European Journal of Internal Medicine
Volume 20, Supplement 2 , Pages S303-S308, July 2009

Unraveling the Science of Incretin Biology✩

  • Michael A. Nauck, MD, PhD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Michael A. Nauck, MD, Diabeteszentrum Bad Lauterberg, Kirchberg 21, 37431 Bad Lauterberg im Harz, Germany.

Bad Lauterberg Diabetes Center, Bad Lauterberg, Germany

published online 22 June 2009.

Article Outline

Abstract 

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in β-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide–1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase–4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances—defects in the incretin system—contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of β-cell function) associated with type 2 diabetes.

Keywords: GLP-1 receptor agonist, DPP-4 inhibitor, liraglutide, exenatide, sitagliptin, vildagliptin

 

The incidence of type 2 diabetes mellitus in US adults has approximately doubled over the past 30 years [1]. The US Centers for Disease Control and Prevention (CDC) estimated that in 2007, 23.6 million Americans (7.8% of the population) had diabetes; type 2 diabetes accounts for 90% to 95% of this total in adults [2]. Similar prevalence figures have been identified in Europe. Type 2 diabetes constitutes about 85% to 95% of all diabetes cases in developed countries, and accounts for an even higher percentage in developing nations [3], [4], [5].

Thus, type 2 diabetes is responsible for an enormous public health and cost-of-care burden. Risk rates for cardiovascular disease and stroke are elevated 2- to 4-fold in individuals with diabetes [6], [7]. Type 2 diabetes is also highly correlated with microvascular disorders such as retinopathy and nephropathy, which, respectively, can culminate in blindness and renal failure [5]. Every day in the United States, 66 people lose their eyesight as a result of diabetes and 112 people begin treatment for diabetes-related end-stage renal disease [7]. Cardiovascular events have been found to occur approximately 15 years earlier in individuals with diabetes than in nondiabetic people [8]. The problems of patients with type 2 diabetes have not been solved with conventional therapeutic options.

Although conventional antidiabetes therapy reduces the microvascular complications of type 2 diabetes, the effect of conventional therapy on macrovascular complications has not been unequivocally established [9]. Current antidiabetes therapies are also accompanied by a range of adverse effects. These include hypoglycemia and weight gain with sulfonylureas, insulin, and glinides; and edema, weight gain, and increased risk of bone fracture with thiazolidinediones [10], [11], [12], [13], [14]. Metformin appears to modestly reduce weight when given as monotherapy, [13] but it can produce hypoglycemia and gastrointestinal adverse events and has been linked to lactic acidosis [10], [11], [14]. Recent studies have disputed the latter association. A review of >200 controlled trials and cohort studies found no evidence of an increased risk of lactic acidosis with metformin [15]. A case-control study found that lactic acidosis was associated with comorbidities and was no more common with metformin than with sulfonylureas [16].

Type 2 diabetes is associated with additional cardiovascular risk factors, including obesity, hypertension, and an atherogenic dyslipidemia profile typified by high levels of triglycerides, low levels of high-density lipoprotein cholesterol, and an increased fraction of atherogenic small, dense low-density lipoprotein cholesterol particles [17], [18]. Antidiabetes therapies should at least not worsen these risk factors and ideally should improve some or all of them.

The need for improved therapies for type 2 diabetes is indicated. Recent advances in our understanding of the metabolic roles played by the intestinal “incretin” hormones, glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have led to important therapeutic advances in type 2 diabetes, including the development of incretin-based agents [19]. This review explores the pathophysiologic rationale for the administration of incretin-based agents in the treatment of type 2 diabetes.

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1. Type 2 Diabetes Mellitus: Looking Beyond Glucose and Insulin 

1.1. Insulin Production and Secretion in Type 2 Diabetes 

In healthy individuals, insulin production and secretion respond to metabolic needs. An oral glucose load or a mixed meal stimulates a rapid rise in insulin levels. The metabolic process is switched from a fasting state to a prandial state, hepatic glucose production is suppressed, and tissues are primed for glucose disposal [20]. Patients with type 2 diabetes have abnormalities of basal and meal-stimulated insulin secretion. The fasting plasma insulin level is typically “normal” or even high in absolute terms but low in relation to elevated fasting plasma glucose (FPG), and the insulin response to an oral glucose load is delayed and reduced. Impairment of insulin secretion contributes to the prolonged and elevated rise in plasma glucose levels observed after a meal in patients with type 2 diabetes [20].

Abnormalities of insulin response in patients with type 2 diabetes reveal an underlying deficit in β-cell health, which manifests as secretory impairments and a loss of β-cell mass [21]. The latter is believed to result primarily from increased apoptosis of β-cells [21], [22], owing to glucotoxicity, increased levels of proinflammatory cytokines, chronic leptin exposure, and amyloid deposition [21]. The deterioration of β-cell function progresses with time. Progressively worsening glucose control, despite treatment, has been demonstrated in clinical trials such as the UK Prospective Diabetes Study (UKPDS) [23] and by experimental studies [24], [25]. Loss of the insulin response to meals is the main defect in patients with type 2 diabetes, but in severe disease, fasting insulin secretion may also be reduced [24]. At the time of type 2 diabetes diagnosis, typically ≥50% of β-cell reserve has been lost [10].

1.2. Insulin Resistance in Type 2 Diabetes 

Insulin resistance is often observed in type 2 diabetes and may contribute to hyperglycemia and β-cell exhaustion. In insulin-resistant individuals who do not have diabetes, compensatory increases in insulin secretion—both transient first-phase secretion and a sustained second phase—compensate for increasing tissue resistance to the stimulatory effect of insulin on glucose uptake. However, in insulin-resistant individuals who go on to develop diabetes, high rates of insulin secretion cannot be maintained, and β-cell deterioration accelerates. Chronically inadequate levels of insulin result in loss of regulatory control over pancreatic α-cells and hepatic glucose production. Elevated glucagon secretion and hepatic glucose production in the prandial state contribute to fasting hyperglycemia, glucose intolerance, and type 2 diabetes [20], [24].

1.3. Clinical Implications of the Pathophysiology of Type 2 Diabetes 

The pathogenesis and subsequent progression of type 2 diabetes have obvious implications for its management. Agents that stimulate insulin secretion (e.g., sulfonylureas) or increase insulin sensitivity (e.g., thiazolidinediones) might be most effective early in the course of type 2 diabetes, when some β-cell reserve still remains. Alternatively, an agent that suppresses hepatic glucose production (e.g., metformin, also an insulin sensitizer) might become progressively less effective as declining levels of endogenous insulin, the result of declining β-cell function, become increasingly unable to regulate hepatic glucose production. These observations may explain why conventional agents, which do not prevent β-cell loss, do not maintain glycemic targets over the long term [26], [27]. Even therapy-adherent patients may eventually require exogenous insulin.

Therapies that protect β-cell health could help delay the progression of type 2 diabetes, particularly if initiated early in the disease process [21]. Heretofore, such therapies have not been available, or alleged effects of these therapies on the β-cell have lacked substantiation. Data from the A Diabetes Outcome Progression Trial (ADOPT), for example, did not provide robust support for the hypothesis that thiazolidinediones can fully prevent the progressive loss of β-cell function and halt the progression of type 2 diabetes [28], [29].

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2. The Incretin System: A Potential Key to Understanding Type 2 Diabetes Mellitus 

Glucose triggers a much greater insulin-secretory response when ingested orally than when administered intravenously (IV) [30]. This phenomenon, known as the “incretin effect,” has been estimated to account for as much as 70% of total insulin secretion in healthy individuals in response to oral glucose or a meal [31]. The insulin secretion associated with the incretin effect is potentiated by 2 gut hormones, GIP and GLP-1, that enter the circulation in response to the absorption of glucose and other nutrients and powerfully augment glucose-induced insulin secretion [31].

2.1. GIP: Physiologic Actions and Regulation 

GIP (also known as gastric inhibitory polypeptide, based on early investigations of its effects on gastric secretion in dogs) [31] is a 42–amino acid hormone secreted by intestinal K-cells, mostly in the proximal small intestine, in response to glucose and fat intake [31]. It potently augments glucose-stimulated insulin release [32] and is inactivated via enzymatic cleavage by dipeptidyl peptidase–4 (DPP-4). Despite a relatively short half-life of 5 to 7 minutes [32], [33], GIP in its nondegraded, intact form may be the hormone most responsible for the incretin effect in healthy humans (Table 1) [32], [33], [34], [35]. GIP may also regulate fat metabolism in adipocytes and, under experimental conditions, it enhances the survival of pancreatic β-cell lines [31], [32]. Experimental studies have described effects of GIP on various tissues including the central nervous system, adipose tissue, and bone [31]. The clinical significance of those effects, however, remains unknown. GIP does not delay gastric emptying in humans [36], nor does it inhibit glucagon secretion—rather, glucagon may be stimulated by GIP under certain conditions [31].

Table 1. Biological actions of endogenous glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in patients with type 2 diabetes mellitus.
ActionGLP-1GIP
Pancreatic β-cells
Glucose-dependent stimulation of insulin secretion↑↑←→
Glucose sensitivity↑?
Insulin biosynthesis↑↑
Differentiation of precursor cells↑↑
Apoptosis↓↓
Pancreatic α-cells/glucagon secretion↓←→or↑
Gastric emptying↓↓←→
Postprandial hyperglycemia↓↓←→or↑
Appetite↓?
Body weight↓?
Additional effects
Neuroprotection↑↑
Cardioprotection↑?
Renal (diuresis, naturiesis)↑?
Bone formation←→↑

↑↑ = markedly increased; ↑ = increased; ←→ = no effect; ↓ = decreased; ↓↓ = markedly decreased; ? = unknown.

Adapted with permission from Lancet [33].

The actions of GIP are mediated by G-protein–coupled receptors located mainly on islet β-cells [31]. The effects of GIP on glucose-induced insulin secretion made it appear promising for the management of type 2 diabetes. Unfortunately, subjects with type 2 diabetes and other forms of diabetes exhibit greatly reduced sensitivity to the insulinotropic activity of this peptide [35], [37], [38]. Although GIP is normally secreted, or even hypersecreted, in type 2 diabetes, its insulinotropic action is largely lost, perhaps as a result of reduced GIP receptor expression or reduced β-cell sensitivity to GIP or as a result of other causes as yet unelucidated [39], [40]. In contrast, the insulinotropic activity of GLP-1 is rather well preserved in patients with type 2 diabetes [39]. Therapeutic attention, accordingly, has been focused on GLP-1.

2.2. GLP-1: Regulation, Incretin Activity, and Additional Actions 

2.2.1. Regulation 

In humans, GLP-1 is secreted by L-cells mainly located in the distal jejunum, ileum, and colon [31], [41]. Two biologically active and equipotent forms of “truncated” GLP-1 are released: GLP-1(7-36) amide (“amidated” GLP-1, the major form in humans) and glycine-extended GLP-1(7-37). Two other minor forms of GLP-1 (1-37 and 1-36) are believed to be inactive [31], [42]. Plasma levels of GLP-1 increase within minutes of eating, which suggests that endocrine and neural signals provoke secretion of GLP-1 before absorbed nutrients directly stimulate L-cells [33]. As with GIP, GLP-1 is rapidly inactivated by DPP-4; >50% of secreted GLP-1 is metabolized even before it reaches the systemic circulation. The half-life of circulating GLP-1 is <2 minutes [31]. GLP-1 activity is mediated by the GLP-1 receptor, which is expressed in pancreatic islet cells, the stomach, heart, and hypothalamus [31]. Stimulation of the GLP-1 receptor activates various intracellular signaling pathways including those regulating insulin secretion and biosynthesis, β-cell proliferation and neogenesis, and inhibition of apoptosis [31], [43], [44].

2.2.2. Biologic activity of GLP-1 

GLP-1 modulates various processes involved in glucose metabolism (Table 1). In healthy subjects, infusion of native GLP-1 at near-physiologic levels stimulates insulin secretion in a glucose-dependent fashion [34], [45]. In subjects with type 2 diabetes, treatment with GLP-1 has been shown to increase fasting and meal-stimulated insulin levels, decrease FPG, and suppress postprandial hyperglycemia without causing hypoglycemia [46], [47]. Extended preinfusion of GLP-1 markedly increases first-phase insulin response to IV glucose while also significantly improving second-phase secretion. In contrast, bolus infusion of GLP-1 immediately before a glucose challenge gives a smaller improvement in first-phase insulin secretion and a greater effect on the second phase [48]. Administration of GLP-1 shortly before an oral meal increases preprandial insulin levels and suppresses postprandial hyperglycemia. Postprandial insulin levels may even be reduced as a result of the lowered glucose levels (Figure 1) [46].

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  • Figure 1. 

    Plasma concentrations of (A) glucose and (B) insulin during the intravenous administration of different doses (0.4, 0.8, and 1.2 pmol/kg per min of glucagon-like peptide 1 (GLP-1) (solid symbols) or placebo (open symbols) administered in the fasting state for 300 minutes in 12 patients with type 2 diabetes mellitus. At 60 minutes a mixed meal (1,050 kJ [250 kcal]) was served. Data are expressed as mean ± SEM. P values for each figure are as follows: (A) p = 0.01 for difference between the doses tested, p<0.001 for differences over time, and p<0.001 for differences due to the interaction of experiment and time; (B) p = 0.96 for difference between the doses tested, p<0.001 for differences over time, and p<0.001 for differences due to the interaction of experiment and time. *p<0.05) vs. placebo at individual time points. (Reprinted with permission from J Clin Endocrinol Metab) [46].

GLP-1 helps to maintain insulin stores by promoting glucose-stimulated insulin gene transcription and biosynthesis [31]. The hormone has been associated with the restoration of glucose-resistant β-cells to a state of glucose competence [31], [49]. Preclinical studies suggest that GLP-1 augments and protects β-cell “health.” In culture, GLP-1 promotes the differentiation of islet progenitor cells into endocrine cells that produce insulin or glucagon [50], [51]. In vitro studies indicate that GLP-1 protects β-cells from the threat of cell death induced by elevated levels of glucose and lipids, and helps to maintain islet cell morphology [44], [52].

Positive effects on postprandial plasma glucose observed with GLP-1 treatment may also result from the hormone's ability to delay gastric emptying. In healthy subjects, GLP-1 produces a dose-dependent delay of gastric emptying that can inhibit meal-stimulated insulin secretion. In the context of type 2 diabetes, however, partial inhibition of gastric emptying could augment the therapeutic benefit of GLP-1, because slowing nutrient entry into the circulation is an established treatment principle [45]. GLP-1 and GLP-1 receptor agonists reduce hunger, energy intake, and body weight in patients with type 2 diabetes [53]. A number of investigators have suggested that GLP-1's effects on gastric emptying contribute significantly to its observed reduction of postprandial hyperglycemia as well as to weight loss [46], [54], [55]. Gastric emptying effects are probably mediated via effects on vagal neural transmission [45], [46], [54], [55]. GLP-1 also appears to contribute to the “ileal brake” mechanism, whereby nutrients in the small intestine slow upper gastrointestinal functions [45]. The delay in gastric emptying contributing to a persistent sense of fullness may be partly responsible for the reductions in hunger, energy intake, and body weight observed in trials with GLP-1 and GLP-1 receptor agonists [53], [56], [57]. GLP-1-mediated effects on the hypothalamic satiety center or neural pathways implicated in the regulation of energy intake (e.g., pathways that trigger anorexigenic behavior) may also be involved [31].

GLP-1 inhibits the release of glucagon from pancreatic α-cells in healthy subjects [45]; in patients with type 2 diabetes, exogenous infusions of GLP-1 have been shown to reduce glucagon secretion [31], [37], [46]. GLP-1 does not inhibit release of glucagon in the presence of hypoglycemia, nor does it impair hypoglycemia counterregulation, and therefore it is unlikely to produce hypoglycemia [58].

Preclinical data suggest that GLP-1 suppresses glucose production and increases glycogen synthesis in the liver, increases glucose metabolism in muscle, and regulates glucose and fat metabolism in human adipocytes [31], [59]. It is not known whether GLP-1 exerts these actions independently of its pancreatic effects in humans [31]. Some effects of GLP-1 on peripheral glucose metabolism may occur via actions on the central nervous system [31], [60].

A number of studies have reported potentially beneficial effects of GLP-1 on the cardiovascular system (e.g., ischemia/reperfusion injury, myocardial contractility) [61], [62], nervous system (antiapoptotic action on neuronal cells) [31], renal system (e.g., natriuresis) [63], [64], and endocrine [31] systems (e.g., modulation of the hypothalamic-pituitary axis), but their clinical significance remains to be elucidated [65].

2.3. Development of Incretin-Based Therapies for Clinical Use 

GLP-1 represents an attractive therapy for type 2 diabetes because it acts to restore glucose-dependent insulin secretion, preserves and protects the β-cell, and may improve associated risk factors and morbidities, such as overweight and obesity. It has been reported that the postprandial secretion of GLP-1 is diminished in patients with type 2 diabetes [66], but these data are not entirely representative and merely may reflect variability in the secretion of incretins [37]. A recent study found no decrease in GLP-1 levels in patients with type 2 diabetes after oral glucose or mixed meal ingestion [67]. If GLP-1 secretion levels are unaffected by disease, the diminished incretin effect observed in type 2 diabetes may be attributable largely to the all but abolished efficacy of GIP. In subjects with normoglycemia, GIP and GLP-1 appear to interact in an additive manner, enhancing each other's insulinotropic actions through separate receptors on the β-cell [34]. One model of such coordinated action on the β-cell postulates that GIP stimulates exocytosis of available insulin granules, while GLP-1, in addition to helping with exocytosis of available insulin, also activates insulin biosynthesis [40]. Accordingly, physiologically normal secretions of GLP-1, which retains much of its bioactivity even in type 2 diabetes, might nevertheless be insufficient to shoulder the entire burden of the incretin effect. Thus, supraphysiologic or pharmacologic levels of GLP-1 would be necessary to reestablish the insulinotropic effect of both hormones in normal physiology. An alternative etiology for diminished GLP-1 action in type 2 diabetes may be hyperglycemia-induced downregulation of GLP-1 receptor expression in pancreatic islets [68].

Despite the possibilities cited above, the preponderance of evidence indicates that patients with type 2 diabetes remain relatively sensitive to GLP-1, and therefore the hormone is a logical treatment for this condition. Pharmacologic administration of GLP-1 for 6 weeks in patients with type 2 diabetes significantly reduced fasting and 8-hour glucose levels and improved long-term glycemic control, as measured by hemoglobin A1c (HbA1c). These effects occurred in conjunction with improvements in β-cell function, deceleration in gastric emptying, appetite suppression, and a reduction in body weight and free fatty acids [57]. A 48-hour continuous GLP-1 infusion in 6 patients with type 2 diabetes was also associated with nonsignificant decreases in systolic and diastolic blood pressure [69].

The rapid breakdown of endogenous GLP-1 by DPP-4 means that the native peptide must be given by continuous IV or subcutaneous infusion, which is not practicable for chronic therapy. This shortcoming can be overcome either by the inhibition of DPP-4 or by the development of GLP-1 receptor agonists resistant to DPP-4.

DPP-4 inhibitors (e.g., sitagliptin, vildagliptin) have been successfully developed for clinical use [31]; the magnitude of their effect on GLP-1 activity is limited to the available endogenous levels of the hormone. Typically, DPP-4 inhibitors result in a 2-fold increase in GLP-1 levels [70], e.g., changes within the physiologic range. DPP-4 inhibitors have demonstrated reductions in HbA1c of up to 1% and are generally weight neutral [71]. DPP-4 is a ubiquitous enzyme with many substrates including neuropeptides, cytokines, other gastrointestinal hormones, and chemokines; as such, concerns have been raised regarding possible effects of DPP-4 inhibition on other systems and physiologic functions; for example, DPP-4 is expressed on lymphocytes, raising a potential concern about adverse effects of DPP-4 inhibitors on immune function [31], [72]. However, clinical trials to date indicate that DPP-4 inhibitors are well tolerated [33].

In contrast to DPP-4 inhibitors, GLP-1 receptor agonists may be administered at higher pharmacologic concentrations to achieve greater GLP-1 receptor stimulation and β-cell responses. The GLP-1 receptor agonist exenatide has demonstrated HbA1c reductions of ∼1.14% and weight reductions up to 3.1 kg (Figure 2) [33], [53], [73]. Exenatide is a synthetic, 39–amino acid peptide identical to the exendin-4 molecule first isolated from the salivary gland secretions of the Gila monster. Exenatide shares approximately 53% homology with mammalian GLP-1, but it is structurally resistant to metabolism by DPP-4 [19], [74]. It is administered by subcutaneous injection twice daily, within 60 minutes of morning and evening meals [74]. An extended-release formulation given once weekly is under development. GLP-1–based agents in development include liraglutide, a once-daily human GLP-1 analog almost completely homologous to the native peptide. The coupling of a fatty acid acyl group to human GLP-1 prolongs the half-life of the peptide to ∼13 hours by permitting noncovalent binding to albumin [19]. Liraglutide is administered subcutaneously once daily.

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  • Figure 2. 

    Structural features of (A) glucagon-like peptide–1 (GLP-1), (B) exenatide, (C) liraglutide, and dipeptidyl peptidase–4 (DPP-4) inhibitors (D) vildagliptin, (E) sitagliptin, and (F) saxagliptin. (Adapted with permission from Lancet.) [33].

Extensive clinical trial data assessing GLP-1 receptor agonists in patients with type 2 diabetes have demonstrated that these agents exhibit many of the actions of native GLP-1, such as augmentation of glucose-stimulated insulin secretion, significant HbA1c reductions when used as monotherapy or in combination with other agents, weight loss, and reductions in systolic and diastolic blood pressure [75].

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3. Summary 

The pathology of type 2 diabetes involves a progressive failure of β-cell function, often associated with insulin resistance and glucagon hypersecretion. The incretin system, which includes the peptides GIP and GLP-1, helps to regulate many aspects of glucose metabolism, including meal-stimulated insulin secretion in healthy humans. Patients with type 2 diabetes exhibit reduced sensitivity to GIP, but their responses to GLP-1 are largely preserved.

Enhancement of the actions of GLP-1 is a logical treatment for type 2 diabetes. This can be achieved by administration of degradation-resistant GLP-1 receptor agonists or by inhibition of the enzyme DPP-4, which inactivates native GLP-1. GLP-1–based therapies improve the insulin response to meals in patients with type 2 diabetes and reduce postprandial hyperglycemia. GLP-1 receptor agonists have demonstrated additional benefits, including delay of gastric emptying, reduction of appetite, reduction of weight, and, potentially, preservation of β-cell health. The glucose-dependent mode of action of GLP-1 receptor agonists means they are unlikely to cause hypoglycemia. Clinical trials of GLP-1 receptor agonists and DPP-4 inhibitors have produced promising results in patients with type 2 diabetes. In principle, the use of GLP-1–based therapies early in the course of type 2 diabetes may even delay disease progression by arresting the otherwise inevitable deterioration of β-cell function and β-cell mass.

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4. Author Disclosures 

The author of this article has disclosed the following industry relationships:

Michael A. Nauck, MD, has served on the advisory boards of Amylin Pharmaceuticals, Inc., ConjuChem, Inc., Eli Lilly & Co., GlaxoSmithKline, Hoffman-La Roche Inc., Novartis Pharmaceuticals Corp., Novo Nordisk A/S, Probiodrug AG, Restoragen Inc. (formerly BioNebraska, Inc.), and sanofi-aventis; has worked as a consultant to AstraZeneca, Bayer Vital Pharma, Berlin Chemie/Menarini, Biovitrum AB, ConjuChem, Inc., Eli Lilly & Co., Hoffman-La Roche Inc., Merck & Co., Inc., MSD, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, Pfizer Inc, Probiodrug AG, Restoragen Inc. (BioNebraska), sanofi-aventis, and Takeda Pharmaceuticals North American, Inc.; and has received research/grant support from Amylin Pharmaceuticals, Inc., Bayer Vital Pharma, Berlin Chemie/Menarini, Eli Lilly & Co., Leverkusen, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, Probiodrug AG, Restoragen Inc. (BioNebraska), and sanofi-aventis.

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Acknowledgment 

I thank AdelphiEden for providing medical editorial services.

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✩ This article is a copublication with the The American Journal of Medicine, 122, S3-S10. For citation purposes please use European Journal of Internal Medicine, 20, S303-S308.

PII: S0953-6205(09)00095-8

doi:10.1016/j.ejim.2009.05.012

European Journal of Internal Medicine
Volume 20, Supplement 2 , Pages S303-S308, July 2009

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