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3 Vitamin D and Diabetes in Chronic Kidney Disease

3 Vitamin D and Diabetes in Chronic Kidney Disease

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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



Vitamin D, glucose control and insulin

sensitivity in African-Americans

Vitamin D and glucose metabolism in

pediatrics

Effects of vitamin D and calcium

supplementation on inflammatory biomarkers

and adipocytokines in diabetic patients

Effect of vitamin D3 supplementation on

insulin resistance and cardiovascular risk

factors in obese adolescents



NCT 00784511



NCT 00858247



NCT 01662193



NCT 01386736



NCT 01889810



NCT 01736865

NCT 02464462



NCT 01500005



NCT 01855321



NCT 02513875

NCT 01354262



Title

Effect of vitamin D supplementation on blood

pressure and HbA1c levels in patients with

T2D

Prevention of type 2 diabetes with vitamin D

Effect of vitamin D supplementation on

hemoglobin A1c

Effects of treating vitamin D deficiency in

poorly controlled type 2 diabetes

The effect of vitamin D supplementation on

arterial stiffness on diabetic patients

Vitamin D for established type 2 diabetes

The role of vitamin D3 and calcium

supplementation in attenuating T2DM severity

Effect of vitamin D supplementation on insulin

resistance-the DIR study



Code

NTC 01585051



Table 15.1 (continued)



Obesity



Insulin resistance/

VD deficiency

Metabolic disease



Prediabetes/

suboptimal vitamin

D status

DM2



DM2

DM2



Diabetes



DM2



Prediabetes

DM2/VD deficiency



Conditions

DM2



Cholecalciferol



VD/Ca/VD+Ca/placebo



Cholecalciferol vs

microcrystalline cellulose

Vd drops/placebo



Vitamin D3



Cholecalciferol vs placebo

Vitamin D3 vs placebo



Baby D3 drops



Vitamin D vs placebo



Vitamin D vs placebo

Vitamin D



Intervention

Calcidiol vs NaCl 0.9 %



Completed



Recruiting



Recruiting



Completed



Recruiting



Recruiting

Completed



Completed



Completed



Recruiting

Completed



Recruitment

Completed



Has results



No available



No available



No available



No available



No available

No available



No available



No available



No available

No available



Study results

No available



278

E. González Parra et al.



NCT 01170442



NCT 00320853



NCT 00347542



NCT 00552409



NCT 00436475



NCT 01856946



Effect of vitamin D supplementation on oral

glucose tolerance among obese adolescents

Vitamin D and calcium homeostasis for

prevention of type 2 diabetes

Randomized controlled trial of vitamin D3 in

diabetic kidney disease

A trial to study the effect of vitamin D

supplementation on glucose and insulin

metabolism in centrally obese men

A study to evaluate the effect of vitamin D

supplementation on insulin sensitivity and

secretion

Does vitamin D improve glycemic control in

type 2 DM?

DM/VD deficiency



DM non insulin

dependent



DM non insulin

dependent/obesity



Glucose intolerance/

DM2

DM/ CKD



Insulin resistance



2,000 IU VD3/5,000 IU

VD3/placebo



Vitamin D



Vitamin D



Cholecalciferol/placebo



2000UI VD3/Ca/placebo



4,000 UI cholecalciferol



Terminated



Completed



Completed



Completed



Completed



Recruiting



No available



No available



No available



Has results



No available



No available



15

Vitamin D and Diabetes in Chronic Kidney Disease

279



280



E. González Parra et al.



Evidence indicates that vitamin D is important in the pathogenesis of glucose

intolerance and insulin resistance (IR) in patients with CKD. IR is present in the

early stages of CKD and has an inverse association with 25(OH)D levels. Calcitriol

treatment of CKD patients treated by hemodialysis (HD) and with secondary hyperparathyroidism is associated with increased insulin secretion; this is linked to

decreased intracellular free calcium. It is possible that the effect of altered calcium

content in beta cells on insulin secretion depends on the magnitude and duration of

the change. The goal of IR treatment is traditionally aimed at etiologies including

uremic toxins, protein catabolism, vitamin D deficiency, metabolic acidosis, anemia, poor physical fitness, and cachexia.



15.3.2



Vitamin D and Proteinuria in Diabetes Mellitus



Although the close relationship between vitamin D and kidney seems to have even

greater importance, as it is known to activate VDR and can reduce proteinuria and

contribute to nephroprotection [21]. Experimental models have shown the effect of

vitamin D on the blockade of the renin-angiotensin-aldosterone system (RAAS),

protection of podocytes and mesangial cells, inflammation and tubulointerstitial

fibrosis [22].

Albuminuria is a typical finding in patients with diabetic nephropathy (DN).

Evidence from clinical trials and associated data from the NHANES III cohort demonstrated an inverse relationship between 25(OH)D levels and degree of albuminuria. Furthermore, diabetes is closely associated with low 25(OH)D levels. Given the

above findings, patients with established DN are expected to have even lower 25(OH)

D levels than patients with CKD from other causes but a similar estimated glomerular filtration rate (eGFR). In fact, the prevalence of 25(OH)D insufficiency (93 %)

and deficiency (51.5 %) was high in CKD patients with and without diabetes.

Several clinical studies in patients with proteinuric nephropathy have analyzed

the activation role of VDR in relation the decrease in proteinuria, progression of

renal disease, and mortality, some in diabetic nephropathy. The study that has had

the most profound impact is the VITAL study in patients with type-2 diabetes and

renal failure with albuminuria in stages 2–4. This was a double blind, randomized,

case-control study using 2 mg of paricalcitol, a specific activator of VDR, in combination with an inhibitor of RAAS. The findings showed a greater decrease in proteinuria, better control of blood pressure, and a decrease in the progression of kidney

failure. Proteinuria predicts the occurrence of cardiovascular events, mortality, and

hospital admissions, though there is also a deteriorating relationship between proteinuria and glomerular filtration. Studies have shown that vitamin D has a renoprotective effect in patients with diabetes mellitus, possibly due to the reduction in

proteinuria, a reduction of the activity of the renin-angiotensin system, or due to

direct renal effects [22]. However, a recent meta-analysis that included 18 studies of

treatment with vitamin D observed a reduction in proteinuria but without modification on renal function.



15



Vitamin D and Diabetes in Chronic Kidney Disease



15.3.3



281



Vitamin D and Progression of Renal Disease



Few studies have analyzed the effect of 25(OH)D deficiency on progression of kidney disease in patients with type-2 diabetes. In studies of patients with CKD of any

cause, lower 25(OH)D levels were associated with an increased risk of incident

ESRD and contributed to decreased eGFR in early and advanced stages of CKD. In

the study by Ravani et al. baseline 25(OH)D levels correlated directly and significantly with eGFR. The prevalence of 25(OH)D deficiency was observed in several

studies, and the Cox regression analysis showed the 25(OH)D level to be an independent predictor of death and ESRD. The association between lower 25(OH)D

levels and reduced eGFR was strongest in patients with diabetes.

Low 25(OH)D levels in patients with CKD have been associated with a higher

risk of all-cause mortality and faster progression of kidney disease. In the NHANES

III cohort, individuals with 25(OH)D levels, 15 ng/ml had a higher risk for all-cause

mortality despite adjustments for CKD stage and for potential confounders.

Individuals with lower 25(OH)D levels were more likely to have diabetes. 25(OH)

D deficiency is independently associated with a more than 50 % increase in baseline

serum creatinine, end state renal disease, or death in type II diabetic nephropathy in

patients with type II diabetic nephropathy [23].



15.3.4



Vitamin D Supplement Need Among CKD Patients



Stimulation of VDR exerts protective activity through multiple mechanisms, including inhibition of the RAAS, regulation of cell proliferation and differentiation,

reduction of proteinuria, anti-inflammation, and anti-fibrosis. Growing evidence

indicates that vitamin D exerts anti-proteinuric and renoprotective effects in diabetic patients with CKD. Additionally, it has been shown that vitamin D3 repletion

has beneficial effects on urinary albumin and transforming growth factor-β1 excretion in type-2 diabetic patients with CKD undergoing established RAAS inhibition

therapy. Treatment with cholecalciferol led to significantly higher levels of circulating 25(OH)D and 1,25(OH)2D3 levels relative to baseline, and increased levels of

active forms of vitamin D were correlated with a decrease in urinary albumin creatinine ratio and transforming growth factor (TGF)-β1. These data indicate that vitamin D compounds may be useful tools for delaying the progression of diabetic CKD

beyond the effects expected from established RAAS inhibition protocols.

Vitamin D supplementation in CKD has now shifted to ensure that both classic

and non-classic requirements are met. In contrast to the classic endocrine function

of vitamin D, the autocrine/paracrine function of vitamin D appears to remain intact

as long as 25(OH)D, the necessary substrate, is available. 1α-hydrolyase activity is

maintained, even in anephric patients. In patients with DM, circulating 25(OH)D

level is almost universally, lower than 30 ng/ml. Therefore, supplementation should

be universally considered in this population. Unfortunately, the level of evidence to

support 25(OH)D therapy for CKD or DM is low [24]. Several studies of nutritional



282



E. González Parra et al.



vitamin D supplementation in patients with type-2 diabetes are ongoing, although

their results are not yet available. Scant data are available on combining therapy

with both nutritional and active vitamin D compounds; thus, caution should be exercised in clinical practice because of the possibility of vitamin D intoxication. Further

data are necessary in this area [23].

We can hypothesize that vitamin D supplementation decreases insulin resistance

and reduces HbA1c levels in patients with diabetes. However, supplementation

studies have not unambiguously found that vitamin D favors an improvement in

glucose homeostasis parameters.



15.4



Conclusions



Vitamin D supplementation for the general population may lead to a small but significant improvement in mortality, though it did not appear to prevent the development of DM in the largest clinical trial to date [25]. Data from the HD population

consistently suggest that calcitriol improves short-term insulin secretion and insulin

sensitivity. In patients with end-stage renal disease, insulin resistance is an independent predictor of cardiovascular disease and is linked to protein energy wasting and

malnutrition, as well as with systemic inflammation, oxidative stress, elevated

serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed

serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine

signaling. All these mechanisms cause insulin resistance by suppressing insulin

receptor-PI3K-Akt pathways in CKD.



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Raab J, Giannopoulou EZ, Schneider S, Warncke K, Krasmann M, Winkler C, Ziegler AG.

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Chapter 16



Vitamin D and Muscle in Chronic Kidney

Disease

Philippe Chauveau and Michel Aparicio



Abstract Skeletal muscle is frequently impacted in uraemic patients with both

mechanical and metabolic consequences. Muscle wasting, weakness and structural

changes, fundamentally as atrophy of type II muscle fibers, but also insulin resistance are common and however readily overlooked. Beyond a negative effect on

physical activity and quality of life, skeletal muscle loss was reported to be also a

powerful and independent predictor of survival, at least partly in relation with insulin resistance. Muscle loss in uraemic patients appears to be multifactorial. Among

the different mechanisms liable to contribute to muscle wasting vitamin D deficiency, which is present in 50–80 % of incident dialysis patients, is a well-known

factor of reduction of muscle mass, strength, physical performance and of increased

risk of falls.

In these circumstances, vitamin D supplementation appears to be a reasonable,

simple and potentially adequate therapy. Vitamin D supplementation seems to be an

effective strategy to replenish vitamin D stores and to control PTH and more scarcely

other biochemical endpoints. As only few observational studies have been performed, there are not enough data to draw definitive conclusions about the effects of

natural vitamin D supplementation on patients’ outcomes, including mortality, and

a fortiori on muscle disorders and their mechanical and metabolic consequences.

Large, well-designed, randomized controlled trials are still requested to assess

the possible benefits of natural vitamin D supplementation on skeletal muscle in

CKD patients.

Keywords Vitamin D • Muscle • Kidney disease • Uremia • Sarcopenia



P. Chauveau, MD (*)

Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

e-mail: Ph.chauveau@gmail.com

M. Aparicio, MD

Service de Néphrologie Transplantation Dialyse, Centre Hospitalier,

Universitaire de Bordeaux, Bordeaux, France

© Springer International Publishing Switzerland 2016

P.A. Ura Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_16



285



286



16.1



P. Chauveau and M. Aparicio



Introduction



Muscle wasting and weakness were reported in patients with chronic kidney disease

(CKD) more than 50 years ago under the term of uremic myopathy [1] similar

muscle features have also been observed in several varieties of chronic diseases with

normal renal function and in the elderly general population. Multiple observational

studies have shown that, in these different circumstances, circulating 25(OH)D levels were also frequently reduced in parallel to the severity of muscle symptoms, but

such association was neither observed with serum 1,25(OH)2D nor PTH concentrations [2]. It is difficult to clearly delineate the respective role of CKD, age and

vitamin D deficiency in the reduction of skeletal muscle mass and function, only

scarce data have been reported in this field in the literature.

Vitamin D deficiency results in muscle wasting and weakness but there are suggestions that muscle metabolism is also altered, specifically its sensitivity to insulin

resulting in an increase in cardiovascular risk and muscle protein breakdown. These

latter can explain, at least partly, that skeletal muscle wasting and circulating low

25(OH)D levels are independent predictors of poor outcomes including increased

all-cause and cardiovascular mortality in CKD patients as within healthy populations and in a number of clinical situations [3–6]. The resulting morbidity and mortality risk justifies a high priority for early detection of muscle wasting, prevention

and treatment. Among various therapeutic possibilities, correction of vitamin D

deficiency has logically raised up a growing interest [7].

In the present chapter, we will first describe muscle abnormalities in CKD, then

the effects of vitamin D deficiency and of vitamin D supplementation on muscle

function and their contractile and metabolic impact. Vitamin D epidemiology and

relationship between vitamin D deficiency and fractures are described elsewhere in

this book.



16.2

16.2.1



Skeletal Muscle Abnormalities in CKD Patients

Alteration of Muscle Mass and Function



Loss of muscle function is frequently overlooked in CKD patients, and yet muscle

wasting and reduction in maximal exercise capacity have been reported at every

CKD stage, their prevalence usually runs in parallel with the progression of renal

failure to concern more than 50 % of patients on dialysis treatment [8].

The term of uremic sarcopenia has been recently proposed to characterize this

muscle wasting which affects predominantly the proximal lower limb associated

with proximal myalgia. The different physical performance testing and self-reports

confirm the decline in physical activity and muscle force associated with an early

weakness in response to exercise, particularly pronounced in CKD malnourished

patients. Values of VO2 max and of tests of overall exercise capacity and strength do



16



Vitamin D and Muscle in Chronic Kidney Disease



287



not exceed 50 % of those of age-matched controls [9]. Given the old age of most

dialysis patients, age-related sarcopenia is a likely contributor to muscle wasting,

however not all studies have confirmed this proposal [10].

Physical examination, electromyographical studies and muscle enzymes are usually normal. There is no evidence of defective excitation-contraction coupling, the

most prominent abnormality of muscle function is slowing of relaxation likely

linked to the atrophy of type II fibers which have fast-twitch contractile characteristics and a high rate of energy utilization [11]. Assessment of body composition

confirms the reduction of the cross sectional area (CSA) of the contractile tissue,

without a mandatory reduction in total muscle area because of a frequent increase

in non-contractile tissue content (fat and collagen) negatively related with the values

of the physical performance tests [12].

Muscle biopsies have shown predominance of type II muscle fibers loss and atrophy. Type II fibers are quicker to fatigue and the first to be recruited when fast reaction is needed, such as in the prevention of fall, their proportion and diameter is

significantly predictor for falls. Mean muscle type II fiber cross-sectional area is

25–30 % smaller than in healthy age- and sex-matched controls [13]. In addition,

scattered necrosis, enlarged intermyofibrillar spaces and infiltration with amorphous

material, predominantly fat, are frequently observed, independently of BMI and

visceral fat. Substantial alteration of mitochondria shape and number is common,

associated with a decrease in mitochondrial enzymes activity and a slower energy

production. Compared to controls muscle fiber capillarization is reduced [14].

Interestingly, similar histological abnormalities have been observed as well in nonlocomotor (rectus abdominis) and semi-non-locomotor (deltoid) muscles suggesting that, these lesions are not only resulting from a potential disuse atrophy [15].

As above-mentioned for the clinical symptoms, the morphological changes

which affect type II muscle fibers correlate with serum 25(OH)D levels, they are not

a specific hallmark of CKD since quite similar findings have been found in adults

with severe vitamin D deficiency not related to CKD and in individuals with agerelated sarcopenia.



16.2.2



Pathophysiology



The loss of muscle mass observed in CKD results from persistent imbalances

between reduced protein synthesis and stimulated protein degradation. Complications

associated with CKD such as metabolic acidosis, inflammation, increased

angiotensin II levels, “uremic toxins” and poor vitamin D status have in common to

lead to defects in the insulin growth factor -1 (IGF-1)/Insulin/PI3K/Akt intracellular

signaling pathway which result in the up-regulation of the main catabolic pathways

involved in the development of muscle wasting: caspase-3, ATP-dependent ubiquitin proteasome (UPS) and myostatin [16–19].

Among the different factors liable to impact negatively skeletal muscle in CKD

patients we will emphasize more particularly on vitamin D deficiency.



288



16.3

16.3.1



P. Chauveau and M. Aparicio



Vitamin D and Skeletal Muscle Mass and Function

Vitamin D and Skeletal Muscle: Mode of Action



Apart from its classic effects on bone and on the regulation of calcium and phosphate homeostasis, vitamin D has also ubiquitous non-calcemic functions, linked to

the presence of receptors (VDRs) that are distributed in almost every tissue including skeletal muscle [20]. Activation of muscle VDRs accounts for the range of

effects that vitamin D exerts in skeletal muscle, so the decline of muscle VDR

expression with age makes the elderly more vulnerable to vitamin D deficiency.

On a cellular level, vitamin D metabolites modulate the function of skeletal muscle via three different mechanisms:

• A genomic transcriptional effect. It has been suggested that activation of the

nuclear VDR resulted in a regulatory effect on calcium flux, mineral homeostasis

and signaling pathways promoting muscle growth and myogenic differentiation.

• A non genomic effect mediated by a VDR translocated in the cell-membrane of

muscle fibers, supporting a rapid non-transcriptional calcium transport, within

seconds to minutes, into the muscle cell relevant to muscle contraction.

• VDR polymorphisms associated with variability in muscle contractile capacity.



16.3.2



Vitamin D Supplementation and Muscle Function



Vitamin D deficiency is common in the elderly and institutionalized people and

most studies on the effects of vitamin D supplementation on muscle mass and function have been performed in these populations.

Numerous observational studies have linked vitamin D deficiency (serum

25(OH)D levels <20 ng/mL) with muscle wasting, mainly related to the reduction

in type II muscle fibers number and size. Proximal muscle weakness, diffuse muscle

pain, gait impairments and increased susceptibility to falls and fractures, these latter

favored by an associated fragile skeleton, are the main clinical consequences of

muscle wasting.

Positive effects of vitamin D on muscle performance are well known for a very

long time. As early as the ancient Greece, sun exposure was already prescribed as a

cure for weak and flabby muscles and Olympian athletes were instructed to train in

sunlight to improve their physical performance. During the last 50 years, an extensive

literature has widely shown that UV radiation and vitamin D compounds, nutritional

or active forms, had a positive effect on serum 25(OH)D levels, bone mineral density

and the associated muscle dysfunction: physical performance, weakness, decreased

mobility, body sway and rate of falls and fractures, the effect on other functional

outcomes such as pain and quality of life is less clear [21]. Lastly, biopsies in a handful of cases have shown that vitamin D supplementation induced a potentially

increase in the relative number and cross-sectional size of type II muscle fibers [22].



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