The Leu7Pro Polymorphism of Neuropeptide Y is Associated with Younger Age of Onset of Type 2 Diabetes Mellitus and Increased Risk for Nephropathy in Subjects with Diabetic Retinopathy

Jaakkola, Ulriikka; Pesonen, Ullamari; Vainio-Jylhä, Elina; Koulu, Markku; Pöllönen, Matti; Kallio, Johanna

doi:10.1055/s-2006-924079

Cited by 22 publications

(18 citation statements)

References 14 publications

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“…The L7P polymorphism, first described by our group, is associated with earlier onset of type 2 diabetes in obese carriers of L7P (35) and with other traits of the metabolic syndrome (36 -39). Clinical studies have also shown that L7P carriers have altered insulin and ghrelin responses (40,41).…”

Section: Discussionmentioning

confidence: 95%

Transgenic Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

et al. 2008

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OBJECTIVE-A functional polymorphism leucine 7 proline in the human neuropeptide Y (NPY) gene leading to increased NPY release from sympathetic nerves is associated with traits of metabolic syndrome. Although hypothalamic NPY neurons play an established role in promoting positive energy balance, the role of NPY colocalized with norepinephrine in sympathetic nervous system and brain noradrenergic neurons remains obscure.RESEARCH DESIGN AND METHODS-To clarify the role of NPY in noradrenergic neurons, we generated a transgenic mouse overexpressing NPY under dopamine-␤-hydroxylase promoter and characterized the metabolic phenotype of the OE-NPY D␤H mouse.RESULTS-NPY levels are increased by 1.3-fold in adrenal glands and 1.8-fold in the brainstem but not in the hypothalamus in OE-NPY D␤H mice. They display increased white adipose tissue mass and cellularity and liver triglyceride accumulation without hyperphagia or increased body weight. Hyperinsulinemia and impaired glucose tolerance develop by the age of 6 months in the OE-NPY D␤H mice. Furthermore, circulating ghrelin is significantly increased in comparison with wild-type mice.CONCLUSIONS-The present study shows that even a moderate increase in NPY levels in noradrenergic neurons leads to disturbances in glucose and lipid metabolism. The OE-NPY D␤H mouse is an interesting new model to investigate the pathophysiology of some key components of the cluster of abnormalities characterizing the metabolic syndrome. Diabetes 57: [1517][1518][1519][1520][1521][1522][1523][1524][1525] 2008 N europeptide Y (NPY) plays a well-established role in the hypothalamic control of body energy balance. It is one of the key components of the interconnected orexigenic network, which is upregulated in states of negative energy balance. NPY is a very potent orexigenic peptide, and when chronically administered into the central nervous system, it leads to increased food intake, weight gain, and adiposity (1-3). NPY-induced obesity is not only due to hyperphagia; centrally administered NPY also promotes white adipose tissue (WAT) lipid storage, inhibits brown adipose tissue thermogenesis, and induces hyperinsulinemia and hypercorticosteronemia (4 -6). Increased hypothalamic NPY is also an essential feature of leptin-deficient obesity, which is attenuated by genetic depletion of NPY (7). Although there is plenty of evidence on the key role of NPY in the regulation of energy balance in rodents, the evidence is scarce in humans and based mainly on the functional leucine 7 proline (L7P) polymorphism of the preproNPY associated with alterations in glucose and lipid metabolism and development of atherosclerosis (8).In addition to the NPY neurons of the hypothalamus, NPY is widely distributed in the central and peripheral nervous system. In the periphery, NPY is co-stored and co-released in postganglionic sympathetic neurons and chromaffin cells of adrenal medulla with norepinephrine (NE) (9,10). In the brain, NPY is also colocalized with NE in noradrenergic neurons in the medulla and the brain...

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Section: Discussionmentioning

confidence: 95%

Transgenic Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

et al. 2008

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“…Several studies to date have looked at the molecular determinants of age of type 2 diabetes onset [19][20][21][22][23][24][25][26][27]; however none have explored mtDNA content as a candidate factor. Our study suggests that an earlier age of type 2 diabetes onset is associated with a lower PBMC mtDNA content and that this relationship occurs primarily in patients without diabetes complications.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications

et al. 2009

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Aims/hypothesis We examined whether age of type 2 diabetes onset is related to mitochondrial DNA content in peripheral blood monocytes (PBMCs). Methods PBMCs were isolated from 65 patients with type 2 diabetes. To minimise age as a confounder, only patients aged ≥50 years were studied. Sample mitochondrial DNA (mtDNA) content was determined by amplification of the mitochondrial gene CYT-B (also known as MT-CYB) and adjusted for single-copy nuclear control genes (36B4 [also known as RPLPO] and GAPDH). Results Age of diabetes onset ranged from 25 to 69 years. There was a significant positive relationship between age of diabetes onset in quartiles and mtDNA content for the whole group (p= 0.02 for trend). When stratified by the presence of diabetes complications, a strong positive relationship was observed between age of diagnosis and mtDNA content for participants without diabetic complications (r = 0.7; p = 0.0002), but not for those with complications (r=−0.04; p=0.8). Multivariate analysis confirmed age of onset and complication status as independent determinants. There was co-linearity between age of onset and disease duration, with similar relationships also seen between duration and mtDNA content. Conclusions/interpretation An earlier age of type 2 diabetes onset is associated with a lower PBMC mtDNA content, but only in patients without diabetes complications. This may reflect a differing biology of PBMC mtDNA in those with early-onset diabetes and those who are prone to complications. PBMC mtDNA depletion may accelerate diabetes onset; however the independent effect of diabetes duration remains to be evaluated.

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“…Leucine 7 to Proline 7 polymorphism in the NPY gene (substitution of leucine for proline in human prepro-NPY) was linked to an increased predisposition to develop diabetic retinopathy in Type 2 diabetic patients (Jaakkola et al, 2006;Koulu et al, 2004;Niskanen et al, 2000). However, this was not considered a risk factor for exudative age related macular degeneration (Kaarniranta et al, 2007).…”

Section: Npy System In Retinal Vascular Cells: Pericytes and Endothelmentioning

confidence: 99%