Leu7Pro polymorphism of PreproNPY associated with an increased risk for type II diabetes in middle-aged subjects

Abstract

Objectives: Neuropeptide Y (NPY) plays a central in energy homeostasis and potentially in the development of obesity-related comorbidities, like type II diabetes. As the PreproNPY Leu7Pro polymorphism probably changes the intracellular processing of the synthesized preproNPY peptide, we assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance and hypertension. Design: Blood pressure recordings and oral glucose tolerance test were performed in the hypertensive (n ¼ 515) and control cohorts (n ¼ 525) of our well-defined Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study. The prevalence of type II diabetes was 9% (n ¼ 93). The genotypes, insulin and glucose metabolism indexes and plasma ghrelin of the subjects were determined. Results: Pro7 allele frequencies were 5.9, 5.3 and 11.3% in the total cohort, in subjects without and with type II diabetes, respectively. The PreproNPY Pro7 carrier status was a significant risk factor for type II diabetes, and the effect remained significant after adjustment for age, sex, waist circumference and study group (odds ratio ¼ 3.02, confidence interval: 1.67-5.44 and Po0.001). Pro7 carriers were more insulin resistant and showed lower ghrelin levels compared to non-carriers. Conclusions: The PreproNPY Pro7 allele is associated with an increased risk for type II diabetes. The risk seems to be associated with a higher insulin resistance among Pro7 carriers whereas low ghrelin concentrations in Pro7 carriers are possibly a consequence of high insulin levels. Sponsorship: None. IntroductionCentral mechanisms including the activation of hypothalamic neuropeptide Y (NPY) control energy homeostasis (Williams et al., 2001). As most of the patients with type II diabetes are obese, NPY is also potentially involved in the development of obesity-related comorbidities, like type II diabetes. NPY is, therefore, a good candidate gene for type II diabetes. The functional leucine 7 to proline (Leu7Pro) polymorphism in the signal peptide of NPY has been earlier associated with plasma NPY levels (Kallio et al., 2001(Kallio et al., , 2003, insulin metabolism (Kallio et al., 2003;Jaakkola et al., 2005), type II diabetes (Nordman et al., 2005) and its complications (Niskanen et al., 2000a, b;Koulu et al., 2004). The results have been, however, contradictory, and the mechanisms behind these associations largely unknown. Interestingly, the PreproNPY Leu7Pro polymorphism has been associated with delayed ghrelin suppression during oral glucose tolerance test (Jaakkola et al., 2005). The orexigenic potency of ghrelin is suggested to be caused by the activation of hypothalamic NPY neurones (Shintani et al., 2001). We have earlier reported an association of low plasma ghrelin with type II diabetes (Pöykkö et al., 2003). We assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance (IGT), and hypertension. Secondly, we studied whether Leu7Pro polymorphism is asso...

Metabolism disrupting chemicals and metabolic disorders

“…Conversely, when NPY synthesis and release are increased and POMC is decreased, the result is an increase in food intake [75-77]. Dysfunction of the NPY system has been implicated in obesity and T2D in humans [78, 79]…”

Neuropeptide Y polymorphism significantly magnifies diabetes and cardiovascular disease risk in obesity: the Hoorn Study

“…The SNP NPY 1228 T4C (rs16139) leading to an amino-acid chance leucine7 to proline7 (Leu7Pro) in the signal peptide of NPY is relatively common in European populations; about 7-12% of subjects have the minor Pro7 allele in a heterozygous (Leu7Pro7) or, very rarely, homozygous (Pro7Pro7) genotype (Karvonen et al, 1998;Ding, 2003). The Pro7 allele has been associated with increased blood pressure, accelerated atherosclerosis and type II diabetes (Karvonen et al, 2001;Nordman et al, 2005;Ukkola and Kesaniemi, 2007). Since obesity is a major risk factor for diabetes and cardiovascular diseases, among other comorbidities (Poirier et al, 2006), and the effect of interaction obesity on genotype has not been well appreciated in all SNP association studies, we wanted to evaluate the impact of the interaction of obesity with the Leu7Pro polymorphism of preproNPY on blood pressure elevation, cardiovascular events and abnormal glucose regulation in elderly people.…”

Neuropeptide Y gene polymorphisms are not associated with obesity in a South Indian population

“…Since then, this polymorphism has been linked to a number of disease conditions, hypertension (Karvonen et al, 2001;Pettersson-Fernholm et al, 2004), increased BMI (Ding et al, 2005;van Rossum et al, 2006), low-density lipoprotein cholesterol (Karvonen et al, 1998;Salminen et al, 2008), serum triglycerides Pihlajamaki et al, 2003), carotid atherosclerosis (Karvonen et al, 2001) type-I diabetes (Ma et al, 2007) and type-II diabetes (Niskanen et al, 2000;Ukkola and Kesaniemi, 2007). As NPY is a plausible candidate for obesity, we conducted a populationbased case-control study to investigate the association between NPY gene single-nucleotide polymorphisms (SNPs) and obesity.…”