Association of Variation in the Interleukin-1 Gene Family with Diabetes and Glucose Homeostasis

Luotola, Kari; Pääkkönen, Rauni; Alanne, Mervi; Lanki, Timo; Moilanen, Leena; Surakka, Ida; Pietilä, Arto; Kähönen, Mika; Nieminen, Markku S.; Kesäniemi, Y. Antero; Peters, Annette; Jula, Antti; Perola, Markus; Salomaa, Veikko

doi:10.1210/jc.2009-0666

Cited by 37 publications

(37 citation statements)

References 27 publications

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“…Furthermore, expression of several pro-inflammatory genes like IL-1␣ and CXCL5 increased with HFD. Interestingly, IL-1␣ and CXCL5 have previously been linked to hyperglycemia and diabetes susceptibility in humans (16,27). These changes suggest a hyperactive inflammatory response pathway and could explain, at least in part, the ␤-cell dysfunction in BLKS animals treated with HFD.…”

Section: Discussionmentioning

confidence: 93%

Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains

Sims

Hatanaka

Morris

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-Impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are polygenic disorders with complex pathophysiologies; recapitulating them with mouse models is challenging. Despite 70% genetic homology, C57BL/6J (BL6) and C57BLKS/J (BLKS) inbred mouse strains differ in response to dietand genetic-induced obesity. We hypothesized these differences would yield insight into IGT and T2DM susceptibility and response to pharmacological therapies. To this end, male 8-wk-old BL6 and BLKS mice were fed normal chow (18% kcal from fat), high-fat diet (HFD; 42% kcal from fat), or HFD supplemented with the PPAR␥ agonist pioglitazone (PIO; 140 mg PIO/kg diet) for 16 wk. Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were undertaken. BL6 mice gained weight and adiposity in response to HFD, leading to peripheral insulin resistance that was met with increased ␤-cell proliferation and insulin production. By contrast, BLKS mice responded to HFD by restricting food intake and increasing activity. These behavioral responses limited weight gain and protected against HFD-induced glucose intolerance, which in this strain was primarily due to ␤-cell dysfunction. PIO treatment did not affect HFD-induced weight gain in BL6 mice, and decreased visceral fat mass, whereas in BLKS mice PIO increased total fat mass without improving visceral fat mass. Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment. C57BL/6J; C57BLKS/J; diet-induced obesity; pioglitazone; mouse models of T2DM GENOMEWIDE ASSOCIATION STUDIES (GWAS) indicate that the vast majority of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are polygenic and represent a complex interplay between genetic susceptibility, dietary and lifestyle choices, and environment (48). The initial treatment of T2DM typically consists of a combination of antihyperglycemic agents, including metformin, sulfonylureas, PPAR␥ agonists, or thiazolidinediones (TZDs), and incretin-based therapies; however, this approach is associated with high secondary failure rates, and many patients will ultimately transition to insulin therapy in order to achieve glycemic targets (45). While the field of T2DM pharmacogenomics is relatively undeveloped compared with other complex diseases, large clinical studies have revealed important differences in response to these therapies based on sex, ethnicity, and other genetic differences (9, 51). Given the heterogeneous nature of IGT and T2DM susceptibility and treatment response, modeling these disorders in the laboratory setting using inbred strains of mice is fraught with inherent challenges.C57BL/6J (BL6) mice are one of the most widely utilized inbred strains in biomedical research (1). Many knockout and transgenic mouse models are bred congenic on the BL6 background for metabolic...

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Section: Discussionmentioning

confidence: 93%

Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains

Sims

Hatanaka

Morris

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…IL-1β is induced and IL-1Ra is repressed in human islets cultured in high glucose or treated with leptin suggesting a role for adipose secreted factors in the pathogenesis of islet destruction (414). In human subjects, a strong association between variation in the IL-1 gene family and indices of glucose homeostasis and T2D prevalence have been documented (408) and circulating IL-1β levels are elevated in type 2 diabetic patients and subjects with the MS, however, show a direct causal role for IL-1β and IL-1Ra in insulin resistance and β-cell destruction have yet to be confirmed.…”

Section: Adipose-secreted Proinflammatory Cytokines and Liver-secretementioning

confidence: 99%

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

Roberts

Hevener

Barnard

2013

Comprehensive Physiology

466

425

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Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.

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“…IL-1 has a central role in regulation of inflammatory and immune responses, and IL-1α and IL-1β are pro-inflammatory cytokines (Banerjee and Saxena, 2012). Polymorphisms in the IL-1 gene have been reported to be associated with obesity, which is a risk factor for the onset of diabetes (Carter et al, 2008), and play a role in glucose homeostasis and diabetes prevalence (Luotola et al, 2009). The IL-1 gene cluster on chromosome 2q, particularly IL-1α, has been implicated in susceptibility to a large number of neoplastic, autoimmune, and chronic inflammatory disorders (Timms et al, 2004;Han et al, 2010;Liu et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The IL-1 gene cluster on chromosome 2q, particularly IL-1α, has been implicated in susceptibility to a large number of neoplastic, autoimmune, and chronic inflammatory disorders (Timms et al, 2004;Han et al, 2010;Liu et al, 2010). Luotola et al (2009) reported that the rs1800587 polymorphism in IL-1α was associated with higher blood glucose in a cross-sectional study (Luotola et al, 2009). Therefore, we conducted this study to investigate whether the rs1800587 polymorphism in the IL-1α gene plays a role in T1D risk.…”

Section: Discussionmentioning

confidence: 99%

Association of IL-1α gene polymorphism with susceptibility to type 1 diabetes in Chinese children

Zhou

Peng

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The interleukin-1α (IL-1α) gene appears to play a role in the pathogenesis of type 1 diabetes (T1D). Therefore, the aim of this study was to investigate the contribution of the IL-1 rs1800587 gene polymorphism to susceptibility to T1D in Chinese children. This casecontrol study included 332 Chinese children with T1D and 332 healthy controls. Identification of genetic variants of rs1800587 in the IL-1α gene was performed by polymerase chain reaction amplification. The IL-1α rs1800587 polymorphism demonstrated a significant association with T1D risk. The allelic frequency significantly differed between the T1D and control groups [odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.52-0.86; P = 0.002]. Furthermore, significant differences were observed in the dominant model (CC/CT + TT; OR = 0.6; 95%CI = 0.46-0.85; P = 0.003). In T1D patients, the prevalence of hypertension in T allele carriers was 4.2-fold higher than that in C allele carriers, (95%CI = 2.67-6.58; P < 0.001). In conclusion, the present study found evidence of a significant association between the rs1800587 polymorphism in the IL-1α gene and T1D.

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Association of Variation in the Interleukin-1 Gene Family with Diabetes and Glucose Homeostasis

Abstract: These results suggest that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and prevalent diabetes.

Cited by 37 publications

References 27 publications

Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains

Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

Association of IL-1α gene polymorphism with susceptibility to type 1 diabetes in Chinese children

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