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2 Relationship Between Vitamin D and Diabetes in Healthy Populations

2 Relationship Between Vitamin D and Diabetes in Healthy Populations

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Vitamin D and Diabetes in Chronic Kidney Disease



273



gene promoter, it is reasonable to hypothesize that a relationship exists between

vitamin D and diabetes mellitus. Via its ability to regulate calcium fluxes, vitamin D

may furthermore influence insulin release as well as insulin action. Moreover, by

affecting cytokine production, vitamin D plays a beneficial role in pancreatic betacell survival and insulin sensitivity. Nevertheless, while rickets and osteomalacia

are rarely diagnosed disorders, subclinical hypovitaminosis D is recognized as a

common condition. Studies from all over the world clearly report that an inadequate

vitamin D status is a global issue and, even more, that vitamin D deficiency is a

recognized risk factor for increased risk of mortality in the general population. Due

to the key role of UV-B radiation of the skin in vitamin D synthesis, sunscreen use,

clothing, skin pigmentation, and the winter season reduces vitamin D production.

At latitudes above 33° (i.e., all of Europe), UV-B radiation is only effective during

the summer months; indeed, studies have shown that even in Mediterranean countries—often considered to receive bountiful sunlight—elevated prevalence of hypovitaminosis D has been found during the winter months. Our group reported a

prevalence of vitamin D insufficiency of 84 % according to a cutoff of 50 nmol/L for

calcidiol serum levels in a population of outpatient postmenopausal women from a

rheumatology clinic [7]. Recently, a 57 % prevalence of vitamin D insufficiency was

observed in a population of patients with coronary artery disease, with both studies

being performed in Madrid (Spain) [8]. What is more, in studying a control group

made up of healthy, young military personnel on active duty receiving adequate

outdoor physical activity and aged 27.9 years (SD 5.2 years), we recorded mean

serum calcidiol levels under the threshold of vitamin D sufficiency (75 nmol/L),

showing a prevalence of insufficiency of 75 and 44 % for respective cut-offs of 75

and 50 nmol/L in circulating 25-hydroxyvitamin D.



15.2.3



Type 1 Diabetes and Vitamin D



Based on experimental models showing that vitamin D deficiency inhibits insulin

secretion by the pancreas and that this beta-cell function is normalized by calcitriol

and on epidemiologic studies in populations with hypovitaminosis D suggestive of

pancreatic beta-cell dysfunction, vitamin D deficiency has been associated with risk

of diabetes. It has been suggested that CYP27B1 polymorphism variants that lead to

a decrease in the local expression of 1α-hydroxylase would increase the risk of both

diabetes type-1 and hypovitaminosis D [9]. Also, epidemiological similarities exist

between diabetes type 1 and vitamin D deficiency, as incidence rates of both disorders are more elevated in the geographic areas with less ultraviolet irradiance [10].

Similarly, some studies have found an inverse correlation between vitamin D and

diabetes type-1, although studies of vitamin D deficiency in these diabetic patients

are limited. Another cross-sectional study reported a prevalence of inadequate levels

of vitamin D in type-1 diabetic patients of 76 %, employing a cut-off of 75 nmol/L

in calcidiol serum levels to define hypovitaminosis D. A later study showed that

children who have multiple positive islet autoantibodies without manifest type-1

diabetes have lower levels of vitamin D in their blood than children without the



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E. González Parra et al.



autoantibodies; however, the progression of the disease remained unaffected by the

vitamin D levels in the pre-diabetic group (defined as the presence of multiple islet

autoantibodies) [11]. These studies mostly examined the links between vitamin D

levels in pregnancy or childhood and the risk of type-1 diabetes in children, although

about 60 % of type 1 diabetes cases occur after age 20. A 6-year study of 2,000

individuals by the European Association for the Study of Diabetes tested the

association between vitamin D deficiency and risk of type-1 diabetes in a way that

provided a dose response relationship. A comparison of serum 25(OH)D levels

between healthy people who later developed type 1 diabetes and healthy controls

estimated that the level of calcidiol needed to prevent half the cases of type 1

diabetes is 50 ng/mL (125 nmol/L). Another prospective case-control study of U.S.

military personnel analyzed serum samples of 310 individuals diagnosed as having

type-1 diabetes between 1997 and 2009 and collected before the onset of the disease,

comparing the obtained values with those of 613 healthy subjects. The results of the

study showed that healthy young adults with serum levels of vitamin D above

75 nmol/L had about half the risk of developing type-1 diabetes as those individuals

with lower levels. Another study that evaluated vitamin D as a predictor of

microvascular complications and mortality in type-1 diabetes after a 5-year followup concluded that severe vitamin D deficiency independently predicts all-cause

mortality (hazard ratio for mortality 2.7), but not development of microvascular

complication in the eye and kidney [12]. Nevertheless, most of these studies do not

focus on the adverse effects of vitamin D inadequacy on beta-cell function.



15.2.4



Type 2 Diabetes and Vitamin D



Vitamin D deficiency is reported to be more common in type 2 than in type-1 diabetes. Several studies evidence the relationship between vitamin D and type 2-diabetes

[13]. The National Health and Nutrition Examination Survey (NHANES) demonstrated that serum calcidiol levels were inversely correlated with the incidence of

type-2 diabetes and insulin resistance. Also, in elderly subjects—a population at

increased risk of vitamin D deficiency and in whom type 2 diabetes is particularly

common—serum calcidiol levels <50 nmol/L doubled the risk of newly diagnosed

type 2 diabetes after adjustment for confounding factors. Furthermore, low vitamin

D status was associated with markers of impaired glucose metabolism, such as glycosylated hemoglobin (HbA1c). The link between vitamin D and type-2 diabetes is

different than that of type-1 diabetes. Several factors may contribute to this difference. Obesity, an important determinant of type-2 diabetes, is commonly associated

with hypovitaminosis D. Several polymorphisms in vitamin D binding protein

(VDBP) and VDR genes could be associated with impaired glucose tolerance and

obesity [14]. Absolute fat mass is inversely related to serum calcidiol levels, but at

present, it is unclear whether vitamin D deficiency itself contributes to obesity. Fatsoluble vitamin D3 sequestered in the large adipose compartment may contribute to

inadequate circulating levels of calcidiol and calcitriol, though at same time this



15



Vitamin D and Diabetes in Chronic Kidney Disease



275



vitamin D unavailability could increase intracellular calcium in adipocytes and

stimulate adipogenesis and the development of obesity. In this regard, some evidence shows a role for leptin in downregulation of calcitriol synthesis, as leptin

levels are positively correlated with obesity. A recent study [15] has helped clarify

the connection between vitamin D, obesity, and diabetes by comparing vitamin D

levels in people at a wide range of weights (from lean to morbidly obese subjects).

The results of this study evidenced a decrease in calcidiol serum levels in prediabetic and diabetic subjects compared to normoglycemic subjects (independently

of body mass index (BMI)). Also, vitamin D levels were closely related to glucose

metabolism, suggesting that hypovitaminosis D is more closely associated with carbohydrate metabolism than with obesity [15]. Furthermore, the authors also analyzed VDR gene expression during pre-adipocyte differentiation and in vitro

stimulation with 1,25(OH)2D3 of adipose tissue from donors with different BMI

values, finding that VDR gene expression was higher in tissue from obese patients.

On the other hand, central obesity (using waist circumference as a surrogate marker)

is related to metabolic syndrome. Some authors find a powerful association between

hypovitaminosis D and metabolic syndrome in obese patients independently of

body fat mass. The relationship between vitamin D with altered carbohydrate

metabolism and activation of the renin-angiotensin system—mechanisms involved

in the pathophysiology of metabolic syndrome—make this association plausible.

Finally, current data suggest that type-2 diabetic patients with vitamin D deficiency

have elevated C-reactive protein (CRP), fibrinogen, and HbA1c levels compared

with healthy controls, indicating that inflammation is implicated in insulin resistance and type-2 diabetes. What is more, the exogenous administration of vitamin D

ameliorates markers of systemic inflammation and possibly improves insulin sensitivity and beta-cell function by directly modulating the generation and effect of

inflammatory cytokines.



15.2.5



Treatment with Vitamin D



On the basis of these links, vitamin D sufficiency may provide protection against the

development of diabetes mellitus, and intervention studies are needed to elucidate

whether vitamin D supplementation could prevent development of diabetes in atrisk populations or improve prognosis in diabetic patients. Several animal trials with

vitamin D3 or active vitamin D in glucose metabolism have been performed. Early

intervention with calcitriol in non-obese diabetic (NOD) mice diminished the incidence of both insulitis and diabetes, and late intervention throughout childhood and

puberty also reduced clinical diabetes in NOD mice [16]. In spite of this, clinical

trials in humans have yielded conflicting results. The EURODIAB group suggested

an association between vitamin D supplementation in infancy and a decreased risk

of type-1 diabetes in a multicenter case-control study [17]. A recent study concluded that vitamin D3 supplement improves HbA1c in pediatric patients with

type-1 diabetes and vitamin D deficiency. Another intervention trial involving



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E. González Parra et al.



administration of a small dose of 1,25(OH)2D3 in new-onset diabetic children

showed no improvements of C-peptide levels, although insulin requirements

decreased. However, there is scarce clinical data on diabetes intervention with

1,25(OH)2D3 starting at the decline of beta-cell function, and they failed to induce

preservation of the same, possibly due to a safety concern, as the doses of calcitriol

or analogs needed to prevent or ameliorate type 1 diabetes have a hypercalcemic

effect. Results of intervention studies on type-2 diabetes have also yielded unconvincing results. While some studies show that administration of vitamin D2 or D3

could prevent or improve the disease, other trials have found no benefits after supplementation with vitamin D. A review and meta-analysis of fifteen trials comparing vitamin D or analogs with placebo showed insufficient evidence of a beneficial

effect to recommend vitamin D supplementation as a means of improving glycemic

control or insulin resistance in patients with diabetes [18]. However, these contradictory results could be explained by several factors including, dose size, method of

supplementation, genetics, and previous status of vitamin D. Moreover, vitamin D

deficiency should be avoided in populations at risk of diabetes. Long-term intervention studies are needed to demonstrate whether vitamin D treatment decreases the

risk of diabetes. At present, more than fifty clinical trials are evaluating the effects

of vitamin D supplementation on different aspects of diabetes mellitus (Table 15.1).



15.3



Vitamin D and Diabetes in Chronic Kidney Disease



The kidney plays an important role in the systemic endocrine action of vitamin

D. These actions, which are analyzed in depth in this chapter, are compromised in

diabetic patients with chronic kidney disease.

As renal function declines, serum levels of 1,25(OH)2D decrease progressively,

leading to active vitamin D deficiency. Somewhat less commonly recognized is the

high prevalence of nutritional vitamin D deficiency in patients with renal disorders.

Serum 25(OH)D levels begin to decrease in stage 2 CKD, and 25(OH)D deficiency

is prevalent in all subsequent stages of CKD, including ESRD [19]. Proteinuria may

be accompanied by high urinary loss of vitamin D-binding protein, leading to

increased renal loss of vitamin D metabolites.



15.3.1



Relationship Between Vitamin D and Diabetes

in Patients with Chronic Kidney Disease



Several studies suggest that vitamin D status may also have a significant role in glucose homeostasis in general and on pathophysiology and progression of metabolic

syndrome and type-2 diabetes in particular [20]. In diabetic patients at various CKD

stages, 25(OH)D levels were negatively correlated with HbA1c values. These observations may suggest a beneficial effect of vitamin D on HbA1c levels in CKD patients.



NTC 02513888



NTC 01942694

NTC 01726777



NTC 01854463



NTC 00985361



NTC 01991054



NTC 00400491



NTC 02112721



NTC 01412710



NTC 02101151



Prediabetes



Prediabetes/DM2

DM2/VD deficiency



DM2



DM2



DM2/VD deficiency



DM2



DM2



DM2



DM2/obesity



Vitamin D + diet and

lifestyle/placebo + diet and

lifestyle



Cholecalciferol vs placebo

Vitamin D vs placebo



Cholecalciferol vs placebo



VD3/vitamin C



cholecalciferol



Cholecalciferol vs placebo



Vitamin D vs placebo



Cholecalciferol



Cholecalciferol



Recruiting



Recruiting

Recruiting



Completed



Completed



Recruiting



Completed



Recruiting



Completed



Completed



Recruitment

Completed



(continued)



No available



No available

No available



No available



No available



No available



No available



No available



No available



No available



Study results

No available



Code

NTC 01741181



Intervention

Vitamin D vs placebo



Table 15.1 Main clinical trials about vitamin D supplementation in patients with diabetes mellitus

Conditions

DM2/VD deficiency



Vitamin D and Diabetes in Chronic Kidney Disease



Title

Vitamin D supplementation in patients with

diabetes mellitus type 2

Effect of vitamin D supplementation on the

metabolic control and body composition of

type 2 diabetes

Effect of vitamin D supplementation on

cardiovascular risk factors among Hispanic

and African americans with type 2 diabetes

Can vitamin D supplementation prevent type 2

diabetes?

Vitamin D supplementation to patients with

type 2 diabetes

The effects of vitamin D supplementation on

patients with type 2 diabetes and vitamin D

deficiency

Effect of vitamin D supplementation on

haemoglobin A1c in patients with uncontrolled

type 2 diabetes

The effect of vitamin D supplementation in

type 2 diabetes

Vitamin D and type 2 diabetes study

Effect of vitamin D supplementation on

glucose tolerance in subjects at risk for

diabetes with low vitamin D

Prevention of type 2 diabetes with vitamin D

supplementation



15

277



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