0.0001), and more likely to be Caucasian (97 vs. 90%, P = 0.05), but there were similar numbers with preconception Type 2 diabetes mellitus [2/90 (2.2%) vs. 1/252 (0.4%), P = 0.17]. Pre-eclampsia in PCOS (5/97 pregnancies, 5.2%), did not differ (P = 0.5) from controls (9/252, 3.6%), nor did it differ (P = 1.0) in PCOS vs. control primigravidas [2/45 (4.4%) vs. 4/91 (4.4%)]. Development of gestational diabetes in PCOS did not differ from controls [9/95 pregnancies (9.5%) vs. 40/251 (15.9%), P = 0.12]. Of the 100 live births to 90 women with PCOS, there were no major birth defects. Mean +/- sd birth weight of the 80 live births >/= 37 weeks gestation in women with PCOS (3414 +/- 486 g) did not differ from controls' 206 live births >/= 37 weeks (3481 +/- 555 g), P = 0.34, nor did the percentage of >/= 37 week gestation neonates >/= 4000 g (12.5 vs. 17.5%, P = 0.3) or >/= 4500 g (1.3 vs. 2.9%, P = 0.7). Conclusions Metformin is not associated with pre-eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus.

J Assoc Physicians India. 2003 Nov;51:1061-4.
Beneficial effects of triple drug combination of pioglitazone with glibenclamide and metformin in type 2 diabetes mellitus patients on insulin therapy.
Panikar V, Chandalia HB, Joshi SR, Fafadia A, Santvana C.
Department of Diabetes, Lilavati Hospital and KJ Somaiya Medical College.
BACKGROUND: The thiazolidinediones are a class of antidiabetes medication that enhance the actions of insulin in muscle, liver, and adipose tissue. Data have been lacking on their use in combination with both sulfonylurea and metformin among patients of type 2 diabetes who are on insulin therapy secondary to failure of routine oral hypoglycemic drugs in controlling their diabetes. OBJECTIVE: To determine the effects of pioglitazone in combination with sulphonylurea and metformin on diabetes control in patients being treated with insulin due to secondary failure of oral hypoglycemic agents. PATIENTS: One hundred and twenty-four consecutive type 2 diabetes patients (mean age, 57.13 years) attending four centres in Mumbai, who were being treated with insulin were selected. They were switched on to triple drug combination of glibenclamide 5 mg, metformin 500 mg and pioglitazone 15 mg along with insulin. Study participants were required to have type 2 diabetes mellitus for atleast 5 years. Patients were excluded if they had any of the following: serum creatinine concentration greater than 1.5 mg/dl, alanine aminotransferase (ALT) level more than two times the upper limit of normal, symptomatic angina, cardiac insufficiency or history of myocardial infarction. RESULTS: Pioglitazone 15 mg with glibenclamide 5 mg and metformin 500 mg, significantly decreased hemoglobin HbA1c level from 11.5% to 7.32% (P < 0.001), average fasting blood glucose from 194.8 mg/ dl to 124.06 mg/dl (p < 0.01), average post-prandial blood glucose from 256.24 to 162.32 mg/dl (p < 0.01). At 6 months, 43.35% of patients did not need to be continued on insulin. The total insulin requirement in 124 patients reduced by 71.81%. There were no significant side effects, liver enzymes were within acceptable levels, average weight gain was 2.23 kg, significant hypoglycemia was observed in 28 patients with two requiring hospitalisation, these patients were those who did not stick to follow-up schedules. CONCLUSIONS: With proper patient selection, pioglitazone with glibenclamide and metformin can be safely used in patients receiving insulin with good results.

Cochrane Database Syst Rev. 2003;(3):CD003053.
Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.
Lord JM, Flight IH, Norman RJ.
Department of Endocrinology and Metabolism, Peninsula Medical School, South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon, UK, PL6 8DH.
BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogenaemia and insulin resistance. Hyperinsulinaemia is known to be associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES: To assess the effectiveness of insulin sensitising drugs in improving clinical and biochemical features of PCOS. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (December 2002), the Cochrane Central Register of Controlled Trials (Cochrane Library, Issue 4, 2002), MEDLINE (January 1966 to December 2002), and EMBASE (January 1985 to December 2002). SELECTION CRITERIA: Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS: Performed by two reviewers, one blinded to information that could have identified the authors, publisher or results of each study. Fifteen trials were included for analysis, 13 of them using metformin and involving 543 participants. MAIN RESULTS: Meta-analysis showed that metformin is effective in achieving ovulation in women with PCOS with odds ratios of 3.88 (CI 2.25 to 6.69) for metformin versus placebo and 4.41 (CI 2.37 to 8.22) for metformin and clomifene versus clomifene alone. An analysis of pregnancy rates suggests a significant treatment effect for metformin and clomifene (OR 4.40, CI 1.96 to 9.85). Metformin has a significant effect in reducing fasting insulin levels (WMD -5.37, CI -8.11 to -2.63), blood pressure and low-density lipoprotein cholesterol (LDL). There was no evidence of effect on body mass index or waist:hip ratio. Metformin was associated with a significantly higher incidence of nausea, vomiting and other gastrointestinal disturbance, but no serious adverse effects were reported. REVIEWER'S CONCLUSIONS: Metformin is an effective treatment for anovulation in women with PCOS. Its choice as a first line agent seems justified, and there is some evidence of benefit on parameters of the metabolic syndrome. Ovulation rates are higher when combined with clomifene (76% versus 46% when used alone), but there is no evidence to indicate whether there is an increased multiple pregnancy rate with this combination. There is no data regarding its safety in long-term use in young women. It should be used as an adjuvant to general lifestyle improvements, and not as a replacement for increased exercise and improved diet.

Nippon Rinsho. 2003 Jul;61(7):1224-9.
Insulin-sensitizing agents: metformin and thiazolidinedione derivatives.
Satoh J.
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine.
Both metformin and thiazolidinedione derivatives(TZDs) improve insulin resistance, a major pathogenesis of type 2 diabetes, and decrease blood glucose levels without stimulating insulin secretion. Metformin inhibits glucose output from the liver, while TZDs increase glucose utilization in the peripheral tissues. In addition, there has been indicated that these agents ameliorate metabolic syndrome beyond glucose-level lowering. Molecular targets of these agents have recently been revealed; AMP-activated protein kinase (AMPK) for metformin and adiponectin, while PPAR gamma for TZDs which induce gene expression of adipocyte glycerol kinase and adiponectin. Insulin-sensitizing agents are clinically useful for obese diabetic patients with insulin resistance. However, periodical examinations are necessary to avoid serious adverse effects such as lactic acidosis, although rare, by metformin and liver injury by TZDs.

J Clin Endocrinol Metab. 2003 Jun;88(6):2600-6.
Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.
Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de Zegher F.
Endocrinology Unit, Hospital Sant Joan de Deu, University of Barcelona, Barcelona 08950, Spain.
Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

Curr Drug Targets Immune Endocr Metabol Disord. 2003 Jun;3(2):151-69.
Metformin and its liver targets in the treatment of type 2 diabetes.
Radziuk J, Bailey CJ, Wiernsperger NF, Yudkin JS.
Department of Medicine, Ottawa Hospital and University of Ottawa, ON, Canada.
Although a number of assessments disagree, the preponderance of the evidence indicates that the major therapeutic action of metformin in type 2 diabetes (DM2) is on the liver, and glucose production (EGP) in particular. At the level of this organ, the actions of metformin can be characterized as pleiotropic. The major questions addressed here are therefore: (i) the methodological aspects of the determination of glucose fluxes: when glucose production is not found to be elevated in type 2 diabetes, it is not surprising that little action of metformin on this flux is found. The issues of populations examined, experimental protocols, and quantitative methods of flux determination are important in answering this question. Early morning EGP is increased and constitutes a valid target for metformin. (ii) the multiple targets of metformin: metformin acts at a number of sites and interacts with metabolites and hormones. Some of these actions may be expressed at different doses. Although their net effect is therapeutic, not all are oriented towards lowering hyperglycemia, perhaps explaining the more modest effect of this drug than could be anticipated from individual actions. Sites of metformin action can therefore be considered as a compilation of valid therapeutic targets in DM2. Gluconeogenesis, glycogenolysis and glycogen synthesis can be altered by metformin, although in vivo, this also depends on the methodology. Component processes from substrate supply and liver uptake, through a number of glucogenic enzymes, as well as glycogen synthase and phosphorylase have all been shown to be affected. (iii) unifying concepts: reported actions of metformin on the mitochondrial respiratory chain, free fatty acid metabolism, AMP-activated protein kinase, and on membrane proteins directly may all explain subsets of actions that are seen, providing more integrated targets for consideration in the therapy of DM2.

Metabolism. 2003 May;52(5):586-9.
An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress.
Bonnefont-Rousselot D, Raji B, Walrand S, Gardes-Albert M, Jore D, Legrand A, Peynet J, Vasson MP.
Laboratoire de Biochimie Metabolique et Clinique (EA 3617), Faculte de Pharmacie, Paris, France.
Metformin (dimethylbiguanide) is an antihyperglycemic agent used in type 2 diabetes. Beyond its action on glycemic control, metformin exhibits other intrinsic effects that could play a role in prevention against diabetes complications. Some studies thus reported an improvement in the antioxidant status in patients treated with metformin. This might be in part related to its property to limit formation of advanced glycation end products (AGEs) and to decrease the overproduction of free radicals in diabetic subjects. The aim of this study was to investigate the in vitro ability of metformin to modulate the action of reactive oxygen species (ROS) generated either by water gamma radiolysis or by stimulated human leukocytes. Our results showed that metformin at pharmacologically relevant concentrations was in vitro able to scavenge hydroxyl ((.)OH) but not superoxide (O(.-)(2)) free radicals and that hydrogen peroxide did not react with metformin. Nevertheless, when polymorphonuclear cells (PMN) are stimulated by phorbol myristate acetate (PMA), or above all by formyl methionine leucyl phenylalanine (fMLP), a systematic (although nonsignificant) decrease of the ROS-induced chimiluminescence (CL) was observed. These results suggest that metformin could directly scavenge ROS or indirectly act by modulating the intracellular production of superoxide anion, of which NADPH oxidase constitutes the major source. This could contribute to the additional benefits of metformin, especially those related to the improvement in the cardiovascular outcomes in diabetes.

Obstet Gynecol. 2003 Apr;101(4):785-93.
Metformin for the treatment of polycystic ovary syndrome.
Barbieri RL.
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
OBJECTIVE: To familiarize obstetrician-gynecologists with the use of metformin for the treatment of polycystic ovary syndrome (PCOS). DATA SOURCES: Using OVID, 94 English-language articles published after 1966 indexed with the key words "metformin" and "polycystic ovary syndrome" were identified. METHODS OF STUDY SELECTION: Studies were excluded if they did not have a control group, did not use the National Institutes of Health definition of PCOS, did not have a clinical outcome as an end point, and were not in the English language. Reviews were also excluded, leaving 21 articles for inclusion. TABULATION, INTEGRATION, AND RESULTS: Three clinical trials reported that for the treatment of anovulatory infertility caused by PCOS, metformin plus clomiphene is more effective than clomiphene alone in inducing ovulation. For the treatment of irregular menses caused by PCOS in women not attempting conception, metformin therapy may restore ovulatory menses in the majority of women. However, most women will require 4-6 months of metformin therapy before they achieve ovulatory menses. In obese women, metformin plus a low-calorie diet may be associated with more weight loss than a low-calorie diet alone. CONCLUSION: Polycystic ovary syndrome is a common gynecologic endocrine disorder. Obstetrician-gynecologists should be familiar with the indications and contraindications for the use of metformin in their practice.

J Clin Endocrinol Metab. 2003 Mar;88(3):1133-41.
Modulation of hunger by plasma glucose and metformin.
Schultes B, Oltmanns KM, Kern W, Fehm HL, Born J, Peters A.
Department of Internal Medicine I, University of Luebeck, D-23538 Luebeck, Germany.
The plasma glucose concentration is a major short-term regulator of hunger and food intake. In patients with diabetes, therapies lowering plasma glucose are frequently associated with body weight gain, suggesting that lowered plasma glucose leads to increased feelings of hunger and food intake. However, as many physiological and symptomatic responses to low plasma glucose are attenuated after repeated episodes of hypoglycemia, this may also pertain to feelings of hunger. Here we tested whether the stimulatory effect of low plasma glucose on feelings of hunger is likewise reduced by repeated episodes of hypoglycemia. As metformin has been shown to reduce plasma glucose levels without increasing body weight and also to decrease food intake, we tested for possible interacting effects of this substance with hypoglycemia-induced hunger. Feelings of hunger were assessed by rating scales during 3 consecutive hypoglycemic clamps performed on 2 consecutive d in 15 normal weight men. Subjects were tested once while being treated with 850 mg metformin twice daily and once while receiving placebo. Treatment was started 14 d before the clamp experiments and was performed in a random order and double-blind fashion. Hypoglycemia markedly enhanced feelings of hunger (P < 0.001). However, rated feelings of hunger on the first and last hypoglycemic clamps were comparable (P = 0.304). Compared with placebo, metformin decreased feelings of hunger during hypoglycemia (P = 0.015). This reduction was not associated with a decrease in posthypoglycemic food intake as measured by the number of cookies consumed after the last clamp (P = 0.676). Data indicate that the stimulatory effect of low plasma glucose on hunger is not attenuated after repeated episodes of hypoglycemia, which implies that, in contrast to other symptoms, hunger is not subject to adaptive attenuation upon repeated hypoglycemia. Metformin attenuates hypoglycemia-induced hunger, but does not appear to influence posthypoglycemic food intake.

Am J Med Sci. 2003 Feb;325(2):66-9.
Beneficial effects of a glyburide/metformin combination preparation in type 2 diabetes mellitus.
Bokhari SU, Gopal UM, Duckworth WC.
Carl T. Hayden VA Medical Center, Phoenix, Arizona 85012, USA.
BACKGROUND: Type 2 diabetes mellitus is characterized by both insulin deficiency and insulin resistance. Effective treatment often requires therapy directed at both abnormalities. Patients on monotherapy might benefit from a combination agent such as glyburide/metformin, which increases insulin secretion and reduces insulin resistance. METHODS: All patients taking a glyburide/metformin preparation at the Carl T. Hayden VAMC were identified from pharmacy records. Patients with documented hemoglobin A values within 31 weeks prior and between 3 and 33 weeks after initiation of therapy (92 subjects) were examined. RESULTS: Glyburide/metformin combination therapy reduced hemoglobin A levels from 0.087 to 0.083 (P < 0.06). Significant reductions were seen in those patients with initial levels higher than 0.08 (0.094 to 0.087; P < 0.01). No significant reductions were seen in those patients with initial levels lower than 0.08. CONCLUSIONS: In patients on monotherapy or on dual oral therapy with inadequate control, changing to a glyburide/metformin combination preparation may improve glucose control.

Diabetes Care. 2003 Jan;26(1):138-43.
Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial.
Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D.
Division of Endocrinology, Hospital for Sick Children, Toronto, Ontario, Canada.
OBJECTIVE: To evaluate whether, in adolescents with type 1 diabetes, the addition of metformin to insulin and standard diabetes management results in 1) higher insulin sensitivity and 2) lower HbA1c, fasting glucose, insulin dosage (units per kilogram per day) and BMI. RESEARCH DESIGN AND METHODS: This was a randomized, placebo-controlled 3-month trial of metformin therapy in 27 adolescents with type 1 diabetes, high insulin dosage (>1 unit. kg(-1). day(-1)), and HbA1c >8%, with measurements of insulin sensitivity (by frequently sampled intravenous glucose tolerance test [FSIGT]), HbA1c, insulin dosage, and BMI at the onset and end of treatment. RESULTS: At t = 0, HbA1c was 9.2 +/- 0.9%, insulin dosage was 1.2 +/- 0.2 units. kg(-1). day(-1), fasting glucose was 10.6 +/- 2.4 mmol/l, and BMI was 24.2 +/- 3.9 kg/m2 (means +/- SD), with no difference between the metformin and placebo groups. At the end of the study, HbA1c was 0.6% lower in the metformin group than in the placebo group (P < 0.05). This was achieved at lower daily insulin dosages (metformin group -0.14 +/- 0.1 vs. placebo group 0.02 +/- 0.2 units. kg(-1). day(-1); P < 0.05), with no significant change in BMI. Fasting glucose levels improved significantly in the metformin group (P < 0.05). Change in insulin sensitivity, measured by FSIGT, was not significantly different between the two groups at study end. Mild hypoglycemia occurred more frequently in the metformin-treated than in the placebo subjects (1.75 +/- 0.8 vs. 0.9 +/- 0.4 events. patient(-1). week(-1); P = 0.03). There were no differences in frequency of severe hypoglycemic episodes or gastrointestinal complaints between the two groups. CONCLUSIONS: Metformin treatment lowered HbA1c and decreased insulin dosage with no weight gain in teens with type 1 diabetes in poor metabolic control. Changes in insulin sensitivity were not documented in this study using the FSIGT. Long-term studies will determine whether these improvements are sustained and whether certain subgroups accrue greater benefit from this therapy.

Diabetes Care. 2002 Dec;25(12):2133-40.
Combination of insulin and metformin in the treatment of type 2 diabetes.
Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD.
Department of Internal Medicine, Bethesda Hospital Hoogeveen, Drenthe, the Netherlands.
OBJECTIVE: To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin. RESEARCH DESIGN AND METHODS: Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured. RESULTS: Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P < 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P < 0.0001); reduced weight gain (-0.4 vs. +1.2 kg, P < 0.01); and decreased plasma LDL cholesterol (-0.21 vs. -0.02 mmol/l, P < 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS-In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less.

J Nephrol. 2002 Jul-Aug;15(4):398-402.
Metformin-associated lactic acidosis: case reports and literature review.
Chang CT, Chen YC, Fang JT, Huang CC.
Department of Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
BACKGROUND: Lactic acidosis is a widely recognized, though rare, side effect of metformin. This paper describes five patients admitted to Chang Gung Memorial Hospital from 1 September 1998 to 31 May 2001 suffering severe lactic acidosis caused by metformin, and reviews the literature. PATIENTS: Five cases diagnosed as having meftormin-associated lactic acidosis (MALA) were discovered during the study period. Three had normal renal function before the onset of MALA and two had attempted suicide bytaking large amounts of metformin. One patient with end-stage renal disease developed MALA despite regularhemodialysis three times a week. One of the patients who had taken metformin to attempt suicide was not diabetic. RESULTS: All patients suffered severe metabolic acidosis with a high anion gap and blood lactate level. Four developed profound hypotension, and three of these also suffered acute respiratory failure. Three patients received conventional hemodialysis and two continuous renal replacement therapy. A young non-diabetic female who had taken a large dose of metformin to commit suicide died from multiple organ failure despite aggressive treatment. CONCLUSIONS: Lactic acidosis is a serious reaction to metformin, and hemodialysis (the treatment of choice) should be done urgently to prevent serious complications. MALA should be suspected in patients presenting with wide anion gap metabolic acidosis and high blood lactate, even when they are non-diabetic.

Diabetes Care. 2002 Jan;25(1):89-94.
Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial.
Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ.
University of California, San Diego Medical Center, San Diego, California 92093, USA.
OBJECTIVE: Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. RESEARCH DESIGN AND METHODS: This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age. RESULTS: Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin. CONCLUSION: Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients.

Br J Clin Pharmacol. 2001 Aug;52(2):137-44.
The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: The Fremantle Diabetes Study.
Davis TM, Jackson D, Davis WA, Bruce DG, Chubb P.
University of Western Australia, Department of Medicine, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959.
AIMS: To determine (i) which factors, including metformin, are associated with the fasting plasma lactate concentration in type 2 diabetes, and (ii) whether plasma lactate is associated with haemodynamic and metabolic effects. METHODS: We measured fasting plasma lactate in 272 well-characterized diabetic patients from a community-based sample, 181 (67%) of whom were taking metformin with or without other therapies. Linear regression analysis was used to identify predictors, including metformin therapy, of the plasma lactate, and to investigate associations between plasma lactate and resting pulse rate and serum bicarbonate. Factor analysis assessed independent relationships between groups of cosegregating variables. RESULTS: Metformin-treated patients had higher plasma lactate concentrations than nonmetformin-treated subjects (geometric mean [s.d. range] 1.86 [1.34-2.59] vs 1.58 [1.09-2.30] mmol x l(-1), respectively; P < 0.001). In a linear regression model, plasma glucose, BMI and metformin use (but not dose) were independently associated with plasma lactate (P < or = 0.028); after adjustment for the former two variables, metformin-treated patients had a mean plasma lactate 0.16 mmol l-1 greater than in subjects not taking the drug. Factor analysis revealed that plasma lactate, plasma glucose, BMI and pulse rate cosegregated but serum bicarbonate was not in this grouping. CONCLUSIONS: The present results show that metformin therapy increases the fasting plasma lactate in ambulant patients with type 2 diabetes from a community-based cohort. From associations in the data we hypothesize that this increase reflects (i) increased sympathetic activity in patients with the metabolic syndrome (ii) increased substrate (glucose) availability and (iii) a direct metformin effect.