Vitamin D Deficiency, Obesity and Diabetes

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are main chronic diseases harming human health. Although the association between obesity and T2DM is well established, the molecular mechanism is still unclear. Accumulating evidence suggests vitamin D plays a role in the development of these diseases. Vitamin D is a necessary nutrient for humans. People usually do not pay attention to supplementing vitamin D, since vitamin D can be produced when their skin is exposed to the sunlight. Nevertheless, even in highly sunny regions, vitamin D deficiency exists, suggesting vitamin D deficiency is a global problem. Vitamin D deficiency has previously been considered only to influence bone metabolism. Accumulating evidence counters this opinion. In vivo studies have revealed that vitamin D deficiency reduces insulin secretion capacity of the islet beta cells in pancreas. Moreover, epidemiological studies have demonstrated that vitamin D deficiency is closely related to obesity and increased risk of T2DM. This review introduces the current work on vitamin D, obesity and diabetes.

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35
Copyright © 2015. All rights reserved.
Vitamin D Deciency, Obesity and Diabetes
Y. Li1,2 and L. Zhou1,2
1 College of Animal Science and Technology, Guangxi University, Guangxi, China
2 Guangxi Experiment Centre of Science and Technology, Guangxi University, Guangxi, China
Corresponding author: : Prof. Lei Zhou, College of Animal Science and Technology, Guangxi University, Nanning city, Guangxi Zhuang Auto-
nomous Region, P.R.China, 530004. E-mail: zhoulei@gxu.edu.cn
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are main chronic diseases harming human health. Although the association between obesity and T2DM is well esta-
blished, the molecular mechanism is still unclear. Accumulating evidence suggests vitamin D plays a role in the development of these diseases. Vitamin D is a
necessary nutrient for humans. People usually do not pay attention to supplementing vitamin D, since vitamin D can be produced when their skin is exposed to the
sunlight. Nevertheless, even in highly sunny regions, vitamin D deciency exists, suggesting vitamin D deciency is a global problem. Vitamin D deciency has
previously been considered only to inuence bone metabolism. Accumulating evidence counters this opinion. In vivo studies have revealed that vitamin D deciency
reduces insulin secretion capacity of the islet beta cells in pancreas. Moreover, epidemiological studies have demonstrated that vitamin D deciency is closely related
to obesity and increased risk of T2DM. This review introduces the current work on vitamin D, obesity and diabetes.
Key words: Adipocyte, Insulin resistance, Insulin secretion, Vitamin D, T2DM.
Cellular & Molecular Biology
Cell. Mol. Biol. 2015; 61 (3): 35-38
Published online June 10, 2015 (http://www.cellmolbiol.com)
Received on May 18, 2015, Accepted on June 8, 2015.
doi : 10.14715/cmb/2015.61.3.8
Introduction
Obesity and type 2 diabetes mellitus (T2DM) have
become main chronic diseases that harm human health
not only in developed countries but also in developing
countries. With improvement of living standards and
lifestyle changes, the number of diabetic patients is
increasing dramatically. It is estimated that by the year
2020 there will be approximately 300 million people
affected by T2DM, most of which will occur in deve-
loping countries (1). In China, the number of people
affected by T2DM is 92.4 million, which was estimated
by a recent study using the Oral Glucose Tolerance Test
(OGTT) in 46,239 adults from 14 provinces (2). A large
patient base will adversely inuence both the medical
insurance system and people’s social life. Therefore,
obesity and diabetes are not only a health problem but
also a social problem worldwide.
Control and treatment of obesity and diabetes must
be based on the understanding of their development
mechanisms, which remain unclear. However, over
the past few decades, research has revealed a number
of factors closely correlated with obesity and diabetes.
Among them, the role of vitamin D is gaining more and
more attention.
Source and metabolism of vitamin D
Vitamin D is a necessary nutrient for human health.
Previously, vitamin D supplementation was only used to
prevent rickets. Hence, vitamin D was considered only
to participate in the formation and development of bone.
However, recent studies have revealed that vitamin D
also plays a crucial role in nerve, reproduction, immu-
nity and the endocrine system (3). Vitamin D comprises
two categories: vitamin D2 and vitamin D3. Vitamin D3
is the main form in humans (4) and activates vitamin D
receptor (VDR) which is a nuclear receptor expressed
nearly ubiquitously.
Humans get vitamin D via the sun and through
their diet. When people are exposed to sunlight, solar
ultraviolet B radiation penetrates the skin and converts
7-dehydrocholesterol to previtamin D3, which is rapidly
converted to vitamin D3 that enters the circulation. Most
vitamin D3 is transported in the blood by binding to vita-
min D binding protein (DBP) (85%-88%) or albumin
(12%-15%). In the diet, vitamin D mainly comes from
animal derived food, such as salmon and cod liver oil.
Vitamin D via sun-exposed skin and from the diet
has no biological activity and must be transported to
the liver, where it is metabolized by 25-hydroxylase to
25-hydroxyvitamin D (25-(OH)D3), which is the major
circulating metabolite and a determinant of a patient’s
vitamin D status. However, 25-(OH)D3 has little biolo-
gical activity and needs to be transported to the kidney
for further hydroxylation to its active form, 1,25-dihy-
droxyvitamin D (1,25-(OH)2D3).
Vitamin D and obesity
Obesity is a major risk factor for T2DM (5). Abun-
dant studies have revealed that adipocyte dysfunction
plays a key role in the development of obesity. Interes-
tingly, researchers discovered that vitamin D is stored
in adipocytes, which regulate its levels by storing and
releasing vitamin D. And vitamin D level is signicant
inversely related to BMI (6), indicating vitamin D de-
ciency is related to increased body fat (7). These studies
support that lower vitamin D level increases the risk
of obesity. Another groups also conrmed this conclu-
sion, nding an inverse association between vitamin D
levels and excess weight (8, 9). Moreover, Wortsman et
al. discovered that not only the vitamin D level but the
bioavailability of vitamin D also decreased in obesity

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Copyright © 2015. All rights reserved.
Y. Li and L. Zhou / VD, Obesity & Diabetes.
(10). Conversely, high vitamin D intake reduces diet-in-
duced obesity (11). Although the specic mechanism of
how vitamin D inuences lipogenesis is still not clear,
some groups have discovered a few clues: Duque et al.
reported 1,25-(OH)2D3 directly suppresses the expres-
sion of peroxisome proliferator-activated receptor γ2
(PPARγ2), which promotes lipogenesis and differen-
tiation of 3T3-L1 preadipocytes (12). In addition, Lee
et al. identied a novel 1,25-(OH)2D3 response element
in the promoter region of insulin-induced gene-2 (In-
sig-2), showing 1,25-(OH)2D3 stimulates the expression
of Insig-2, which inhibits lipogenesis and blocks diffe-
rentiation of preadipocytes (13). These ndings suggest
1,25-(OH)2D3 may also control fat deposits via these
key factors.
Vitamin D and diabetes
In addition to being risk factors for obesity, abnor-
mal insulin secretion and insulin resistance are closely
correlated with the development of diabetes. Some stu-
dies have also revealed a relationship between vitamin
D and these factors.
Vitamin D and insulin secretion
Accumulating evidence demonstrated vitamin D sti-
mulates the islet β cells to secrete insulin through its
active form 1,25-(OH)2D3 (14). It is believed that vita-
min D might regulate insulin signal transduction and
glucose-induced insulin secretion by this pathway. Stu-
dies on ob/ob mice indicated that vitamin D deciency
reduces insulin secretion and that supplementing with
vitamin D increases insulin levels (15). Previous work
conrmed the presence of vitamin D receptor (VDR)
in pancreatic islet β cells and showed impaired insulin
secretion in mice lacking functional VDR (16). These
data suggest vitamin D regulates insulin secretion via
VDR. Moreover, Bland et al. found pancreatic islets
express 1α-hydroxylase, which catalyzes 25-(OH)D3
to 1,25-(OH)2D3, suggesting the local production of
1,25-(OH)2D3 is an important autocrine link between vi-
tamin D status and insulin secretion (17). Furthermore,
an epidemiological study showed vitamin D deciency
increases the risk of metabolic syndrome (18). All these
data support vitamin D is involved in the regulation of
insulin secretion.
Vitamin D and insulin resistance
Insulin resistance is also a major risk factor for
T2DM. Some groups have reported that vitamin D
levels are inversely related to glycated hemoglobin
(HbA1c) (19) and insulin resistance (20, 21). Moreo-
ver, OGTT data from non-diabetic patients revealed an
inverse association between vitamin D and insulin resis-
tance, implying vitamin D deciency increases the risk
of insulin resistance (22). Currently, India has the largest
number of diabetic patients in the world. Although India
has enough sunshine, Indians tend to have low vitamin
D levels, which has been suggested to lead to high risk
for insulin resistance and obesity in Indians (23).
Skeletal muscle and liver are key metabolic tissues
and have a close relationship with insulin sensitivity
and glucose tolerance. Consequently, skeletal muscle
and hepatic insulin resistance are also presumed to be
chiey responsible for the development of T2DM. It is
worth noting that both these tissues express VDR, mea-
ning vitamin D plays a role in them (24, 25). However,
the specic mechanism by which vitamin D inuences
insulin sensitivity is complicated. Maestro et al. identi-
ed a vitamin D response element in the insulin recep-
tor gene promoter, discovering that 1,25-(OH)2D3 sti-
mulates its transcription and enhances insulin response
(26). These ndings demonstrate vitamin D directly
regulates insulin signaling. On the other hand, accumu-
lating evidence indicates obesity and diabetes actually
are conditions associated with chronic low level inam-
mation. Since NF-κB is able to stimulate many pro-in-
ammatory cytokines, its activation aggravates insulin
resistance. Researchers have discovered 1,25-(OH)2D3
downregulates activation of NF-κB and vitamin D de-
ciency is associated with increased inammation, sug-
gesting vitamin D also has its effects through anti-in-
ammatory actions (21, 27).
Vitamin D status and type 2 diabetes
Researchers are paying more and more attention
to the role of vitamin D in T2DM. Many studies have
demonstrated there is an association between plasma
25-(OH)D3 levels and T2DM (28). Data from the Third
National Health and Nutrition Examination Survey
(USA) indicates lower 25-(OH)D3 increases the risk of
T2DM (29). Analysis of the blood glucose and vitamin
D levels of diabetic patients showed an inverse associa-
tion between 25-(OH)D3 and T2DM (30). Interestingly,
there is a seasonal difference in the effect of vitamin D
on blood glucose. This may be partly attributed to the
lower vitamin D levels in winter (31). Moreover, vita-
min D levels in the diabetic population are signicantly
lower than in the non-diabetic population. Therefore,
researchers have proposed vitamin D levels should be
monitored in diabetic patients (32).
Other studies have investigated the prediction of
T2DM based on vitamin D levels. After a follow-up pe-
riod of 17 years, Mattila et al. found people with higher
vitamin D levels had a 40% lower risk of T2DM com-
pared to those with lower vitamin D levels (33). Ano-
ther study after a follow-up period of 22 years indicated
women have lower serum vitamin D levels than men
and the incidence of T2DM in men is 72% less than
women (34). These data suggest higher vitamin D levels
prevent incidence of T2DM.
Conclusions
Because humans can synthesize vitamin D when ex-
posed to sunlight, it had been previously thought vita-
min D deciency would be unlikely. However, even in
the sunniest regions of the world, vitamin D deciency
is common. In Qatar, which is highly sunny, researchers
demonstrated 68.8% of children had vitamin D decien-
cy (35). Moreover, studies in other countries also shown
30 to 50% of the population have lower than normal
vitamin D levels (36-39). These data reveal vitamin D
deciency has become a global health problem. Due to
the differences of diet, Asians tend to get less vitamin D
from food compared to westerners. Therefore, Asians
may be at especially high risk of vitamin D deciency
than westerners. Undoubtedly, this situation is more

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Copyright © 2015. All rights reserved.
Y. Li and L. Zhou / VD, Obesity & Diabetes.
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89-90: 121-5.
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serious in diabetic patients (40). We consider the work
introduced here is just the beginning in this eld. More
work remains to be done to clarify the role of vitamin D
in the development of obesity and T2DM.
Acknowledgements
This work was supported by the grants from National Na-
tural Science Foundation of China (31301947), the Fok
Ying Tong Education Foundation (141025), Guangxi
Natural Science Foundation (2014GXNSFDA118014),
Guangxi Experiment Centre of Science and Technology
(YXKT2014006), and the Scientic Research Founda-
tion of Guangxi University (XTZ130719).
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