Background The metabolic effects and mechanism of action ofmetformin are still poorly understood, despite the fact thatit has been used to treat patients with non-insulin-dependentdiabetes mellitus (NIDDM) for more than 30 years.
Methods In 10 obese patients with NIDDM, we used a combinationof isotope dilution, indirect calorimetry, bioimpedance, andtissue-balance techniques to assess the effects of metforminon systemic lactate, glucose, and free-fatty-acid turnover;lactate oxidation and the conversion of lactate to glucose;skeletal-muscle glucose and lactate metabolism; body composition;and energy expenditure before and after four months of treatment.
Results Metformin treatment decreased the mean (±SD)glycosylated hemoglobin value from 13.2±2.2 percent to10.5±1.6 percent (P<0.001) and reduced fasting plasmaglucose concentrations from 220±41 to 155±28 mgper deciliter (12.2±0.7 to 8.6±0.5 mmol per liter)(P<0.001). Although resting energy expenditure did not change,the patients lost 2.7±1.3 kg of weight (P<0.001),88 percent of which was adipose tissue. The mean (±SE)rate of plasma glucose turnover (hepatic glucose output andsystemic glucose disposal) decreased from 2.8±0.2 to2.0±0.2 mg per kilogram of body weight per minute (15.3±0.9to 10.8±0.9 µmol per kilogram per minute) (P<0.001),as a result of a decrease in hepatic glucose output; systemicglucose clearance did not change. The rate of conversion oflactate to glucose (gluconeogenesis) decreased by 37 percent(P<0.001), whereas lactate oxidation increased by 25 percent(P<0.001). There were no changes in the plasma lactate concentration,plasma lactate turnover, muscle lactate release, plasma free-fatty-acidturnover, or uptake of glucose by muscle.
Conclusions Metformin acts primarily by decreasing hepatic glucoseoutput, largely by inhibiting gluconeogenesis. It also seemsto induce weight loss, preferentially involving adipose tissue.
The metabolic abnormalities of non-insulin-dependent diabetesmellitus (NIDDM) are generally acknowledged to result from acombination of insulin resistance and impaired insulin secretion.1Since 1975, when the biguanide phenformin was withdrawn fromthe market,2 the only drugs available to treat NIDDM orallyin the United States have been sulfonylureas, which act primarilyby improving insulin secretion.3
Another biguanide, metformin, has recently been approved bythe Food and Drug Administration. Although metformin is as effectiveas the sulfonylureas,4 the drugs differ in several respects:metformin reduces insulin resistance without directly affectinginsulin secretion,4,5 causes weight loss rather than weightgain,4 and has lactic acidosis rather than hypoglycemia as itsmost serious side effect.4
Despite the fact that metformin has been in use for more than30 years, little is known about its primary mode of action orits effects on body composition, energy balance, and lactatemetabolism.4,5 The rate of entry of lactate into plasma andthe conversion of lactate to glucose are both increased in patientswith NIDDM.6 Metformin reduces hepatic glucose output in NIDDM.7,8,9,10In vitro studies suggest that this may be due to the inhibitionof gluconeogenesis.11,12 Such a mechanism of action might diminishthe removal of lactate from plasma and present a risk of lacticacidosis. Phenformin, which was withdrawn from the market becauseof a high incidence of lactic acidosis,2 impaired lactate disposaland increased its production.13,14 This study was thereforeundertaken to determine the primary mechanism by which metforminimproves glycemic control in patients with NIDDM and its effectson lactate metabolism, body composition, and energy expenditure.
Methods
Subjects
We studied 10 otherwise healthy obese patients with NIDDM (6men and 4 women). Their mean (±SD) age was 58±9years, and their body-mass index (the weight in kilograms dividedby the square of the height in meters) was 32.1±3.2;their weight had been stable for several months. The mean (±SD)duration of diabetes was 6±3 years. Two patients werebeing treated with diet, and eight were being treated with sulfonylureadrugs, which were discontinued two weeks before the study. Twopatients were taking levothyroxine, two estrogen, one a thiazide,and two an angiotensin-converting–enzyme inhibitor; thesedrugs were continued at a constant dose throughout the study.The protocol was approved by the Scripps Clinic InstitutionalReview Board, and all the patients gave written informed consent.
Study Design
The patients underwent the metabolic studies described belowbefore and at the end of a 16-week period of metformin treatment.They were advised to maintain their usual diet and activitiesduring the study. The initial dose of metformin was 850 mg oncedaily. It was increased to 1700 mg (850 mg twice daily) andthen to 2550 mg (850 mg three times daily) at two-week intervals,unless a patient had a fasting plasma glucose concentrationbelow 140 mg per deciliter (7.8 mmol per liter), but that didnot happen. During the final 12 weeks, the patients were seenin the clinic every 4 weeks for a pill count and evaluation.
Metabolic Studies
The patients were admitted to the general clinical researchcenter on the evening before the experiments, having consumeda weight-maintaining diet containing approximately 200 g ofcarbohydrate and having abstained from alcohol for at leastthree days. At about 6 p.m., they ate a standard dinner (10kcal per kilogram of body weight, 50 percent carbohydrate, 35percent fat, and 15 percent protein). The next morning, at approximately6 a.m., primed continuous intravenous infusions of [3-14C]lactate(30 µCi, 0.3 µCi per minute) and [6-3H]glucose (30µCi, 0.3 µCi per minute) were started and a bolusdose of [14C]sodium bicarbonate (50 µCi) was administeredintravenously (all from Amersham International, Little Chalfont,United Kingdom). About 2.5 hours later, an ipsilateral dorsalhand vein was cannulated retrogradely and placed in a thermoregulateddevice (65°C) for sampling arterialized venous blood. Atapproximately the same time, a deep vein in the contralateralarm was cannulated retrogradely for sampling venous blood drainingmuscle tissue. An hour later, a primed continuous intravenousinfusion of [9,10-3H]palmitate (0.3 µCi per minute, AmershamInternational) was started. At approximately 10 a.m. and every40 minutes thereafter for 2 hours, blood was drawn simultaneouslyfrom the deep vein and the arterialized hand vein for determinationsof plasma substrate and hormone concentrations and of the specificactivities of glucose, lactate and palmitate. During this 2-hourinterval, total carbon dioxide production and oxygen consumptionwere measured three times for 30-minute periods with a metabolicmonitor (Sensormedics, Anaheim, Calif.) and breath samples werecollected for the determination of the specific activity of[14C]carbon dioxide. Forearm blood flow was determined immediatelybefore the first and after the last blood sampling with electrocapacitanceplethysmography.15
Analytic Procedures
The samples from both the pretreatment and post-treatment studieswere analyzed at the same time. Plasma glucose concentrationswere measured with a glucose analyzer (Yellow Springs Instrument,Yellow Springs, Ohio), plasma lactate by a fluorometric method,15and plasma free fatty acid by an enzymatic method.16 The specificactivities of plasma [3H]glucose, [14C]glucose, and [14C]lactatewere measured after lactate and glucose had been isolated withion-exchange chromatography.17 The concentration and specificactivity of plasma palmitate were determined by high-performanceliquid chromatography.18 Since palmitate represents 30 percentof total plasma free fatty acids, the palmitate results wereextrapolated to represent the total plasma free-fatty-acid concentrationby dividing the values by 0.30. Total-body muscle mass was calculatedfrom anthropometric measurements according to the equationsof Heymsfield et al.19 Carbohydrate oxidation, lipid oxidation,and resting energy expenditure were measured by indirect calorimetry.20Body composition (fat mass and fat-free mass) was determinedby bioelectrical impedance (RJL Systems, Mt. Clemens, Mich.).21
Calculations
The turnover of plasma glucose, lactate, and free fatty acidswas calculated with steady-state equations.22 The percentageof glucose derived from lactate was calculated as the specificactivity of [14C]glucose ÷ (2 x specific activity of[14C]lactate). Glucose turnover from lactate was calculatedby multiplying plasma glucose turnover by the percentage ofplasma glucose turnover derived from lactate. Plasma lactateoxidation was calculated as (VCO2 x specific activity of [14C]carbondioxide) ÷ (specific activity of [14C]lactate x 0.81),where VCO2 is carbon dioxide production and the factor 0.81is introduced to correct for the retention of [14C]carbon dioxidein the bicarbonate pool.6 The clearance of plasma glucose andlactate was calculated as the turnover rate of each dividedby the arterial concentration. The uptake of glucose by theforearm was determined by multiplying the arteriovenous differencein the glucose concentration by the forearm blood flow (expressedas milliliters per 100 ml of tissue per minute). Forearm netbalance, fractional extraction, and the uptake and release oflactate were calculated with standard formulas.23 Values per100 ml of forearm tissue were converted to values per kilogramof forearm muscle as previously described23 and were then extrapolatedto represent whole-body muscle by multiplying the values bytotal-body muscle mass. The clearance of muscle glucose andlactate was calculated by dividing the uptake of each by thearterial concentration.
Statistical Analysis
Unless stated otherwise, the results are expressed as means±SE. Plasma glucose, lactate, and free-fatty-acid resultsrepresent the mean of four samplings at metabolic steady state.Data before and after treatment with metformin were comparedby two-tailed Student's t-test for paired samples and by least-squaresregression analysis with a commercially available software package(CSS Statistica, Tulsa, Okla.).
Results
Dosage and Symptoms
All patients received 2550 mg of metformin daily for the last12 weeks of the 16-week treatment period. Compliance, as determinedby regular pill counts, exceeded 95 percent. Most patients initiallyhad some slight abdominal discomfort, bloating, and alteredsense of taste lasting one to four weeks. All acknowledged havinga mild persistent decrease in appetite.
Weight Loss, Body Composition, and Energy Expenditure
The patients lost approximately 3 kg of weight (Table 1) despitethe absence of change in resting energy expenditure or self-reportedphysical activity. A decrease in body fat mass accounted forabout 88 percent of the weight loss, whereas lean body massdid not change.
Table 1. Effect of Metformin on Body Composition, Energy Expenditure, and Glycemic Control in Patients with NIDDM.
Glycemic Control and Systemic Glucose Metabolism
Both fasting plasma glucose concentrations and glycosylatedhemoglobin values decreased substantially, as did plasma insulinconcentrations; plasma glucagon concentrations did not change.The rate of plasma glucose turnover (hepatic glucose outputand systemic glucose disposal) decreased from 2.8±0.2to 2.0±0.2 mg per kilogram per minute (15.3±0.9to 10.8±0.9 µmol per kilogram per minute, P<0.001)(Figure 1). As shown in Figure 2, hepatic glucose output andfasting plasma glucose concentrations both before and aftermetformin treatment were highly correlated (r = 0.76, P<0.001).Although metformin did not alter the rate of systemic glucoseclearance (1.3±0.1 ml per kilogram per minute beforetreatment vs. 1.3±0.1 ml per kilogram per minute afterward,P = 0.90) or carbohydrate oxidation (0.8±0.1 vs. 0.8±0.1mg per kilogram per minute [4.6±0.3 vs. 4.6±0.3µmol per kilogram per minute], P = 0.94), the proportionof glucose disposal accounted for by oxidation increased significantly,from 32±4 to 45±4 percent (P<0.001).
Figure 1. Fasting Plasma Glucose Concentrations, Clearance, and Turnover and Rates of Carbohydrate Oxidation before and after Metformin Treatment in Patients with NIDDM.
To convert values for plasma glucose to millimoles per liter, multiply by 0.05551; to convert oxidation and turnover values to micromoles per kilogram per minute, multiply by 5.551. Means ±SE are shown, as well as the values for individual subjects.
Figure 2. Correlation of Fasting Plasma Glucose Concentrations with Hepatic Glucose Output (Circles) and Lactate Gluconeogenesis (Diamonds) before and after Metformin Treatment in Patients with NIDDM.
Open symbols refer to pretreatment values, and solid symbols to post-treatment values. To convert values for hepatic glucose output to micromoles per kilogram per minute, multiply by 5.551; to convert values for plasma glucose to millimoles per liter, multiply by 0.05551.
Muscle Glucose Metabolism
Metformin treatment did not alter forearm blood flow, skeletal-musclemass, or skeletal-muscle glucose uptake (Table 2). The clearanceof glucose by muscle increased, as did the proportion of systemicglucose disposal accounted for by muscle.
Table 2. Effect of Metformin on Skeletal-Muscle Glucose and Lactate Metabolism in Patients with NIDDM.
Systemic and Muscle Lactate Metabolism
Metformin treatment did not significantly alter the mean fastingplasma lactate concentration (Table 1) or the rate of plasmalactate turnover (15.2±1.4 µmol per kilogram perminute before treatment vs. 14.4±1.3 µmol per kilogramper minute afterward, P = 0.40) (Figure 3). However, the rateof plasma lactate oxidation increased by 25 percent (from 6.3±0.6to 7.9±0.6 µmol per kilogram per minute, P<0.001),whereas the rate of conversion of plasma lactate to plasma glucosedecreased by 37 percent (from 7.3±0.7 to 4.6±0.6µmol per kilogram per minute, P<0.001). Both beforeand after metformin treatment, the rate of conversion of lactateto glucose and the fasting plasma glucose concentration werehighly correlated (r = 0.64, P = 0.002) (Figure 2).
Figure 3. Plasma Lactate Turnover, Clearance, and Oxidation and Rates of Conversion of Lactate to Glucose before and after Metformin Treatment in Patients with NIDDM.
Means ±SE are shown, as well as the values for individualsubjects.
Metformin treatment did not alter the clearance, fractionalextraction, uptake, or release of lactate by muscle (Table 2).
Plasma Free Fatty Acids and Lipid Metabolism
The mean plasma cholesterol concentration decreased, whereasthe mean plasma triglyceride concentration, plasma free-fatty-acidconcentration and turnover rate, and whole-body lipid oxidationdid not change after metformin treatment (Table 3).
Table 3. Effect of Metformin Treatment on Plasma Free Fatty Acids and Lipid Metabolism in Patients with NIDDM.
Discussion
In this study, metformin led to an improvement in glycemic controlsimilar to that reported in large, controlled clinical trials.4This improvement was attributable primarily to a reduction inhepatic glucose output, since overall glucose disposal decreasedand the rate of systemic glucose clearance did not change. Furthermore,the reduction in hepatic glucose output could be accounted forlargely by the inhibition of gluconeogenesis.
After metformin treatment, hepatic glucose output decreasedby 0.7 mg (4.5 µmol) per kilogram per minute and the amountof glucose produced from lactate decreased by 0.2 mg (1.4 µmol)per kilogram per minute. Conventional isotopic measurementsof the incorporation of lactate into glucose underestimate theamount of lactate converted to glucose by as much as 40 percent,6because of the dilution of radiolabeled carbon in the Krebscycle. Moreover, the incorporation of lactate into plasma glucosenormally accounts for only about 60 percent of overall gluconeogenesis.24Taking these factors into consideration, we estimate that metformincould have reduced overall gluconeogenesis by as much as 0.6mg (3.3 µmol) per kilogram per minute. Such a decreasewould account for approximately 75 percent of the reductionin hepatic glucose output.
Our results are consistent with those of in vitro studies demonstratingthat metformin inhibits hepatic gluconeogenesis11,25 and thoseof clinical studies indicating that most of the increase inhepatic glucose output in patients with NIDDM is due to increasedgluconeogenesis.6 Our results, however, do not exclude the possibilitythat metformin may also inhibit glycogenolysis.
Despite the reduced use of lactate for gluconeogenesis duringmetformin treatment, neither the plasma lactate concentrationnor the rate of plasma lactate turnover was changed. Our findingthat metformin increases lactate oxidation provides at leasta partial explanation for this phenomenon and indicates thatmetformin differs considerably from phenformin in its effectson lactate metabolism.
Treatment with phenformin increases the plasma lactate concentrationand entry of lactate into plasma,26 inhibits lactate oxidation,14impairs oxidative phosphorylation,13 and increases the releaseof lactate from muscle.27 Metformin increased lactate oxidationand the proportion of glucose disposal undergoing oxidationwhile not altering the release of lactate from muscle. Thesedifferences may explain why phenformin is associated with a10-fold to 20-fold greater incidence of lactic acidosis thanmetformin.4 Nevertheless, under conditions impairing the oxidativeremoval of lactate, the reduced rate of removal of lactate fromplasma resulting from decreased conversion of lactate to glucoseby metformin could cause excessive increases in plasma lactateand, possibly, lactic acidosis.
Like previous investigators,7,28 we found that energy expendituredid not change during metformin treatment. Since our patientsall had a decrease in appetite and denied any change in physicalactivity, the weight loss accompanying metformin treatment wasprobably attributable to reduced caloric intake. An unexpectedfinding was that the weight loss during metformin treatmentwas largely accounted for by the loss of adipose tissue. Inprevious studies of body composition in people eating caloricallyrestricted diets,29,30 both fat and lean body mass decreased.For example, in a diet study in which subjects lost amountsof adipose tissue similar to those lost in the present study,the loss of lean body mass averaged 1.5 kg,30 five times morethan the small, nonsignificant loss found in the present study.
Differential effects of metformin on adipose tissue and musclemay explain the apparent selective loss of adipose tissue. Whereasthe results of in vitro studies31 and this study indicate thatmetformin improves insulin sensitivity in muscle glucose metabolism,it does not affect the antilipolytic action of insulin on adiposetissue.32 Since plasma insulin concentrations decrease duringmetformin treatment,4 one would expect lipolysis to increase.On the other hand, if the metformin-induced increase in thesensitivity of muscle to insulin included an anticatabolic effectof insulin on protein metabolism, one would expect no changein lean tissue mass.
In many4,8 but by no means all studies,7,9,10 metformin treatmentwas accompanied by an improvement in insulin-stimulated systemicglucose disposal. We found that the uptake of glucose by muscledid not decrease despite a reduction in plasma glucose concentrations,indicating that the efficiency of muscle glucose uptake wasincreased. This increase was documented by our finding of anincrease in the clearance of glucose by muscle. Since thesechanges occurred despite the presence of reduced plasma insulinconcentrations, it appears that metformin treatment improvedthe sensitivity of muscle to insulin. However, whether thisimprovement represents a direct effect on muscle or an indirecteffect due to weight loss33 or a decrease in glucose-inducedinsulin resistance34 is unclear.
In conclusion, metformin treatment improves glycemic controland decreases fasting hyperglycemia in patients with NIDDM,primarily by decreasing hepatic glucose output, an effect largelyaccounted for by the inhibition of gluconeogenesis. Metforminimproves the sensitivity of muscle to insulin and the oxidativedisposal of glucose and lactate in the whole body, while notaltering muscle lactate metabolism, the plasma lactate concentration,or plasma lactate turnover. Finally, weight loss associatedwith metformin treatment appears to involve a preferential lossof adipose tissue.
Supported in part by grants from the National Institute of Diabetesand Digestive and Kidney Diseases (DK-20411); the National Institutesof Health, Division of Research Resources, General ClinicalResearch Center (5MO1-RR 00044 and 5MO1-RR 000954); Lipha Pharmaceuticals,Inc.; and the Deutsche Forschungsgemeinschaft (Stu-192/1-2,to Dr. Stumvoll). Dr. Stumvoll is on leave of absence from theMedizinische Klinik der Universität Tübingen, Germany.
We are indebted to the staff members of the general clinicalresearch center, especially Ms. Marcia Hankammer, Ms. CarolynKoumaras, and Ms. Sue Dastrup; to the study patients; and toour laboratory personnel for their excellent technical help.
Source Information
From the University of Rochester School of Medicine, Rochester, New York (M.S., N.N., G.P., J.E.G.), and the Division of Endocrinology and Metabolism, Scripps Clinic, La Jolla, Calif. (G.D.).
Address reprint requests to Dr. Gerich at the University of Rochester School of Medicine, 601 Elmwood Ave., Box Med/CRC, Rochester, NY 14642.
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