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Diabetes & Metabolism
Vol 29, N° 4-C2  - septembre 2003
pp. 635-
Doi : DM-09-2003-29-4-1262-3636-101019-ART4
Articles

Reducing insulin resistance with metformin: the evidence today
 

R Giannarelli, M Aragona, A Coppelli, S Del Prato
[1]  Department of Endocrinology and Metabolism, Section of Diabetes, School of Medicine, University of Pisa, Italy

Tirés à part : S Del Prato

[2]  Department of Endocrinology and Metabolism, Section of Diabetes, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy. Phone: +39 050 995103 Fax: +39 050 541521 E-mail:

Abstract

Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.

Keywords: Insulin resistance , Type 2 diabetes , Metabolic syndrome , Cardiovascular risk factors


Although overt hyperglycaemia does not develop until ?-cell failure develops, insulin resistance is a main feature of type 2 diabetes. The term insulin resistance identifies the inability of insulin to exert a normal biological action at the level of its target tissues. Though insulin exerts a variety of effects, in the current clinical use, insulin resistance refers to the inability of circulating insulin to promote glucose utilisation in the skeletal muscle and adipose tissue, and to properly suppress endogenous glucose production (mainly in the liver). As such insulin resistance not only characterises type 2 diabetes [1]but it is very common in pre-diabetic patients [2]as well as in individuals with central obesity, dyslipidaemia, hypertension, endothelial dysfunction, hyperuricemia, and microalbuminuria [3]. Moreover, insulin resistance is considered central to the metabolic syndrome [4], while more recent epidemiological studies have indicated that insulin resistance may be an independent risk factor for cardiovascular mortality both in the general [5]and diabetic [6]population. Therefore, the comprehension of the mechanisms responsible for impaired insulin action is fundamental in the attempt to ameliorate insulin resistance and to account for the favourable effects of insulin sensitisers. Among these compounds, metformin has the largest clinical use. Employed for almost 50 years in Europe, it has been more recently introduced in the United States. The drug exerts an antihyperglycaemic effect, with minimal risk of hypoglycaemia. The initial observation that metformin reduces plasma glucose levels without increasing, and sometime decreasing circulating insulin levels, has indicated that the drug improves insulin sensitivity. Because of the effect on insulin sensitivity and the low risk of hypoglycaemia, metformin has been recently used for prevention of type 2 diabetes [7]. Moreover, in overweight type 2 diabetic patients, metformin was shown to reduce the risk of both micro- and macrovascular complications [8]. In order to appreciate this insulin sensitising effect, a brief discussion of the pathophysiology and cellular mechanisms of insulin resistance in diabetes and associated conditions is indicated.

Pathophysiology of insulin resistance

Insulin resistance, as measured with the hyperinsulinaemic euglycaemic clamp technique [9], reflects impaired insulin action on glucose metabolism at the level of skeletal muscle, adipose tissue, and the liver.

At the level of the liver, insulin modulates glucose output and enhances the ability of hyperglycaemia to promote glucose uptake. Though the latter is mainly a facilitating effect, insulin activates glycogen synthase and inhibits glycogen phosphorylase thus enhancing glycogen deposition [10]. A more direct effect is played on glucose production. In type 2 diabetic patients with fasting hyperglycaemia the rate of endogenous glucose output is increased in spite of normal or increased fasting plasma insulin concentration [11]. The concomitance of increased endogenous glucose production and high plasma insulin levels provide direct evidence for the liver insulin resistance. Accelerated gluconeogenesis is the major determinant of the excessive glucose release from the liver in diabetic individuals [12]. It is conceivable, in these patients, that reduced glucose oxidation and concomitant increase of anaerobic glycolysis in peripheral tissue could ensure an excessive supply of 3-carbon atom compounds to the liver. Therefore, insulin resistance in peripheral tissues and liver may result in a vicious cycle resulting in progressive increase in fasting plasma glucose levels.

In peripheral tissues, insulin resistance causes impaired glucose utilisation. In insulin-resistant individuals, in response to elevation of circulating plasma insulin, less glucose is transported, phosphorylated, and metabolised inside the cell [13]. By using the combination of the insulin clamp technique, indirect calorimetry, multiple tracers, and arterial-venous forearm balance technique, we have previously shown that the glucose transport and, to a greater extent, phosphorylation [14]in response to insulin are markedly impaired in type 2 diabetic patients. Not only less glucose is transported inside the cell, but the metabolic fate of phosphorylated glucose is altered as well. In mild type 2 diabetic patients, we showed reduced glycogen synthesis and glucose oxidation but increased anaerobic glycolysis [15].

In the adipose tissue, impairment of insulin-mediated glucose- and lipid metabolism results in accelerated lipolysis and increased free-fatty acid (FFA) release [16]. Excessive FFA release is also supported by the lack of the inhibitory effect of insulin on hormone-dependent lipase. Increased FFA availability can worsen hepatic and peripheral insulin resistance [17]and favour VLDL-triglyceride synthesis and release from the liver. Ectopic accumulation of fat in the liver and muscle [18]correlates with the degree of insulin resistance and it is believed to contribute drastically to the impairment of insulin action.

Finally, the progressive increase in plasma glucose and FFA concentration will exacerbate insulin resistance through gluco- [19]and lipotoxicity [17]resulting in a self-perpetuating cycle.

Molecular mechanism of insulin resistance

Insulin-mediated glucose utilisation and metabolism is the final result of the activation of a complex cascade of events involved in the insulin signalling process [20]. Alteration of one or more of these events can result in impaired insulin action. Though complex, three main steps are likely to be involved in the generation of insulin resistance: 1) insulin binding to the cell membrane receptor, 2) insulin receptor phosphorylation, and 3) intracellular insulin signalling.

The insulin receptor is a heterotetrameric protein consisting of two ?-subunits in the extracellular domain and two ß-subunits with main intracellular domain. Upon insulin binding of the ?-subunits, the intrinsic kinase activity in the ß-subunits is activated leading to phosphorylation of the adjacent ß-subunit. The autophosphorylation of the insulin receptor allows the activation of insulin receptor substrate (IRS-1, -2, -3, -4) protein family. These proteins exert an important regulatory action on other mediators like phospho-inositol-3-kinase (PI3-kinase). The contribution of IRS-1 and -2 to insulin resistance has been recently demonstrated with knock-out genetic experiments. These studies proved that IRS-2 can play a vicariate role in absence of IRS-1, while IRS-2 knock-out results in impaired insulin action as well as insulin secretion [21]. Activation of PI3-kinase catalyses the formation of PI-3,4,5-phosphate allowing the activation of PKB/AKT and phosphatidilinositol-3,4,5-phosphate kinase-1 (PDK-1). The phosphorylation of PKB/AKT regulates the kinase cascade involved in the insulin signal transduction responsible for GLUT-4 translocation from the intracellular membrane compartment to the cell membrane allowing active transmembrane glucose transport and phosphorylation, activation of the glycolytic flux, as well as glycogen and protein synthesis. Moreover, PDK-1 determines the phosphorylation and activation of atypical protein kinase ?/?, also modulating GLUT-4 translocation [20].

Given the complexity of the cascade of insulin signalling, several of the steps involved in the generation and propagation of the insulin signal can contribute to the molecular defect of insulin action. A reduced expression and a phosphorylation of the elements involved in the first steps of insulin signalling (IRS, PI3-kinase, PKB) have been found in tissue of type 2 diabetic patients, even if these alterations are primitive (genetic) rather than secondary to the alteration of metabolic milieu, this is still object of debate. The role of specific defects of these proteins has been established by knock-out animal models [21]. For instance, IRS-1, IRS-2, and GLUT-4 knock-out mice have been shown to develop insulin resistance and glucose intolerance. However, it is when polygenic defect is created that an overt diabetes develops, leaving open the possibility that multiple defects are likely to contribute to the pathogenesis of insulin resistance and therefore of type 2 diabetes.

A role for the insulin signalling cascade has been recently demonstrated at the level of the ß-cell as well. ß-cell insulin receptor knock-out (ßIRKO) mice lose acute insulin response to glucose and they develop glucose intolerance [21]. Similarly, IRS-1 deficient islets show impaired glucose-mediated insulin secretion. Human pancreatic islets carrying the Gly972 --> Arg IRS-1 polymorphism also have impaired insulin release as well as a maturation block of the insulin granules and increased apoptosis [22]. Thus, insulin resistance at the level of the ß-cell might play a pathogenetic role in the development of hyperglycaemia of type 2 diabetes.

Effects of metformin of insulin action

The antihyperglycemic effect of metformin is the result of the drug action on the insulin sensitivity on the liver, the muscle, and the adipose tissue. Though the effect on hepatic glucose production is considered preponderant, it is likely that it is the interaction among the effect on the three different tissues that bring about the overall beneficial effect of metformin.

Hepatic glucose production

Metformin exerts its antihyperglycemic effect mainly by inhibiting liver glucose output. Both gluconeogenesis and glycogenolysis are reduced by metformin, though the former seems to play a major role. By using nuclear magnetic resonance spectroscopy, Hundal et al. [23]determined the relative contribution of metformin effects on gluconeogenesis and glycogenolysis. In poorly controlled type 2 diabetic patients, metformin lowered the rate of glucose production through a reduction in gluconeogenesis (Fig 1). The inhibition of gluconeogenesis was associated with overall reduction in hepatic glucose production and 25-30% reduction of fasting plasma glucose. Similar findings have been reported by other investigators using different techniques [24], [25]. Consideration has to be paid to the methodology employed to assess metformin's effect on glucose metabolism in the liver as recently discussed by Radziuk et al. [26].

Nonetheless, the in vivo data are consistent with in vitro studies, also confirming an inhibitory effect of metformin on gluconeogenesis [27], [28]. There are several mechanisms that may account for this effect. In perfused liver, metformin decreases gluconeogenesis through inhibition of hepatic lactate uptake [27]. In isolated rat hepatocytes, metformin lowers intracellular concentrations of ATP, an allosteric inhibitor of pyruvate kinase [28]. Moreover, metformin inhibits pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PEPCK) activity and activates the pyruvate to alanine conversion [29]. A potentiation effect of metformin on the suppressive action of insulin on gluconeogenesis also has received support by in vitro experiments [30]. The primary site of metformin action appears to be the hepatocyte mitochondria. Inhibition of cellular respiration decreases gluconeogenesis [31]and may induce expression of glucose transporters and, therefore, glucose utilisation [32]. Studies carried out in primary human hepatocytes have demonstrated that the mechanism of action of metformin in liver involves the activation of insulin receptor, followed by selective IRS-2 stimulation, and increased glucose uptake via increased GLUT-1 translocation [33]. It is unclear whether metformin acts on mitochondrial respiration directly by slow permeation across the inner mitochondrial membrane or by unidentified cell-signalling pathways. In addition to the effect on gluconeogenesis, in vitro studies have indicated that metformin can reduce the overall rate of glycogenolysis [26].

Glucose utilisation in peripheral tissues

Several studies have assessed the ability of metformin to enhance insulin-mediated glucose utilisation in type 2 diabetic patients, yielding quite variable results. However, metformin appears to improve glucose utilisation both through direct and indirect mechanisms [34], while the result variability is the likely reflection of differences in the patients'characteristics (body weight, diabetes duration, severity of hyperglycaemia…) as well as in the dose of metformin (1-3 g/day) used in the studies. In placebo controlled studies, metformin has been shown to increase insulin-mediated glucose utilisation by 20-30% [35]. The improvement of glucose utilisation (Fig 2)is almost completely due to non-oxidative glucose metabolism, a marker for glycogen synthesis (Fig 3), though in the fasting state it is glucose oxidation that increases after metformin treatment [36]. Consistent with these results are the findings obtained in diabetic rats [37]. In these animals, the drug was able to normalise insulin-mediated glucose disposal and muscle glycogen synthesis. Therefore, in humans as well, the main post-receptor event of insulin action stimulated by metformin seems to be the glycogenic pathway.

The in vivo studies are supported by in vitro data. Metformin increases glucose uptake in cultured human muscle cells [38], muscle strips from diabetic subjects [39], and muscles from streptozotocin-treated rodents [37], [40]. This effect has been associated with multiple actions, including increased insulin receptor tyrosine kinase activity [37], enhanced glycogen synthesis [41], and augmented GLUT-4 transporter number and activity [42].

The mechanism leading to GLUT-4 translocation is unclear. In erythrocytes [43], monocytes [44]and fat cells [45], metformin increases insulin receptor binding and tyrosine kinase activity [42], and insulin receptor internalisation [46]. In muscle from streptozotocin-diabetic rodents [37], metformin improves abnormal insulin receptor tyrosine kinase activity. A recent study performed in type 2 diabetic subjects found that treatment with metformin increased insulin-stimulated whole-body glucose disposal by 22% but did not alter insulin receptor substrate-1-associated phosphatidylinositol 3-kinase or AKT activity in skeletal muscle [47].

Adipose tissue

Biguanides have been shown to reduce fatty acid oxidation [48]. Basal lipid oxidation, as measured by indirect calorimetry, is lowered by metformin treatment in type 2 diabetic patients [36], [49], an effect that is not fully apparent when plasma insulin concentrations are increased and lipolysis suppressed [36]. Studies employing 14C-palmitate have shown that one month treatment with metformin reduces palmitate turnover and oxidation with a concomitant increase in glucose oxidation (Table I) [36]. These changes were not related to prevailing plasma insulin concentrations. The mechanism responsible for decreased FFA turnover is not completely understood, but it seems to be more likely related to increased re-esterification rather than decreased lipolysis [49]. Metformin treatment is often associated with a reduction of circulating triglycerides as a consequence of decreased synthesis and increased clearance of VLDL lipoproteins [50], [51]. Reduction of FFA supply to the liver, lower triglyceride synthesis, and increased insulin sensitivity may all contribute in reducing fat accumulation in the liver [52].

The reduction in the concentration and oxidation of plasma FFA can contribute to the improvement in insulin action that follows metformin treatment in obese type 2 diabetes. In these individuals, the common elevation in plasma FFA levels favours hepatic glucose production and peripheral insulin resistance [17]. At the level of the liver, FFA excess induce the allosteric activation of the early steps of gluconeogenesis, while increased oxidation provides the required energy. In skeletal muscle, FFA can inhibit pyruvate dehydrogenase (Randle's cycle) but they can also impair glucose transport and/or phosphorylation [17]. In vitro studies have shown how FFA inhibit insulin receptor substrate-1-associated PI3-kinase activity and, subsequently, attenuate transmembrane glucose transport [53].

Increased plasma FFA concentration exerts a lipotoxic effect on the ß-cell as well [54]. Thus, by decreasing FFA levels, metformin not only improves insulin sensitivity but may also help to correct impaired insulin secretion by ß-cells [55]. This aspect may become of even greater interest if one considers that insulin signalling ( i.e. insulin action) may be involved as well in the regulation of the secretory insulin function.

ß-cell

Though metformin is not considered to exert a significant effect on pancreatic ß-cells, isolated studies have claimed treatment to result in a potentiation of first-phase insulin secretion in response to glucose [56]. More solid results have been obtained in vitro , where metformin has been shown to improve insulin secretion after long-term exposure to FFA or hyperglycaemia [55]. In our own experience, carried out in isolated human islets, metformin potentiates insulin release [57], and exerts a protective effect against gluco- [58]and lipotoxicity [59]by restoring glucose-stimulated insulin release.

Searching for the cellular mechanism of action of metformin

Biguanides and, therefore, metformin have been used for treating human disease for a very long time. The original active principle, guanidine, was initially extracted from Galega officinalis , a plant used in the Middle age to alleviate intense urination, to fight plague epidemics, to cure from snake bites, and to control the San Vito dance. Only, in the past decades, improvement of insulin resistance was included in this odd list of effects. In spite of the fact that metformin was the only available insulin sensitiser for a long time and still remains a main drug for improving insulin sensitivity, its intimate mechanism of action remains elusive.

A theory suggests that metformin can alter the physicochemical properties of cell membranes. In particular the drug could restore cell membrane fluidity perturbed by non-enzymatic glycation supported by hyperglycaemia [60].

An effect on the respiratory chain oxidation has been claimed as well [61]. Metformin might increase permeation across the inner mitochondrial membrane or generate unidentified cell-generated signals interfering with mitochondrial respiration. Inhibition of cell respiration can trigger glucose transporter expression [31]and suppress gluconeogenesis [30].

More recently, Zhou et al. [62]have suggested that metformin may act by increasing phosphorylation and activation of AMP-dependent protein-kinase (AMPK). AMPK is a heterotrimeric complex consisting of a catalytic (?;) subunit and two regulatory subunits (ß and ?). AMPK works as an intracellular fuel gauge that is activated by decrease in the ATP/ADP and phosphocreatine (PCr)/creatine ratios [63]. The increase in AMPK activity is associated with translocation of GLUT-4 to the plasma membrane, stimulation of glucose uptake in muscle and liver, fatty acid oxidation in muscle and liver, and suppression of hepatic glucose output, triglyceride and cholesterol synthesis and lipogenesis [63]. Activation of AMPK by metformin was reported to be required for the decrease in glucose production and the increase in fatty acid oxidation in hepatocytes and for the increase in glucose uptake in skeletal muscle [62]. AMPK, moreover, is involved, in gene regulation, by decreasing SREBP-1 mRNA (an insulin-stimulated transcription factor, implicated in pathogenesis of insulin resistance, dyslipidaemia and type 2 diabetes). Whether or not AMPK is the target of action of metformin or its activation is secondary to the generation of still unknown cell signals, remains to be established. Metformin activation of AMPK does not depend on depletion of cellular energy charge [64], and occurs without changes in ATP levels [62]. The effect of metformin is not as specific as rosiglitazone, a different insulin sensitiser, which also activates AMPK [65]. Interestingly enough, however, the mechanism of activation of metformin and rosiglitazone are distinct, so that the combination of the two could result in greater improvement of insulin sensitivity in insulin-resistant individuals. Therefore, some light has been shed on the molecular mechanism of action of metformin, though the precise target of the drug within the cell will require more investigation.

Conclusion

In summary, metformin represents an effective way to improve insulin resistance, active at all sites of impaired insulin action. At the level of the liver, metformin increases insulin-mediated suppression of hepatic glucose production, mainly by reducing gluconeogenesis. In skeletal muscle it promotes the insulin receptor phosphorylation, GLUT-4 translocation resulting in increased glucose uptake and glycogen synthesis. At the level of the adipose tissue it favours FFA re-esterification and inhibits lypolysis (Fig 4). Reduced levels of circulating FFA relieve lipotoxicity at the level of liver, skeletal muscle, and ?-cell. In this way, metformin indirectly increases insulin action and contributes to preserve ?-cell function. Thus, many of the metabolic alterations brought about by insulin resistance are improved by metformin, making the drug an ideal candidate for the treatment of type 2 diabetes and the metabolic syndrome [66]. This, together with the beneficial effects on body weight, lipid metabolism, coagulation profile, heart and vascular function [35]can account for the favourable effect on cardiovascular disease documented by the UKPDS [8]. Since metformin is an insulin sensitizer, its action is fully operating in the presence of insulin resistance. As such, metformin is an antihyperglycaemic drug with very low risk for hypoglycaemia, therefore, making it a suitable tool for pharmacological prevention of type 2 diabetes [7].

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