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Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.

ABSTRACT: Proinflammatory cytokines are thought to play a significant role in the pathogenesis of type 2 diabetes (T2D) and are elevated in the circulation even before the onset of the disease. However, the full complement of cytokines involved in the development of T2D is not known. In this study, 32 serum cytokines were measured from diabetes-prone BKS.Cg-m+/+Lepr(db)/J (db/db) mice and heterozygous age-matched control mice at 5 weeks (non-diabetic/non-obese), 6-7 weeks (transitional-to-diabetes), or 11 weeks (hyperglycemic/obese) and then correlated with body weight, blood glucose, and fat content. Among these 32 cytokines, C-X-C motif ligand 1 (CXCL1) showed the greatest increase (+78%) in serum levels between db/db mice that were hyperglycemic (blood glucose: 519±23?mg/dl, n=6) and those that were non-hyperglycemic (193±13?mg/dl, n=8). Similarly, increased CXCL1 (+68%) and CXCL5 (+40%) were associated with increased obesity in db/db mice; note that these effects could not be entirely separated from age. We then examined whether islets could be a source of these chemokines. Exposure to cytokines mimicking low-grade systemic inflammation (10?pg/ml IL1?+20?pg/ml IL6) for 48?h upregulated islet CXCL1 expression by 53±3-fold and CXCL5 expression by 83±10-fold (n=4, P<0.001). Finally, overnight treatment with the combination of CXCL1 and CXCL5 at serum levels was sufficient to produce a significant decrease in the peak calcium response to glucose stimulation, suggesting reduced islet function. Our findings demonstrated that CXCL1 and CXCL5 i) are increased in the circulation with the onset of T2D, ii) are produced by islets under stress, and iii) synergistically affect islet function, suggesting that these chemokines participate in the pathogenesis of T2D.

SUBMITTER: Nunemaker CS

PROVIDER: S-EPMC4135511 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.

Nunemaker Craig S CS Chung H Grace HG Verrilli Gretchen M GM Corbin Kathryn L KL Upadhye Aditi A Sharma Poonam R PR

The Journal of endocrinology 20140613 2

Proinflammatory cytokines are thought to play a significant role in the pathogenesis of type 2 diabetes (T2D) and are elevated in the circulation even before the onset of the disease. However, the full complement of cytokines involved in the development of T2D is not known. In this study, 32 serum cytokines were measured from diabetes-prone BKS.Cg-m+/+Lepr(db)/J (db/db) mice and heterozygous age-matched control mice at 5 weeks (non-diabetic/non-obese), 6-7 weeks (transitional-to-diabetes), or 11 ...[more]

PMID: 24928936

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Project description:BackgroundObesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.MethodsThis was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.ResultsThe highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).ConclusionsAmong participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.

Dataset Information

Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.

Publications

Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.

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