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Meeting Reports

48th Annual Meeting of the European Association for the Study of Diabetes (EASD)
October 1 - 5, 2012
Berlin, Germany

ORIGIN TRIAL: INSULIN GLARGINE AND N-3 FATTY ACIDS NEITHER REDUCES CV EVENTS NOR INCREASES CANCERS IN DIABETIC PATIENTS


Insulin glargine used to target normal fasting glucose for more than 6 years had a neutral effect on cardiovascular (CV) outcomes and cancers in high-risk patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or early diabetes. Although it reduced new onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight in the Outcome Reduction with Initial Glargine Intervention Trial [ORIGIN Trial Investigators.N Engl J Med 2012]. In the same trial, daily supplementation with n-3 fatty acids did not reduce CV events. Hertzel C. Gerstein, MD, MSc, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, reported the main results from the study.


The international double-blind trial with a 2x2 factorial design included 12,537 patients with diabetes (88%) or with IFG and/or IGT but no diabetes (12%) randomized to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg/dL) or standard care. Participants also received a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily. The coprimary outcomes of the insulin glargine versus standard care arm were nonfatal myocardial infarction, nonfatal stroke, or death from CV causes, and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight gain, and cancers were also compared between the two groups. The primary outcome in the n-3 fatty acids arm was death from CV causes. The median follow-up was 6.2 years.


Rates of incident CV outcomes were similar in the glargine and the standard care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (MI, stroke, or CV death; HR, 1.02; 95% CI, 0.94 to 1.11; p=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (MI, stroke, CV death, revascularization, heart failure; HR, 1.04; 95% CI, 0.97 to 1.11; p=0.27). Differences in the incidence of any cancer were not significant (HR, 1.00; 95% CI, 0.88 to 1.13; p=0.97).


Among patients receiving n-3 fatty acids versus placebo, the incidence of primary outcome was not significantly decreased (574 patients [19.1%] vs 581 patients [9.3%]; HR, 0.98; 95% CI, 0.87 to 1.10; p=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients vs 1017 patients; HR, 1.01; 95% CI, 0.93 to 1.10; p=0.81), death from any cause (951 vs 964; HR, 0.98; 95% CI, 0.89 to 1.07; p=0.63), or death from arrhythmia (288 vs 259; HR, 1.10; 95% CI, 0.93 to 1.30; p=0.26; Figure 1). Triglyceride levels were reduced by 14.5 mg/dL more among patients receiving n-3 fatty acids versus placebo (p<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups [ORIGIN Trial Investigators. N Engl J Med2012].


Figure 1. Event Rates.


Matthew C. Riddle, MD, Oregon Health & Science University, Portland, Oregon, USA, presented new ORIGIN trial subgroup data. The findings indicate that target-directed intervention early in dysglycemia can maintain baseline HbA1C levels for at least 5 years and that the glargine-based regimen is more likely to keep HbA1C <6.5% than standard care. 


The main independent predictors of maintaining mean HbA1C <6.5% up to 5 years were type 2 diabetes versus no type 2 diabetes, baseline HbA1C per 1%, alcohol use >2 times/week, and glargine versus standard treatment (p<0.001 for all). 


The data showed that <50% of diabetic patients had HbA1C levels <6.5% at baseline, but this figure rose to 60% at 5 years among those randomized to glargine and dropped to 45% among those on standard therapy. In the group without diabetes, 91% of patients had baseline HbA1C levels <6.5%. This number fell to 87% at 5 years in those randomized to glargine and to 79% at 5 years among those on standard therapy.


Both titrated glargine and a standard care approach kept HbA1C levels near baseline values for at least 5 years. According to Dr. Riddle, more data and further analyses are needed to define the benefits versus the risks of the two approaches.


For more information, please see the MD Conference Express review of the ORIGIN presentation in our ADA Report.



POPULATION-BASED SCREENING FOR TYPE 2 DIABETES: THE ADDITION CAMBRIDGE TRIAL


After completing a randomized controlled trial to examine the impact of a population-based diabetes screening program on mortality in England, Rebecca K. Simmons, PhD, Medical Research Council Epidemiology Unit, Cambridge, United Kingdom, concluded that screening for diabetes was not associated with a reduction in mortality and that the benefits of screening may be limited to those with detectable disease.


Although modeling studies suggest that screening might reduce diabetes-related mortality by 26% to 40% if conducted among middle-aged adults every 3 to 5 years, there was no evidence from randomized trials to confirm if these estimates are correct. The ADDITION-Cambridge cluster-randomized controlled trial was conducted to assess the impact of a population-based screening program on mortality among people at high risk of undiagnosed diabetes [Simmons RK et al. Lancet 2012].


The study population comprised 20,184 individuals aged 40 to 69 years, from 32 general practices in Eastern England, who were considered to be at high risk of diabetes based on a validated risk score that Included age, sex, body mass index (BMI), and prescription of antihypertensive medication or steroids as criteria. Twenty-seven practices were cluster randomized to a screening group (comprised of 16,047 individuals) and 5 practices to a no-screening control group (4137 individuals). Both the patients and practitioners in the no-screening group were unaware of the patients’ high-risk status. All participants were tagged for mortality at the Office for National Statistics and followed for 10 years. Screening included random capillary blood glucose and HbA1C tests, a fasting capillary test, and a confirmatory oral glucose tolerance test. The primary analysis was a comparison of allcause mortality rates and cardiovascular, cancer, and diabetes-related mortality rates between the screening and control groups. Analysis was by intention to screen accounting for clustering.


Baseline practice characteristics (list size, mean diabetes prevalence, and mean index of multiple deprivation score) were similar between screening and no-screening groups. Mean age (58 years), percentage of male participants (64%), BMI (30.5 kg/m2), and prescribed antihypertensives (45% were also similar between groups.


Over a median of 9.6 years of follow-up, 15,089 (94%) of the 16,047 high-risk individuals in screening practices were invited for screening. In all, 11,737 (73.1%) attended and 466 (2.9%) were diagnosed with diabetes. A total of 4137 individuals were followed in the no-screening practices. 


There were no differences in mortality rates by study group (Table 1). The difference in the cumulative incidence of death between the groups over time was not significant (HR, 1.06; 95% CI, 0.90 to 1.25; p=0.46). Compared with the control group, screening attenders had lower mortality (HR, 0.83; 95% CI, 0.73 to 0.94) and non-attenders had a higher mortality (HR, 1.62; 95% CI, 1.38 to 1.90; Figure 1).


Table 1. Mortality Rate by Study Group.




Figure 1. Cumulative Incidence of Death in Attenders, Nonattenders, and No-Screening Control Group.


 


Reproduced with permission from R. Simmons, PhD.


The investigators concluded that the benefits of screening for diabetes may have been overestimated and restricted to those found to have diabetes and treated early. The benefits of screening might be improved by the detection and management of related cardiovascular risk factors alongside assessment of diabetes risk, repeated rounds of screening, and the identification of non-attenders and strategies to maximize their utilization of screening.


Further reading: Simmons et al. Lancet 2012.



THE CHALLENGES OF PHARMACEUTICAL MANAGEMENT OF PAINFUL DIABETIC PERIPHERAL NEUROPATHY


Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations, which include painful neuropathic symptoms and insensitivity, increase the risk for burns, injuries, and foot ulceration [Tesfaye S, Selvarajah D. Diabetes Metab Res Rev 2012]. Solomon Tesfaye, MD, University of Sheffield, Sheffield, United Kingdom, discussed findings from recent studies on pharmaceutical agents used to treat DPN.

 

Medication for diabetic peripheral neuropathic pain (DPNP) includes tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, duloxetine), anticonvulsants (eg, pregabalin), opiates, membrane stabilizers, the antioxidant α-lipoic acid, and others. New agents that might have fewer side effects have emerged over the past 7 years [Tesfaye S, Selvarajah D. Diabetes Metab Res Rev 2012]. However, current treatments still provide suboptimal pain relief.

 

Questions about the management of DPNP center on the best first-line drug, the best combination of first-line drugs, whether to switch or combine various agents, the nature of a clinically meaningful response for monotherapy, length of time to determine efficacy, and whether to prescribe an early combination of drugs that work by different mechanisms versus a trial of maximum doses of monotherapy.

 

One study found that gabapentin and morphine combined achieve better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth being the most frequent adverse effects [Gilron I et al. N Engl J Med 2005]; another study reported that coadministration of prolonged-release oxycodone and existing gabapentin therapy has a clinically meaningful effect on DPNP [Hanna M et al. Eur J Pain 2008].

 

A randomized, double-blind, crossover trial compared the efficacy and safety of amitriptyline versus pregabalin in painful diabetic neuropathy. Pregabalin 150 mg BID was associated with fewer adverse effects than amitriptyline [Bansal D et al. Diabet Med 2009].

 

A Study in Painful Diabetic Neuropathy [COMBO-DN; Tesfaye S et al. Submitted; EUCTR 2009-010063-16-DE] was the largest double-blind randomized trial to date on combination treatment for DPNP. It investigated the efficacy of a combination treatment of duloxetine plus pregabalin compared with the maximal dose of each drug in monotherapy in patients with DPNP. As such, it addressed a common clinical question: Is it better to increase the dose of the current monotherapy or combine both treatments early in patients who do not respond to standard doses of duloxetine or pregabalin?

 

The trial did not clearly demonstrate that standard dose combination therapy of duloxetine with Pregabalin provides significantly better pain relief compared with high-dose monotherapy of either drug in DPNP patients with insufficient pain relief. There was no evidence that safety and tolerability are negatively affected when duloxetine is combined with pregabalin in these patients. For initial treatment, duloxetine (60 mg/day) provided better analgesia than pregabalin (300 mg/day).



NOVEL ORAL AGENTS: THE SEARCH FOR TRANSFORMATIONAL MEDICINES


In 2011, 366 million people had diabetes; by 2030, that figure is projected to rise to 552 million [International Diabetes Federation. IDF Diabetes Atlas. 5th ed. 2009]. The search for novel oral antidiabetic drugs (OADs) has taken on a growing sense of urgency. Richard D. DiMarchi, PhD, Indiana University, Bloomington, Indiana, USA, discussed efforts underway to develop glucagon-based incretin hybrids.


Dr. DiMarchi focused his discussion on 2 glucagon-based single molecule coagonists: glucagon/glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP)/GLP-1. The clinical benefits of each are shown in Table 1. The glucagon/GLP-1 coagonist hypothesis is that chronic glucagon action decreases fat mass by increasing energy expenditure via the glucagon receptor, GLP-1 decreases fat mass by reducing food intake via the GLP-1 receptor, a GLP-1/glucagon coagonist might decrease fat mass by synergistically affecting both components via 2 receptors, and a GLP-1/glucagon coagonist should minimize the diabetogenic risk of a pure glucagon analogue.


Table 1. Summary of Glucagon-Based Single Molecule Coagonists.



Several parts of the hypothesis have been proven in preclinical and clinical studies. Day et al. [Nat ChemBiol 2009] reported a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Two coagonist peptides that differ from each other only in their levels of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in dietinduced obese (DIO) mice.


Preclinical evidence also indicates that high-activity, longacting leptin analogues are additively efficacious when used with other weight-lowering agents, ie, extendin-4 or fibroblast growth factor 21 (FGF21; Figure 1) [Muller TD et al. J Pept Sci 2012].


Figure 1. High-Activity, Long-Acting Leptin Analogues May Be Additively Efficacious When Used with Other Weight-Lowering Agents.



Reproduced with permission from RD DiMarchi, PhD.


While Schelshorn et al. [Mol Pharmacol 2012] demonstrated that GLP-1 induces G-protein-coupled receptor heteromer formation, Christensen et al. [Diabetes 2011] found that GIP appears to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the 2 main pancreatic glucoregulatory hormones in healthy human subjects.


Based on the data, Dr. DiMarchi concluded that GLP-1 agonists provide significant clinical benefits, yet glucagon/GLP-1 and GIP/GLP-1 coagonists deliver significantly greater activity than GLP-1 in animals. The addition of leptin provides additional efficacy in DIO mice.

 

Targeting the Glucocorticoid Pathway

André J. Scheen, MD, PhD, University of Liège, Liège, Belgium, addressed the question of whether there Is any role of cortisol in the prevention of hyperglycemia in type 2 diabetes mellitus (T2DM). He discussed similarities between T2DM, metabolic syndrome, and Cushing syndrome; the role of cortisol on activation of the hypothalamic-pituitary-adrenal axis and local tissue regulation; the role of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue and the liver; the effects of 11β-HSD1 inhibition (knockout models and chemical inhibitors) in rodents; the effects of selective 11β-HSD1 inhibitors in humans with T2DM (and metabolic syndrome); and limitations and perspectives.


Hollis and Huber [Diabetes Obes Metab 2011] reported that 11β-HSD1 catalyzes the intracellular conversion of inert cortisone to physiologically active cortisol, enhancing local cortisol action beyond what would be predicted based on simple plasma exposures.


Results of a 12-week, placebo-controlled dose-ranging efficacy study by Rosenstock et al. [Diabetes Care 2010] provided the first evidence that decreasing local cortisol exposure through selective 11β-HSD1 inhibition can improve hyperglycemia in T2DM. Treatment with INCB13739 showed statistically significant reductions in HbA1C in the 100-mg (–0.47%; p<0.05) and 200-mg (–0.56%; p<0.01) groups. The 200-mg group also achieved significant reductions relative to placebo in fasting plasma glucose (–24 mg/dL) and homeostasis model assessment insulin resistance (–24%).


In obese men with T2DM, liver 11β-HSD1 is increased, whereas liver 11β-HSD1 is sustained in obese Euglycemic men. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese T2DM subjects [Stimson RH et al. Diabetes 2011].


In addition to 11β-HSD1 inhibitors, which reduce the glucocorticoid effects in liver and fat, other novel approaches to glycemic regulation include the use of sodium-glucose cotransporter 2 inhibitors, which increase renal glucose elimination. Insulin glucokinase activators and pancreatic-G-protein-coupled fatty-acid receptor agonists, glucagon receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery [Tahrani AA et al. Lancet 2011].

 

Enhancing the Action of Insulin

Stefano Del Prato, MD, University of Pisa, Pisa, Italy, discussed new routes to enhancing the action of insulin. Ma et al. [Mol Cell Biochem 2011] have investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid abnormalities in vivo and in vitro. PTP1B is a negative regulator of the insulin signaling pathway. Results demonstrate that CCF06240 could increase insulin sensitivity through the regulation of the insulin signaling pathway, and decrease free fatty acid-insulin-induced hepatocytes lipid accumulation by reducing fatty acid synthesis.


Conti et al. [Diabetes 2011] developed teglicar, a new form of antihyperglycemic agent, through the Selective and reversible inhibition of the liver isoform of carnitine palmitoyl-transferase 1. Investigation of glucose production took place in isolated hepatocytes and during pancreatic clamps in healthy rats. The researchers performed chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats to understand glucose metabolism and insulin sensitivity.


In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72% and 50%, respectively. Antidiabetic activity in hepatocytes and rats was associated with improved insulin sensitivity assessed by the insulin tolerance test. In highfat fed C57BL/6J mice, long-term teglicar administration normalized glycemia (–19%) and insulinemia (–53%).


Members of the fibroblast growth factor family stimulate glucose uptake and update mitochondrial function in key metabolic tissues [Cantó C, Auwerx J. Science 2012]. FGF21 has become particularly interesting as exongenous administration to animal models of diabetes and obesity is generally associated with weight loss [Muise ES et al. Mol Pharmacol 2008; Kharitonenkov A et al. Endocrinology 2007]. The understanding of FGF21 biology is still evolving.



EXTENDING THE REACH OF GLP-1


GLP-1 and Cardiovascular Disease

 Cardiovascular disease (CVD) is a leading cause of death in patients with diabetes mellitus [Yoon JS, Lee HW. Diabetes Metab J 2011]. Mansoor Husain, MD, University of Toronto, Toronto, Ontario, Canada, reported on the relationship between type 2 diabetes (T2DM) and CVD; the CV effects of glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase 4 inhibitor

(DPP-4i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) in experimental systems; the CV effects of GLP-1, DPP-4i, and GLP-1RA in humans; and findings from meta-analyses and CV outcome trials. His main focus was on the role of novel therapeutic agents that target the incretin pathway in humans.

 

Incretin-based treatments have garnered much interest due to use-associated weight loss (GLP-1 agonists), minimal hypoglycemia, and the potential for positive effects on pancreatic β-cell biology and the CV system [Phillips LK, Prins JB. Ann NY Acad Sci 2011]. Although GLP-1 and GLP-1RAs have demonstrated beneficial effects on myocardium and vascular endothelium, including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions, and positive effects on lipid profile and blood pressure [Yoon JS, Lee HW. Diabetes Metab J 2011].

 

The randomized, double-blind, placebo-controlled study To Evaluate the Effect of Liraglutide Versus Glimepiride on Haemoglobin A1C [LEAD-3 Mono; Garber A et al. Lancet 2009] showed that liraglutide is safe and effective as initial pharmacological therapy T2DM diabetes and leads to greater reductions in HbA1C (p=0.0014) as well as weight,

hypoglycemia, and blood pressure than glimepiride.

 

Klonoff et al. [Curr Med Res Opin 2008] found that adjunctive exenatide treatment for ≥3 years in patients with T2DM led to significant improvements in triglycerides (p=0.0003), total cholesterol (p=0.0007), high-density lipoprotein cholesterol (p<0.0001), low-density lipoprotein cholesterol (p<0.0001), systolic blood pressure (p=0.0063), and diastolic blood

pressure (p<0.0001).

 

A recent trial by Gupta et al. [Platelets 2012] found that platelets from 10 normal humans pretreated with 5 and 10 μg/mL of sitagliptin showed 25%±4% and 40%±6% inhibition of thrombin-induced platelet aggregation, respectively. Sitagliptin decreased intracellular free calcium (2.5-fold) and tyrosine phosphorylation of multiple proteins in thrombin-induced

platelet activation. The drug inhibited platelet aggregation in those with T2DM as well as healthy subjects.

 

Gallwitz et al. [Lancet 2012] conducted a 2-year randomized, parallel-group, noninferiority, double-blind comparison of the efficacy and safety of the DPP-4i, linagliptin, and a commonly used sulfonylurea, glimepiride. The primary endpoint, change in HbA1C from baseline to Week 104, met the predefined noninferiority criterion of 0.35%. In addition, fewer participants had hypoglycemia (58 [7%] of 776 vs 280 [36%] of 775 patients; p<0.0001) or severe hypoglycemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was also associated with significantly fewer CV events (12 vs 26 patients; RR, 0.46; 95% CI, 0.23 to 0.91; p=0.02; Figure 1).


Figure 1. Relative Risk of CV Events in Treated Patients.


 

Reproduced from Gallowitz B et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 2012; 380(9840):475-483. With permission from Elsevier.


Based on these and other data, Dr. Husain concluded that GLP-1 receptors are expressed in cardiac and vascular tissues; GLP-1 exerts cardioprotective and vasodilatory effects in isolated tissues; absence or inhibition of DPP-4 improves survival in animal models of myocardial infarction (MI); GLP-1RA reduces infarct size and improves survival in animal models of MI; and GLP-1, DPP-4i, and GLP-1RA exert effects on heart, vessel, blood pressure, and risk factors in humans. He reported that clinical trials are underway to evaluate long-term CV outcomes in diabetes.

 

GLP-1 and the Central Nervous System 

Obesity and T2DM are 2 prevalent chronic diseases that have become major public health concerns in industrialized countries; they affect at least 16 million people in the United States alone [Siegal K, Narayan KMV. Global Health2008]. Darleen Sandoval, PhD, University of Cincinnati, Cincinnati, Ohio, USA, presented data on the relationship between GLP-1, the central nervous system (CNS), and body mass.

 

Precise control of energy intake, storage, and expenditure is indispensable in keeping body weight and Blood glucose concentrations within physiological ranges. Communication of the body’s nutritional state by feedback signaling of peripheral organs to the CNS and the appropriate behavioral and metabolic responses initiated by the brain are pivotal processes in maintaining energy homeostasis [Jordan SD et al. Cell Mol Life Sci2010].

 

Barrera et al. [J Neurosci 2011] report that the regulation of energy balance requires bidirectional communication between peripheral tissues and the CNS, an essential component of which is the gut-brain axis. Of the hormonal, neural, and nutritional signals transmitted during a meal, the preproglucagon-derived peptide GLP-1 lies at both ends of the gut-brain axis.

 

GLP-1 is a physiologic regulator of numerous processes, including glucose homeostasis and food intake [Baggio LL, Drucker DJ. Gastroenterology2007; Williams DL et al. Endocrinology 2009]. Recent evidence suggests that GLP-1, which is released from intestinal L-cells after meals and is also produced in the nucleus of the solitary tract, acts as a short-term satiation signal, limiting meal size and prolonging intermeal intervals. Numerous studies also support a role for CNS GLP-1 in long-term energy balance regulation [Barerra JG et al. J Neurosci 2011].

 

GLP-1Rs are expressed in the periphery and in several brain areas that are implicated in the control of eating. A study by Vahl et al. [Endocrinology 2007] demonstrated that GLP-1Rs are also present in the intestine and on nerve terminals in the hepatic portal bed, indicating that peripheral GLP-1 can act in 2 different sites to inhibit eating [Punjabi M et al. Physiol Behav 2011]. Both central and peripheral administration of GLP-1 reduce food intake, with central administration of GLP-1 causing a dose-dependent reduction [Barerra JG et al. J Neurosci 2011]. Exogenous activation of CNS GLP-1Rs also

reduces food consumption [Hayes MR et al. Endocrinology 2009].

 

Gupta [Indian J Endocrinol Metab 2012] reports that the incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones.” GLP-1 mediates its effects via the GLP-1R, which has a wide tissue distribution that includes the CNS (neocortex, cerebellum, hypothalamus, hippocampus, and brainstem nucleus tractus solitarius). Evidence indicates that therapies that augment the incretin system have beneficial pleiotropic effects.



HUMAN GENETICS AND TYPE 2 DIABETES: BEHIND THE HEADLINES


Significant advancements in the knowledge of human genetics and type 2 diabetes (T2DM) have been made in the last 5 years. It was only in 2007 that one of the first genome-wide association studies (GWAS) for T2DM identified the first genetic polymorphism with a robust relationship to diabetes—a common variant in the fat mass and obesity associated FTOgene that predisposes individuals to diabetes through an effect on body mass index (BMI) [Frayling TM et al. Science 2007]. Researchers have now identified ~65 regions of the genome that influence diabetes [Morris AP et al. Nat Genet

2012].

 

Genetic studies have also become larger. The 2007 study included ~39,000 participants, while current studies of BMI include up to 350,000. These advances are virtually all tied to improvements in technology that now allow researchers to quickly sequence the genomes of thousands of individual patients and to analyze tens of millions of genetic variants.

 

Timothy Frayling, PhD, University of Exeter, Exeter, United Kingdom, discussed the new biology being derived from genetic research and how it can impact research being conducted in nongenetic areas.

 

Most forms of diabetes do not follow strict patterns of inheritance through families; they tend to appear in clusters. Prof. Frayling’s approach to genetic studies focuses on differences in allele frequency based on the principle that variant genes present more frequently in cases than in controls, thus variant status provides probability of disease status. However, he cautioned that it remains extremely difficult to identify a single causal risk factor to explain the huge variation in human beings and to sort out the effects of confounding factors.

 

Geneticists have identified 32 polymorphisms that are robustly associated with normal variation in BMI, some of which overlap with the monogenic causes of severe obesity. Some of the common polymorphisms are located near genes such as POMC, BDNF,SH2B1, and MC4R—mutations known to cause severe appetite disorders and severe obesity in children [Speliotes EK et al. Nat Genet 2010]. However, the FTO genotype still stands out as the having the largest influence on BMI and related metabolic traits, and dual-energy X-ray absorptiometry measures in children participating in the 2007 study [Frayling TM et al. Science 2007] show that theFTO effect is associated entirely with adiposity, as opposed to skeletal or lean tissue mass (Figure 1).


Figure 1. FTP: The Association is with Fat Mass Rather Than Lean Mass.


 

ALSPAC=Avon Longitudinal Study of Parents and Children; DEXA=dual-energy X-ray absorptiometry. Reproduced with permission from TM Frayling, PhD.


Longitudinal studies have also informed today’s knowledge of how the FTO gene functions. Sovio et al. [PloS Genet 2011] have shown that the minor (fat) allele in FTO is associated with children emerging from their adiposity trough earlier than the major (thin) allele by the age of 7 years. Thus, after the age of 7 it is difficult to assess the effects of FTO gene variants in humans because fatter individuals eat, behave, and metabolize differently than thinner individuals as a consequence of being more overweight. This association has also been documented in an animal study in which enhanced expression of FTO led to increased food intake and obesity [Church C et al. Nat Genet 2010].

 

Interactions between the FTO gene and the environment have been the subject of several studies. It was recently shown that the FTO genotype influences individual variation in BMI as well as mean BMI [Yang J et al. Nature 2012]. This concept, which indicates a possible increase in the strength of genetics in today’s environment, was also seen in the results of a twin study that showed strong evidence that adiposity in preadolescent children born since the onset of the obesity epidemic is highly heritable, while environmental effects are small and divided approximately equally between shared and nonshared effects [Wardle J et al. Am J Clin Nutr 2008]. After categorizing subjects as physically inactive or active, results from a meta-analysis of data from 45 studies of adults (n=218,166) and 9 studies of children and adolescents (n=19,268) showed FTO had a weaker effect on the distribution of BMI in physically active individuals, suggesting that the genetic effects in a less obesogenic environment are stronger [Kilpeläinen TO et al. PLoS Med 2011]. Another impact study focused on the interaction of sugar-sweetened beverages with the genetic predisposition to adiposity. The genetic association with BMI and adiposity was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake [Qi Q et al. N Engl J Med 2012]. "There is still much to learn about the FTO gene, but the pieces are starting to come together,” said Prof. Frayling.

 

Genetic studies are also informing epidemiology. Since genes are randomly sorted during meiosis, genetic studies are analogous to a randomized controlled trial. It is generally accepted that testosterone levels in men are inversely associated with several recognized risk factors for T2DM (eg, obesity, central adiposity, and elevated levels of fasting plasma insulin and glucose). A relationship has also been indicated between T2DM and lower baseline levels of free testosterone and sex hormone-binding globulin (SHBG) in men [Tibblin G et al. Diabetes 1996; Haffner SM et al. Am J Epidemiol 1996] and reduced SHBG concentrations among women with polycystic ovary syndrome and hyperinsulinemia [Nestler JE et al. J Clin Endocrinol 1991; Stellato RK et al. Diabetes Care 2000]. Using Mendelian randomization principles, Prof. Frayling’s laboratory has shown that GWAS have shown genetic variants at the SHBG gene influence circulating SHBG levels and that there is a direct relationship between low SHBG levels and increased risk of T2DM. Prof. Frayling predicted that future Mendelian randomization experiments will be useful for predicting which epigenetic and gene expression factors casually influence T2DM.

 

Increased adiponectin levels have been shown to be associated with a lower risk of T2DM. Thus, the relationship between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in diabetes has been studied extensively. One study identified a novel association between a low-frequency single nucleotide polymorphism (SNP; rs17366653) and adiponectin levels, and showed that 7 SNPs exert independent effects on adiponectin levels, which explained 6% of adiponectin variation. No evidence of association with T2DM was found [Warren LL et al. Diabetes 2012]. Large-scale and well-powered Mendelian randomization is recommended for future

studies.

 

Prof. Frayling concluded with a description of an ongoing study comparing ADIPOQ gene splicing, metabolic profiles, and insulin resistance in individuals with lifelong genetically reduced adiponectin levels with a control population. Data for this study and others are and will be available on the Internet. Prof. Frayling reiterated that GWAS findings are important tools to understand the biology of diabetes and should be made freely available to all researchers (Figure 2).


Figure 2. Main Message: GWAS Findings Are Important Tools to Understand the Biology of Diabetes.



DNA=deoxyribonucleic acid; FFA=free fatty acid; SHBG=sex hormone-binding globulin. Reproduced with permission from TM Frayling, PhD.



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