Focus on Vitamin D, Inflammation and Type 2 Diabetes

Nutrients 2012, 4, 52-67; doi:10.3390/nu4010052 OPEN ACCESS nutrients ISSN 2072-6643 www.mdpi.com/journal/nutrients Review Focus on Vitamin D, Infla...
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Nutrients 2012, 4, 52-67; doi:10.3390/nu4010052 OPEN ACCESS

nutrients ISSN 2072-6643 www.mdpi.com/journal/nutrients Review

Focus on Vitamin D, Inflammation and Type 2 Diabetes Carlos Eduardo Andrade Chagas 1, Maria Carolina Borges 2, Lígia Araújo Martini 2 and Marcelo Macedo Rogero 2,* 1

2

Center for Nutrition Practice and Research, Department of Education, Institute of Biosciences, São Paulo State University, Botucatu, SP 18618-970, Brazil; E-Mail: [email protected] Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo 01246-904, Brazil; E-Mail: [email protected] (M.C.B.); [email protected] (L.A.M.)

* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +55-11-3061-7850; Fax: +55-11-3061-7705. Received: 2 December 2011; in revised form: 29 December 2011 / Accepted: 9 January 2012 / Published: 20 January 2012

Abstract: The initial observations linking vitamin D to type 2 diabetes in humans came from studies showing that both healthy and diabetic subjects had a seasonal variation of glycemic control. Currently, there is evidence supporting that vitamin D status is important to regulate some pathways related to type 2 diabetes development. Since the activation of inflammatory pathways interferes with normal metabolism and disrupts proper insulin signaling, it is hypothesized that vitamin D could influence glucose homeostasis by modulating inflammatory response. Human studies investigating the impact of vitamin D supplementation on inflammatory biomarkers of subjects with or at high risk of developing type 2 diabetes are scarce and have generated conflicting results. Based on available clinical and epidemiological data, the positive effects of vitamin D seem to be primarily related to its action on insulin secretion and sensitivity and secondary to its action on inflammation. Future studies specifically designed to investigate the role of vitamin D on type 2 diabetes using inflammation as the main outcome are urgently needed in order to provide a more robust link between vitamin D, inflammation and type 2 diabetes. Keywords: vitamin D; inflammation; diabetes

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1. Introduction Type 2 diabetes is one of the main noncommunicable chronic diseases and its complications have become a major cause of morbidity and mortality worldwide. It has been estimated that 285 million individuals have diabetes, most of them type 2 diabetes [1]. Vitamin D deficiency is also considered a public health problem around the world. In 2008, it was estimated that 1 billion individuals presented vitamin D insufficiency or deficiency [2]. Much evidence suggested that vitamin D is involved in several mechanisms in addition to bone metabolism [3] and its role in abnormal glucose metabolism as well as in type 2 diabetes has been demonstrated [4,5]. A recent review indicates that vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion and type 2 diabetes [6], either through a direct action via vitamin D receptor (VDR) activation or indirectly via calcemic hormones and also via inflammation [7]. Furthermore, in observational studies the risk of diabetes was negatively associated with increased vitamin D concentrations [6,8]. In fact, Mitri et al. [9], in a systematic review, confirmed such evidence by evaluating vitamin D intake and 25-hydroxyvitamin D (25OHD) levels. In 8 observational studies, vitamin D intake >500 international units (IU)/day decreased the risk of type 2 diabetes by 13% compared with vitamin D intake 25 ng/mL) had a 43% lower risk of developing type 2 diabetes (95% confidence interval 24–57%) compared with those in the lowest group ( 30 ng/mL. Weekly supplementation of vitamin D3 for 24 weeks: 50,000 IU in the first 12 weeks and 20,000 IU in the last 12 weeks.

Significant decrease in C-reactive protein.

No differences in C-reactive protein.

Significant decrease in C-reactive protein and interleukin 6.

4. Vitamin D and Type 2 Diabetes In contrast to type 1 diabetes, which is related to autoimmune destruction of pancreatic β cells, leading to absolute insulin deficiency, type 2 diabetes development involves impaired pancreatic β cell function, insulin resistance and inflammation. Although mechanistically unclear, it has been suggested that both environmental and genetic factors seem to be involved in type 2 diabetes development [56]; also, human and experimental data support the role of vitamin D on these pathways [8,57]. Due to the presence of both 1-α-hydroxylase and VDR in pancreatic β cells, vitamin D is important for insulin synthesis and release [8,56]. In rats, vitamin D deficiency induced impairment of insulin secretion and glucose tolerance that was partially corrected after vitamin D replenishment [58,59]. Moreover, vitamin D is also involved in insulin sensitivity by controlling calcium flux through the membrane in both β cells and peripheral insulin-target tissues [57]. The initial observations linking vitamin D to type 2 diabetes in humans came from studies showing that both healthy and diabetic subjects had a seasonal variation of glycemic control [60,61]. Since then, several recent human studies have associated vitamin D status with type 2 diabetes development

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(Table 2). It should be highlighted that after statistical adjustments for potential risk factors of type 2 diabetes, such as body mass index, the association between vitamin D and type 2 diabetes was attenuated in one study [62] and no longer significant in another one [63]. Almost all studies used serum 25OHD as a biomarker for vitamin D stores, while studies investigating vitamin D intake are scarce. Table 2. Human studies that associate vitamin D with type 2 diabetes. Ref. Study design Subjects included Main outcome [62] Cohort (Mini-Finland 4097 individuals followed-up The highest versus the lowest serum 25OHD: Health Survey) for 17 years. RR = 0.70; 95% CI = 0.42–1.16); p for trend = 0.07). [63] Cohort (Tromsø 4157 non-smokers and Baseline serum 25OHD was inversely Study) 1962 smokers followed-up associated with type 2 diabetes. for 11 years. [64] Cohort (Nurses’ 83,779 women followed-up The highest versus the lowest category of Health Study) for 20 years. vitamin D intake from supplements: RR = 0.87; 95% CI = 0.75–1.00; p for trend = 0.004). [65] Nested case-control 412 cases and 986 controls. The highest versus the lowest quartiles of serum 25OHD: OR = 0.28 (95% CI = 0.10–0.81) in men and OR = 1.14 (95% CI = 0.60–2.17) in women. [66] Meta-analysis Polled data from 2 cohorts The highest versus the lowest serum 25OHD: studies with 8627 individuals RR = 0.66; 95% CI = 0.50–0.87. aged 40–79 years. [67] Cohort (Framingham 3066 (1402 men and A higher 25OHD serum levels is associated Study) 1664 women) followed-up with decreased risk of type 2 diabetes. for 7 years. [6] Nested case-control 608 cases and 559 controls. The highest versus the lowest serum 25OHD quartile: OR = 0.52; 95% CI = 0.33–0.83. [68] Cross-sectional 210 individual aged more Vitamin D deficiency was more common in than 40. diabetic compared to control. [69] Cross-sectional 668 individuals aged Serum 25OHD < 50 nmol/L doubled the risk 70–74 years. of newly diagnosed type 2 diabetes. [70] Cohort (AusDiab 5200 individuals; mean age Each 25 nmol/L increment in serum 25OHD study) 51 years. was associated with a 24% reduced risk of type 2 diabetes (OR = 0.76; 95% CI = 0.63–0.92). [71] Cross-sectional 2465 subjects. Serum 25OHD ≥ 80 nmol/L versus ≤37 nmol/L in Caucasians: OR = 0.5; 95% CI = 0.1–0.7. [9] Systematic review of 238,424 individuals aged Vitamin D intake >500 versus 25 ng/mL versus

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