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Cholecalciferol 2000 IU/ 60000 IU, Capsule.


Therapeutic indication: Vitamin D deficiency states including patients of
type 2 diabetes mellitus with vitamin D deficiency.
Dosage & Administration: Sachet of 1g containing 60000 IU to be administered
under medical supervision.
Contraindications: Known hypersensitivity to vitamin D3, Hypercalcemia,
malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin D,
hypervitaminosis D.
Warnings/precautions: Keep out of the reach of children. Chronic or
acute administration of excessive doses may lead to hypervitaminosis D,
manifested by hypercalcemia and its sequelae. Periodic monitoring of serum
calcium, phosphate, magnesium, alkaline phosphatase is recommended for
patients taking vitamin D analogs. For the protection of the fetus, the use of
vitamin D in excess of the recommended dietary allowance during normal
pregnancy & lactation should be avoided. Use with caution in elderly.

Renal: Impairment of renal function with polyuria, nocturia, polydipsia,


hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis,
generalized vascular calcification, or irreversible renal insufficiency which may
result in death.
CNS: Mental retardation.
Soft Tissues: Widespread calcification of the soft tissues, including the heart,
blood vessels, renal tubules, and lungs.
Skeletal: Bone demineralization (osteoporosis) in adults occurs concomitantly.
Decline in the average rate of linear growth, increased mineralization of bones in
infants and children (dwarfism), vague aches, stiffness, and weakness.
Gastrointestinal: Nausea, anorexia, constipation.
Metabolic: Mild acidosis, anemia, weight loss.
Storage: Store protected from light and moisture at a temperature not
exceeding 30C.

ROLE OF OIL-BASED VITAMIN D SUPPLEMENTS IN DIABETICS


Several studies have reported differences in the
bioavailability of various vitamin D supplements.1 Following
are the factors that may affect bioavailability:
Extraction from supplement: Vitamin D needs to be
extracted from its supplement matrix (e.g., fish oil) to
become solubilised and absorbed by intestinal cells.2
Vitamin D is a relatively non-polar sterol (lipid), and thus
need to be solubilised by incorporation into micelles for
its absorption.3
Absorption from the small intestine: Absorption of
vitamin D from oil vehicles may be dependent on micelle
formation and on protein transporters for absorption
from powder vehicles (Figures 1 and 2).1
Bile salts
recycle

Bile salts from liver


coating vit. D

Vit. D

Micelle
formation

Vit. D in
chylomicron

Vit. D

Vit. D

Vit. D+DBP in circulation

Enterocyte

Figure 2: Absorption of powder-based vitamin D


formula in small intestine4,5

Concentration of vitamin D: Vitamin D uptake is mainly


protein-mediated at low, dietary concentrations of
vitamin D, while it is passive at high, pharmacological
concentrations.2

Need for oil-based vitamin D supplements

Golgi
apparatus
Vit. D

Hydrolysis
(pancreatic
lipase)

Vit. D

Golgi
Vit. D in
chylomicron apparatus
Interstitial fluid

Contains: Cholecalciferol (vitamin D3) IP 60000 IU/1gm, Sachet.

Side-effects: Vitamin D analogs are well tolerated in recommended daily doses.


Chronic excessive dosing can lead to hypervitaminosis D characterized by effects
on the following organ systems

Enterocyte

Figure 1: Absorption of oil-based vit. D formula in the upper


part of small intestine1

Interstitial fluid

D-RISE API

Though vitamin D deficiency is commonly seen in diabetics


and at low concentration vitamin D uptake is mainly
protein-mediated, there are studies which show that level
of protein transporters are also diminished in diabetics. An
experimental study by Nyomba BL et al. in animal models,
demonstrated that in diabetes, circulating 1,25-(OH)2D3
concentration is decreased through alterations in DBP

levels. This implies that vitamin D supplements in powder


formulation (which may need DBP for absorption) may
be less bioavailable and highlights the need of oil-based
vitamin D supplements.

Comparison between oil vs. powder vehicles


Oil-based vehicles produced the greatest rate of change in
mean serum 25(OH)D, followed by powder-based vehicles
(4.05, 2.75 nmol/L per 100 IU/day, respectively) (Figure 3).1

Compared to powder-based supplements, oil-based


supplements may improve absorption of fat-soluble
microconstituents (FSM such as vitamin D) by several
mechanisms:2
Oil-based supplements can facilitate the release of FSM
from matrices by providing a hydrophobic phase, where
FSM can be solubilised.
Lipids stimulate biliary secretion and consequently
micelle production; they can increase the proportion of
micellarised FSM available for absorption.
Lipid digestion products, e.g., fatty acids,
monoglycerides, and lysophospholipids, are micelle
components. Therefore, the more lipids digested, more
micelles would be available to solubilise FSM.
Absorption efficiency of vitamin D given in peanut oil
ranged between 55% and 99% in healthy subjects.
Thus, in diabetes, oil-based vitamin D may prove to be
more bioavailable than powder formulations.

Change in mean serum


25(OH)D (nmol/L) per 100 IU/day

Improved absorption with oil-based supplements


9
8
7
6
5
4
3
2
1
0
-1

Vitamin D supplementation resulted in a significant


reduction in pain scores on both the VAS and MPQ at
48.5% and 39.4%, respectively.
Thus, vitamin D3 supplement helps to improve vitamin D
status and the symptoms of neuropathy in patients with
type 2 diabetes.

REFERENCES
1.
4.045
2.747

2.

Oil

Powder

Figure 3: Comparison between vitamin D vehicles in terms


of change in serum concentration of 25(OH)D1

4.

Duby JJ, Campbell KR, Setter SM et al. Diabetic Neuropathy: An intensive


review. American Journal of Health-System Pharmacy. Available at: http://
www.medscape.com/viewarticle/467524_4.

Comparison between two different lipid vehicles

5.

Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance


in patients with type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):8.

6.

Putz Z, Martos T, Nmeth N, et al. Is there an association between diabetic


neuropathy and low vitamin D levels? Curr Diab Rep. 2014;14(10):537.

Supplement vehicle

Holmberg I et al. compared vitamin D absorption levels


between soft gelatin capsules dissolved in peanut oil
(long chain fatty acids) and a medium chain triglyceride
(Figure 4). Results indicated that mean peak concentration
was about three times higher when vitamin D was
administered in peanut oil than in the medium chain triglyceride.7

8.

Shehab D, Al-Jarallah K, Mojiminiyi OA, et al. Does vitamin D deficiency


play a role in peripheral neuropathy in type 2 diabetes? Diabet Med.
2012;29(1):439.

9.

Palomer X, Gonzlez-Clemente JM, Blanco-Vaca F, et al. Role of vitamin


D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab.
2008;10(3):18597.

11. Green RT, Gambhir KK, Nunlee-Bland G, et al. Maintenance of long-term


adequate levels of vitamin D lowers HbA1c in African American patients
with type 2 diabetes. Ethn Dis. 2014;24(3):33541.

Tesfaye S, Boulton AJM, Dyck PJ. Diabetic neuropathies: Update on


definitions, diagnostic criteria, estimation of severity, and treatments.
Diabetes Care. 2010;33(10):228593.
Clayton W, Elasy TA. A review of the pathophysiology, classification,
and treatment of foot ulcers in diabetic patients. Clinical Diabetes.
2009;27(2):528.

Soderstrom LH, Johnson SP, Diaz VA, et al. Association between vitamin D
and diabetic neuropathy in a nationally representative sample: Results from
2001-2004 NHANES. Diabet Med. 2012;29(1):505.

10. Zhou J, Chen H, Wang Z, et al. Effects of vitamin D supplementation on


insulin resistance in patients with type 2 diabetes mellitus. Zhonghua Yi Xue
Za Zhi. 2014;94(43):340710.

Alamdari A, Mozafari R, Tafakhori A, et al. An inverse association between


serum vitamin D levels with the presence and severity of impaired nerve
conduction velocity and large fiber peripheral neuropathy in diabetic
subjects. Neurol Sci. 2015;36(7):11216.

3.

7.

12. Holick MF. Diabetes and the vitamin D connection. Curr Diab Rep.
2008;8(5):3938.
13. Lee P, Chen R. Vitamin D as an analgesic for patients with type 2 diabetes
and neuropathic pain. Arch Intern Med. 2008;168(7):7712.
14. Shehab D, Al-Jarallah K, Abdella N, et al. Prospective evaluation of the effect
of short-term oral vitamin D supplementation on peripheral neuropathy in
type 2 diabetes mellitus. Med Princ Pract. 2015;24(3):2506.

Parameters

Before

After

Differences

P-value

Vitamin D insufficiency was present in 81% of the diabetics,


which was associated with self-reported peripheral
neuropathy symptoms in one of the studies.

NSS
Treatment

5.92 1.29

4.43 1.58

1.49 1.37

Placebo

5.50 1.25

5.45 1.20

0.20 0.59

Treatment

8.4 1.8

8.4 1.8

0.42 1.59

Placebo

7.8 1.9

7.7 1.8

0.03 0.2

<0.001

NDS

A threshold effect for vitamin D in diabetics exists at a level


30 ng/mL.

0.094

Treatment

25.3 10.9

58.2 23.8

32.8 23.7

Placebo

29.2 9.5

30.3 8.9

1.1 3.6

116 27

50

Values represent mean SD.The Mann-Whitney U test was used. The minus sign
indicates that the values decreased after treatment.

Neurons
are
protected
from
apoptosis
and
neurodegeneration due to these effects of vitamin D,
resulting in increased transcription activity of VDR-target
genes.

Thus, short-term oral vitamin D3 supplementation improved


vitamin D status and the symptoms of neuropathy in patients
with type 2 diabetes.

In various studies, vitamin D supplementation resulted


in improved glucose homeostasis and improvement in
neuropathic pain.

SUMMARY
Diabetic neuropathy (nerve disorders caused by diabetes)
is the major cause of morbidity in diabetes.

Each 1 ng/mL increase in serum 25(OH)D was correlated


with 2.2 and 3.4 % decrease in the presence and severity of
nerve conduction velocity (NCV) impairment, respectively.

Around 6070% diabetic patients have some form of


neuropathy. Almost 50% of them experience varying
degrees of neuropathic pain.

Grossmann RE, Tangpricha V. Evaluation of vehicle substances on


vitamin D bioavailability: A systematic review. Mol Nutr Food Res.
2010;54(8):105561.

2.

Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: State of the


art. Critical reviews in food science and nutrition. Available from:
http://www.researchgate.net/publication/262977228_Vitamin_D_
Bioavailability_State_of_the_Art.

3.

Lo CW, Paris PW, Clemens TL, et al. Vitamin D absorption in healthy


subjects and in patients with intestinal malabsorption syndromes.
Am J Clin Nutr. 1985;42(4):6449.

4.

Kidambi S, Patel SB. Cholesterol and non-cholesterol sterol


transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica.
2008;38(78):111939.

5.

Ternes SB, Rowling MJ. Vitamin D transport proteins megalin and


disabled-2 are expressed in prostate and colon epithelial cells and
are induced and activated by all-trans-retinoic acid. Nutr Cancer.
2013;65(6):9007.

6.

Nyomba BL, Bouillon R, Lissens W, et al. 1,25-Dihydroxyvitamin D


and vitamin D-binding protein are both decreased in streptozotocindiabetic rats. Endocrinology. 1985;116(6):24838.

7.

Holmberg I, Aksnes L, Berlin T, et al. Absorption of a


pharmacological dose of vitamin D3 from two different lipid vehicles
in man: Comparison of peanut oil and a medium chain triglyceride.
Biopharm Drug Dispos. 1990;11(9):80715.

39 11

0
Peanut oil capsules
(fasting)

Medium chain
triglyceride capsules
(fasting)
Treatment

<0.0001

The proposed mechanism of action of vitamin D on insulin


sensitivity includes conversion of proinsulin to insulin.

1.

100

25(OH)D levels may prove to be significant predictors of


diabetic neuropathy.

25(OH)D, mmol/l

REFERENCES

150
Vitamin D (nmol/L)

Hyperglycaemia and oxidative stress contribute to


the abnormal glycation of nerve cell proteins and the
inappropriate activation of protein kinase C, resulting in
further nerve dysfunction.

Table 3: Baseline and follow-up values and comparison of differences in NSS,


NDS and vitamin D status before and after treatment between the
treatment and placebo groups

Figure 4: Mean peak concentration of vitamin D3 in serum,


824 h after administration7
Values are means SD; significant at the 5% level. A two way analysis
of interaction was applied.

Conclusion
With reference to clinical studies, it is evident that oilbased formulations of vitamin D greatly increase its serum
concentration in the body compared to solid formulations
in diabetics. It can thus be concluded that to obtain
improved insulin sensitivity for diabetes patients, oilbased vitamin D3 supplements may prove to be an addon treatment option. In addition, peanut oil can be the
preferred lipid vehicle.

Effect of Vitamin D Supplementation on Peripheral


Neuropathy in T2DM14

Table 2: Characteristics, biochemistry, and pain scores at baseline and


3 months after treatment13

D-CODE SERIES OVERVIEW

Variable

Value

No. of subjects

SR.
NO.

TOPICS

MONTH

Role of vitamin D in diabetic foot infection

April

Role of vitamin D in diabetic patients with NAFLD

May

Role of vitamin D in diabetic patients with obesity

June

Sex, No.
Female

37

Male

14

Age, y

Weight, kga
BMI

Role of vitamin D in diabetic nephropathy

July

Role of vitamin D in diabetic hypertension

August

79.7 (9.8)

Role of vitamin D in diabetic retinopathy

Role of vitamin D in osteoporosis in diabetic patients

Role of vitamin D in diabetic gastroparesis

September
October
November

18 (3)
a

Serum iPTH concentration at baseline, pg/mL


a

VAS score for pain at baseline

32.2 (17.1)
3.3 (0.7)

MPQ score at baseline

Serum 25(OH)D concentrations significantly improved after


oral vitamin D supplementation in the treatment group
compared to the placebo group (32.8 23.7 vs. 1.1 3.6,
p < 0.0001).

32.1 (4.6)
a

Serum 25D concentration at 3 mo, ng/mL

30 (5)
a

Serum iPTH concentration at 3 mo, pg/mL


a

VAS score for pain at 3 mo


a

MPQ score at 3 mo

28.1 (10.0)
1.7 (0.8)

Similarly, the improvement in NSS values was significantly


greater in the treatment group than in the placebo group
(1.49 1.37 vs. 0.20 0.59, p < 0.001).

19.4 (7.4)

Role of vitamin D in diabetic neuropathy

December

Change in serum 25D concentration, %

+67.4

10

Vitamin D & immunity in diabetic patients

January

Change in serum iPTH concentration, %

13.4

11

Vitamin D in diabetic ketoacidosis

February

Change in VAS score, %

48.5b

Change in MPQ score, %

39.4b

12

Vitamin D in diabetic cardiomyopathy

March

Diabetic peripheral neuropathy was assessed using a


neuropathy symptom score (NSS), a neuropathy disability
score (NDS) and a nerve conduction study (NCS). Vitamin
D status was determined by measuring the serum total
25(OH)D concentration (Table 3).

30.0 (2.3)

Patients received either oral vitamin D3 (n = 57) or starch


capsules (n = 55) once weekly for 8 weeks.

62 (13)

Serum 25D concentration at baseline, ng/mLa

To assess the efficacy of short-term oral vitamin D


supplementation on peripheral neuropathy, a prospective,
placebo-controlled study was conducted on 112 T2DM
patients.

51

a Data are given as geometric mean (SD); b P < 0.05

Thus, vitamin D supplementation may be an effective


analgesic in relieving neuropathic pain.
7

Vitamin D Repletion: Improvement in Glycaemic


Control12

Also, reduced levels of circulating 25(OH)D may add to


increased risk of large fiber neuropathy in type 2 diabetic
subjects.

Studies have shown that insulin secretion is improved by as much


as 60% when levels of 25(OH)D increased from 12.5 to 30 ng/mL.

Each 1 ng/mL increase in serum 25(OH)D was correlated


with 2.2 and 3.4 % decrease in the presence and severity of
nerve conduction velocity (NCV) impairment, respectively.

Case 1
A 63-year-old woman with 25(OH)D level of 12 ng/mL and
HbA1c levels stable at 8.4%, received 2000 IU of vitamin D3
per day and was increased to 3000 IU/d.

Vitamin D as an Analgesic in Diabetic Neuropathy13


A study was conducted to evaluate the impact of vitamin
D repletion on neuropathic pain in 51 patients with type
2 diabetes and vitamin D insufficiency (serum 25(OH)D
concentration <24 ng/mL3).

After vitamin D supplementation, raising her 25(OH)D level


to 55 ng/mL, HbA1c levels decreased to 7.4%.

Case 2

The study included patients with type 2 diabetes with typical


neuropathic pain, including burning, tingling, numbness,
and throbbing sensations.

A 71-year-old female with type 2 diabetes had 25(OH)D


level of 14 ng/mL and HbA1c level of 13.3%.

These patients also had findings of reduced sensation to


monofilament on physical examination.

Correction of vitamin D deficiency and raising 25(OH)D level


to 41 ng/mL resulted in a decline in HbA1c levels to 12.2%.

Patients were supplemented with vitamin D3 tablets (mean


dose, 2059 IU).

Inverse Association of Low Vitamin D Level with


Neuropathy and its Severity2
A study explored the association between serum 25(OH)D
and diabetic neuropathy.

Pain scores for both the McGill pain questionnaire (MPQ)


and a visual analog self-report scale (VAS) correlated
negatively with serum 25(OH)D concentration.

It was observed that serum vitamin D had an independent


and inverse association with both diabetic neuropathy
presence and severity.

Vitamin D supplementation resulted in a significant


reduction in pain scores on both the VAS and MPQ at
48.5% and 39.4%, respectively (Table 2).

Over the past decades, numerous non-skeletal diseases are found to be associated with vitamin D
deficiency including type 2 diabetes mellitus (T2DM).1 Diabetic neuropathy is one such condition.
Around 6070% diabetic patients have some form of neuropathy.2 Hyperglycaemic state leads to
increased activity of enzymes aldose reductase and sorbitol dehydrogenase, and oxidative stress
which contributes to nerve cell dysfunction.3
There are various studies which have shown a role of vitamin D supplementation in glucose
tolerance through its effects on insulin secretion and insulin sensitivity.1 Activity of vitamin D as
an analgesic is also highlighted, suggesting its role in diabetic neuropathy for reducing
neuropathic pain.
This scientific input mainly focuses on the link between vitamin D deficiency and diabetic
neuropathy and importance of vitamin D supplementation as add-on treatment. We hope that
the information provided will help doctors to enhance patient care.

REFERENCES
1.

Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes.
Diabetol Metab Syndr. 2013;5(1):8.

2.

Bell DSH. Reversal of the symptoms of diabetic neuropathy through correction of vitamin D deficiency in a type 1
diabetic patient. Case Reports in Endocrinology. 2012;Article ID 165056:3 pages.

3.

Clayton W, Elasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic
patients. Clinical Diabetes. 2009;27(2):528.

Significant improvements were seen in HbA1c and HOMAIR after supplementation (Table 1).

VDR expression was significantly increased in diabetic


subjects, which was observed in the cytoplasm, nuclei and
cell membranes of neurons.

Table 1: Significant decrease in HOMA-IR on vitamin D supplementation after


stratifying by different baseline serum levels of 25(OH)D

VDR expression increase was observed in all types of


neurons, most notable in the neurons of small diameter.

Overview of diabetic neuropathy

Pathophysiology of diabetic neuropathy

Vitamin D deficiency: A cause-effect relationship in diabetic neuropathy

Diagnosis of diabetic neuropathy

Incidence of diabetic neuropathy in vitamin D deficient individuals

Need of vitamin D supplementation in diabetic neuropathy

7
8

Vitamin D supplements as an add-on treatment


Summary

5
8

Decrease in HOMA-IR

Results suggested that vitamin D activates the expression


of calcium-binding proteins and upregulates calciumbuffering molecules in cells.
Thus, neurons are protected from apoptosis and
neurodegeneration due to these effects of vitamin D,
resulting in increased transcription activity of VDR-target
genes.

Intervention

Control

P- value

<20 ng/mL group

63

53

P < 0.05

2030 ng/mL group

63

53

P < 0.05

>30 ng/mL group

53

43

P < 0.05

Vitamin D Supplementation: Improvement in


HbA1c11

VITAMIN D SUPPLEMENTS AS AN ADD-ON


TREATMENT

A study examined the long-term effects of vitamin D


supplementation on serum HbA1c as part of drug regimen
over a 3-year continuum.

Vitamin D Supplementation: Improvement in


Insulin Resistance10

Pearson correlations were used for the assessment.


Vitamin D supplementation was inversely associated with
HbA1c (r = 0.286, P = 0.031).

A study was carried out to explore the effects of oral vitamin


D supplementation on insulin resistance in 164 subjects
with T2DM divided in groups of intervention and control.

Significant improvements in HbA1c were obtained with


vitamin D supplementation as part of drug regimen over
time.

At the beginning and end of 12-week supplementation,


serum levels of glucose, insulin, HbA1c and 25(OH)D were
recorded.

INCIDENCE OF DIABETIC NEUROPATHY IN


VITAMIN D DEFICIENT INDIVIDUALS

NEED OF VITAMIN D SUPPLEMENTATION IN


DIABETIC NEUROPATHY

Study 18

With numerous evidences suggesting vitamin D deficiency


is related to diabetic neuropathy, it can be considered that
treatment with vitamin D may correct predisposing metabolic
disturbance and prove protective for neurons.8

Type 2 diabetics were enrolled in a trial conducted to


assess the correlations between neuropathy and vitamin D
deficiency.

Vitamin D: Role in Improvement of Glucose


Homeostasis9

Eighty-seven patients with neuropathy (significantly longer


duration of diabetes and higher HbA1c) and 123 patients
without neuropathy were included.

The proposed mechanism of action of vitamin D on insulin


sensitivity includes conversion of proinsulin to insulin through
a rise in intracellular calcium concentration via non-selective
voltage-dependent calcium channels. The -cell calciumdependent endopeptidases produce the cleavage of
C-peptide, which facilitates the conversion of proinsulin to
insulin.

Among the diabetic patients having neuropathy, the


average serum 25(OH)D concentration was significantly
lower as compared to those without diabetes.
Vitamin D deficiency was found in >81% of the patients with
diabetic neuropathy.

Following are the other proposed mechanisms:

Study 26
The frequency of low 25(OH)D levels among 111 diabetics
suffering from peripheral neuropathy was evaluated in a
study.
Neuropathy was confirmed in 55.8% of type 2 diabetic
patients.

PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY

Diabetic neuropathy is the most common complication of


diabetes mellitus and the major cause of morbidity and
mortality in diabetic patients.1

Development of neuropathy in hyperglycaemic patients is


studied in various animal and in vitro studies. It is observed
that hyperglycaemic state leads to increased activity of
enzymes, aldose reductase and sorbitol dehydrogenase.3

There have been recent speculations that circulating


25-hydroxyvitamin D (25(OH)-D) could be involved in
diabetic neuropathy development and progression.1

This results in the conversion of intracellular glucose to


sorbitol and fructose, which after accumulation decreases the
synthesis of nerve cell myoinositol, thus hampering normal
neuron conduction.3

It develops with longstanding hyperglycaemia, associated


with metabolic derangements:2

In addition, there is depletion of nicotinamide adenine


dinucleotide phosphate stores, which are necessary for the
detoxification of reactive oxygen species and for the synthesis
of the vasodilator nitric oxide.3

Increased polyol flux


Accumulation of advanced glycation end products
Oxidative stress

The resultant increase in oxidative stress on the nerve cell


promotes nerve cell injury and death.3

Lipid alterations
Cardiovascular risk factors

Stimulation of insulin synthesis by activating protein


biosynthesis in pancreatic islets

Alterations of microvessels are found to be associated with


the pathologic alterations of nerves.2

Increased insulin secretion through direct modulation of


-cell growth

The neuropathies developing in diabetic patients vary by


their symptoms, pattern of neurologic involvement, course,
risk covariates, pathologic alterations, and underlying
mechanisms.2

Vitamin D: Protective for Neurons6

Vitamin D deficiency incidence proved to be significantly


higher in the group of patients with neuropathy as compared
to the diabetic group not suffering from neuropathy.

OVERVIEW OF DIABETIC NEUROPATHY

Hyperglycaemia and oxidative stress also contribute to the


abnormal glycation of nerve cell proteins and the inappropriate
activation of protein kinase C, resulting in further nerve
dysfunction3 (Figure 1).

A study conducted to assess the role of vitamin D in vitamin


D receptor (VDR) signalling in diabetic neuropathy.
4

Hyperglycaemia

Microvascular vasoconstriction, capillary basement membrane


thickening, endothelial hyperplasia, haemologic abnormalities

Increased extracellular
protein glycation
AGE formation

Increased intracellular glucose in


nerve and vascular tissue

Neural hypoperfusion and ischaemia

RAGE activation
Sugar + ROSs carbonyls
Carbonyls + proteins or
lipids glycoxidation or
lipoxidation products
Oxidative stress

Increased glycolysis
and TCA cycle activity
Mitochondrial
dysfunction

Vitamin D Deficiency: Effects on Nervous System


Vitamin D deficiency has been the causative factor in the
pathogenesis of several neurological diseases:6
Sclerosis multiplex
Schizophrenia
Parkinsons disease
Dementia

Redox reaction: glucose sorbitol fructose

In neurodegenerative disorders, role of vitamin D deficiency


as a risk factor has also been proven.6

Reduced NADPH + glutathione, NADH:NAD+ misbalance

Soderstrom et al. evaluated relationship between vitamin D


deficiency and the symptoms of neuropathy.7

Increased
diacylglycerol

Protein + glucose

Thus, vitamin D deficiency in diabetics could be a prelude to


the development of diabetic neuropathy.

VITAMIN D LEVELS: A PREDICTOR OF DIABETIC


NEUROPATHY
An association between insufficient vitamin D and selfreported peripheral neuropathy symptoms has been found
at a cut-off level of 30 ng/mL.7
The symptoms were not present when using cut-offs of
20 ng/mL, 10 ng/mL, or quartiles for assessment.7

Polyol pathway flux


Protein kinase C
Increased superoxide

AGEs

Vitamin D insufficiency was present in 81% of the diabetics,


which was associated with self-reported peripheral
neuropathy symptoms (Figure 2).7

Nerve dysfunction and death

50

Vitamin D Deficiency: Effect on Glucose Homeostasis

In a sub-analysis on subjects with diabetes, the association


between serum 25(OH)D and HbA1c was even stronger
with a difference in HbA1c of 0.48% between the highest
and lowest serum 25(OH)D quartiles.6

A direct relation between insulin sensitivity and 25(OH)D level


was found in a study, showing vitamin D deficiency having a
negative effect on -cell function in pancreatic -cells.5

Patients (%)

In a study, the correlation value between serum 25(OH)D


and HbA1c was found to be 0.07 (P < 0.001), and appeared
most pronounced in the subjects with risk factors for T2DM.6

The relationship between 25(OH)D levels and microvascular


complications in diabetic patients was evaluated in a clinical
study using UK screening score.6

60
50

Figure 1: Pathophysiology of diabetic neuropathy4

VITAMIN D DEFICIENCY: A CAUSE-EFFECT


RELATIONSHIP IN DIABETIC NEUROPATHY

So, this indicates that a threshold effect for vitamin D in


diabetics exists at a level 30 ng/mL.7

37

40

38

Mean 25(OH)D levels were lower in subjects with


diabetic neuropathy compared to those without diabetic
neuropathy.6

30
20

Diabetic neuropathy was more prevalent in subjects with


vitamin D deficiency, using a cut-off value 20 ng/mL, than
those with 25(OH)D levels 20 ng/mL.6

10

Paresthesia

Tingling

Numbness

Insensitive feet

Thus, 25(OH)D levels may prove to be significant predictors


of diabetic neuropathy.6

Neuropathy symptoms

Figure 2: Associated of self-reported peripheral neuropathy symptoms with


vitamin D insufficiency in terms of patient percentage7