DIAB-6295; No. of Pages 9 diabetes research and clinical practice xxx (2015) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Invited Review
Vitamin D and diabetes: Where do we stand? Chantal Mathieu Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium
article info
abstract
Article history:
The potential beneficial effects of supplementing vitamin D or treatment with pharmaco-
Received 29 January 2015
logical doses of vitamin D in the prevention or cure of diseases like type 1 (T1D) or type 2
Accepted 30 January 2015
diabetes (T2D) remains the subject of debate. Data from epidemiological and association
Available online xxx
studies clearly indicate a correlation between vitamin D deficiency and a higher prevalence
Keyword:
type 2 diabetes, whereas high doses of vitamin D or its active hormonal form, 1,25-
of both forms of diabetes. In animal models, vitamin D deficiency predisposes to type 1 and Clinical and experimental
dihydroxyvitamin D, prevent disease. Large scale, randomized, blinded prospective studies
endocrinology
however, remain lacking. Here we discuss the current literature on a role for vitamin D in diabetes. We propose, in particular, to avoid vitamin D deficiency in individuals at risk of developing T1D or T2D. Applying international guidelines on supplementation of vitamin D using small daily doses of vitamin D (500–1000 IU) may contribute to reduce the burden of diabetes by preventing vitamin D deficiency. Any other recommendations are at present not supported by data. # 2015 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Vitamin D and the beta-cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Vitamin D and insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Epidemiological data on vitamin D and type 2 diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Type 2 diabetes and therapeutic interventions with vitamin D . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Vitamin D as an immune modulator in vitro and in experimental models of type 1 diabetes 3.2. Clinical interventions with vitamin D in type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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E-mail address: [email protected]. http://dx.doi.org/10.1016/j.diabres.2015.01.036 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mathieu C. Vitamin D and diabetes: Where do we stand?. Diabetes Res Clin Pract (2015), http://dx.doi.org/ 10.1016/j.diabres.2015.01.036
DIAB-6295; No. of Pages 9
2
diabetes research and clinical practice xxx (2015) xxx–xxx
1.
Introduction
Since many years, a role for vitamin D has been suggested outside bone and calcium metabolism, with beneficial effects suggested in defense against infectious agents, correlations with cancer and more recently also in prevention of diabetes. Vitamin D can be obtained from food sources of vegetable origin (vitamin D2, also known as ergocalciferol) or animal (vitamin D3, also known as cholecalciferol). The best food sources are fatty fish and their oils. However, small amounts can also be found in butter and egg yolk. Cow’s milk and human milk are relatively poor in vitamin D. Skim milk, in particular, often does not contain vitamin D. In many parts of the world, especially in North America, certain foods such as margarines, butter and cereals, are fortified with vitamin D. But the actual content of vitamin D is often quite different from the labeling standard and often insufficient to cover the daily needs [1]. Vitamin D3 itself is biologically inert and requires two successive hydroxylations, one in the liver, on the C25 position, the other in the kidney, in the a position on carbon one, to form the active hormone metabolite 1,25dihydroxy vitamin D3 (1,25(OH)2D3). The hydroxylation enzymes belong to the family of cytochrome P450 (reviewed in [2]). Production of 1,25(OH)2D3 in the kidney is tightly regulated by several factors, including the level of parathyroid hormone, and the 1a-hydroxylase enzyme (CYP27B1) is subject to down-regulation by 1,25(OH)2D3 itself. The main site of production of 1,25(OH)2D3 by 1a-hydroxylation is the renal proximal tubule, but the presence of high levels of 1ahydroxylase mRNA levels were also found in other tissues, human keratinocytes, dendritic cells and macrophages. This extra-renal production of 1,25(OH)2D3 is set in a completely different way. Production in macrophages, for example, is insensitive to stimulation by parathyroid hormone, but is directly activated by immune-stimulators such as IFN-g and lipopolysaccharide (LPS) [3]. Circulating vitamin D metabolites are linked to a carrier protein, vitamin-D binding protein (DBP). The optimal circulating levels of vitamin D remains subject of discussion [4], but levels of 25 (OH)D3 of 20–30 ng/mL (50–75 nmol/L) are considered adequate, whereas levels 1200 mg of calcium supplements. This supplementary treatment was inversely correlated with the incidence of T2D when compared to an intake of
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Invited Review
Vitamin D and diabetes: Where do we stand? Chantal Mathieu Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium
article info
abstract
Article history:
The potential beneficial effects of supplementing vitamin D or treatment with pharmaco-
Received 29 January 2015
logical doses of vitamin D in the prevention or cure of diseases like type 1 (T1D) or type 2
Accepted 30 January 2015
diabetes (T2D) remains the subject of debate. Data from epidemiological and association
Available online xxx
studies clearly indicate a correlation between vitamin D deficiency and a higher prevalence
Keyword:
type 2 diabetes, whereas high doses of vitamin D or its active hormonal form, 1,25-
of both forms of diabetes. In animal models, vitamin D deficiency predisposes to type 1 and Clinical and experimental
dihydroxyvitamin D, prevent disease. Large scale, randomized, blinded prospective studies
endocrinology
however, remain lacking. Here we discuss the current literature on a role for vitamin D in diabetes. We propose, in particular, to avoid vitamin D deficiency in individuals at risk of developing T1D or T2D. Applying international guidelines on supplementation of vitamin D using small daily doses of vitamin D (500–1000 IU) may contribute to reduce the burden of diabetes by preventing vitamin D deficiency. Any other recommendations are at present not supported by data. # 2015 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Vitamin D and the beta-cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Vitamin D and insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Epidemiological data on vitamin D and type 2 diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Type 2 diabetes and therapeutic interventions with vitamin D . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D and type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Vitamin D as an immune modulator in vitro and in experimental models of type 1 diabetes 3.2. Clinical interventions with vitamin D in type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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000 000 000 000 000 000 000 000 000 000 000
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.diabres.2015.01.036 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mathieu C. Vitamin D and diabetes: Where do we stand?. Diabetes Res Clin Pract (2015), http://dx.doi.org/ 10.1016/j.diabres.2015.01.036
DIAB-6295; No. of Pages 9
2
diabetes research and clinical practice xxx (2015) xxx–xxx
1.
Introduction
Since many years, a role for vitamin D has been suggested outside bone and calcium metabolism, with beneficial effects suggested in defense against infectious agents, correlations with cancer and more recently also in prevention of diabetes. Vitamin D can be obtained from food sources of vegetable origin (vitamin D2, also known as ergocalciferol) or animal (vitamin D3, also known as cholecalciferol). The best food sources are fatty fish and their oils. However, small amounts can also be found in butter and egg yolk. Cow’s milk and human milk are relatively poor in vitamin D. Skim milk, in particular, often does not contain vitamin D. In many parts of the world, especially in North America, certain foods such as margarines, butter and cereals, are fortified with vitamin D. But the actual content of vitamin D is often quite different from the labeling standard and often insufficient to cover the daily needs [1]. Vitamin D3 itself is biologically inert and requires two successive hydroxylations, one in the liver, on the C25 position, the other in the kidney, in the a position on carbon one, to form the active hormone metabolite 1,25dihydroxy vitamin D3 (1,25(OH)2D3). The hydroxylation enzymes belong to the family of cytochrome P450 (reviewed in [2]). Production of 1,25(OH)2D3 in the kidney is tightly regulated by several factors, including the level of parathyroid hormone, and the 1a-hydroxylase enzyme (CYP27B1) is subject to down-regulation by 1,25(OH)2D3 itself. The main site of production of 1,25(OH)2D3 by 1a-hydroxylation is the renal proximal tubule, but the presence of high levels of 1ahydroxylase mRNA levels were also found in other tissues, human keratinocytes, dendritic cells and macrophages. This extra-renal production of 1,25(OH)2D3 is set in a completely different way. Production in macrophages, for example, is insensitive to stimulation by parathyroid hormone, but is directly activated by immune-stimulators such as IFN-g and lipopolysaccharide (LPS) [3]. Circulating vitamin D metabolites are linked to a carrier protein, vitamin-D binding protein (DBP). The optimal circulating levels of vitamin D remains subject of discussion [4], but levels of 25 (OH)D3 of 20–30 ng/mL (50–75 nmol/L) are considered adequate, whereas levels 1200 mg of calcium supplements. This supplementary treatment was inversely correlated with the incidence of T2D when compared to an intake of
