For

the

use

of a

Reg

iste

red

Med

ical

Pra

ctiti

oner

or

a H

osp

ital o

r a

Lab

orat

ory

only

.D

evel

oped

by:

Sc

ien

ce

th

at

ma

tte

rsSCIE

NTI

MED

TM

Disclaimer: Conceptualised, edited, customised & designed by Scientimed Solutions Private Limited with an educational grant from USV Limited. USV Limited is not responsible for the nature of content or any associated copyright or intellectual property issue. The publisher does not endorse the quality or value of the advertised/sponsored products described herein. Please consult full prescribing information before prescribing any of the products mentioned in this publication.

USV Limited Arvind Vithal Gandhi Chowk, BSD Marg,

Station Road, Govandi East, Mumbai - 400 088

Scan the QR code to download the presentation of this topic

D-RISE − API

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

Cholecalciferol 2000 IU/ 60000 IU, Capsule.

Therapeutic indication: Vitamin D defi ciency states including patients of type 2 diabetes mellitus with vitamin D defi ciency.

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.

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 −

Renal: Impairment of renal function with polyuria, nocturia, polydipsia, hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis, generalized vascular calcifi cation, or irreversible renal insuffi ciency which may result in death.

CNS: Mental retardation.

Soft Tissues: Widespread calcifi cation 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 (dwarfi sm), 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 30˚C.

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., fi sh 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

ROLE OF OIL-BASED VITAMIN D SUPPLEMENTS IN DIABETICS

• 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

Though vitamin D defi ciency 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

Inte

rsti

tial

fl ui

d

Vit. D

Bile salts recycle

Bile salts from liver coating vit. D Micelle

formation

Hydrolysis(pancreatic

lipase)

Golgi apparatus

Vit. D in chylomicron

Vit. D

Enterocyte

Vit. D

Figure 1: Absorption of oil-based vit. D formula in the upper part of small intestine1

Inte

rsti

tial

fl ui

d

Vit. D

Vit. D in chylomicron

Golgi apparatus

Vit. DVit. D+DBP in circulation

Enterocyte

Figure 2: Absorption of powder-based vitamin D formula in small intestine4,5

levels.6 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.

Improved absorption with oil-based supplements

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 effi ciency 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.

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

Comparison between two different lipid vehicles

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

Figure 3: Comparison between vitamin D vehicles in terms of change in serum concentration of 25(OH)D1

Supplement vehicle

9876543210

-1

Cha

nge

in m

ean

seru

m

25(O

H)D

(nm

ol/

L) p

er 1

00 IU

/day

Oil

4.045

Powder

2.747

• Vitamin D supplementation resulted in a signifi cant 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. 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 fi ber peripheral neuropathy in diabetic subjects. Neurol Sci. 2015;36(7):1121−6.

2. Tesfaye S, Boulton AJM, Dyck PJ. Diabetic neuropathies: Update on defi nitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285−93.

3. Clayton W, Elasy TA. A review of the pathophysiology, classifi cation, and treatment of foot ulcers in diabetic patients. Clinical Diabetes. 2009;27(2):52−8.

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.

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, Németh N, et al. Is there an association between diabetic neuropathy and low vitamin D levels? Curr Diab Rep. 2014;14(10):537.

7. 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):50−5.

8. Shehab D, Al-Jarallah K, Mojiminiyi OA, et al. Does vitamin D defi ciency play a role in peripheral neuropathy in type 2 diabetes? Diabet Med. 2012;29(1):43−9.

9. Palomer X, González-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):185−97.

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):3407−10.

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):335−41.

12. Holick MF. Diabetes and the vitamin D connection. Curr Diab Rep. 2008;8(5):393−8.

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):771−2.

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):250−6.

9

8

• Thus, short-term oral vitamin D3 supplementation improved vitamin D status and the symptoms of neuropathy in patients with type 2 diabetes.

SUMMARY

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

• Around 60−70% diabetic patients have some form of neuropathy. Almost 50% of them experience varying degrees of neuropathic pain.

• 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.

• Vitamin D insuffi ciency was present in 81% of the diabetics, which was associated with self-reported peripheral neuropathy symptoms in one of the studies.

• A threshold effect for vitamin D in diabetics exists at a level ≥30 ng/mL.

• 25(OH)D levels may prove to be signifi cant predictors of diabetic neuropathy.

• The proposed mechanism of action of vitamin D on insulin sensitivity includes conversion of proinsulin to insulin.

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

• In various studies, vitamin D supplementation resulted in improved glucose homeostasis and improvement in neuropathic pain.

• 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.

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

Parameters Before After Differences P-value

NSS

Treatment 5.92 ± 1.29 4.43 ± 1.58 –1.49 ± 1.37<0.001

Placebo 5.50 ± 1.25 5.45 ± 1.20 –0.20 ± 0.59

NDS

Treatment 8.4 ± 1.8 8.4 ± 1.8 –0.42 ± 1.590.094

Placebo 7.8 ± 1.9 7.7 ± 1.8 –0.03 ± 0.2

25(OH)D, mmol/l

Treatment 25.3 ± 10.9 58.2 ± 23.8 32.8 ± 23.7<0.0001

Placebo 29.2 ± 9.5 30.3 ± 8.9 1.1 ± 3.6

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

Values are means ± SD; signifi cant at the 5% level. A two way analysis of interaction was applied.

Conclusion

With reference to clinical studies, it is evident that oil-based 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, oil-based vitamin D3 supplements may prove to be an add-on treatment option. In addition, peanut oil can be the preferred lipid vehicle.

REFERENCES

1. Grossmann RE, Tangpricha V. Evaluation of vehicle substances on vitamin D bioavailability: A systematic review. Mol Nutr Food Res. 2010;54(8):1055–61.

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):644–9.

4. Kidambi S, Patel SB. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica. 2008;38(7–8):1119–39.

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):900–7.

6. Nyomba BL, Bouillon R, Lissens W, et al. 1,25-Dihydroxyvitamin D and vitamin D-binding protein are both decreased in streptozotocin-diabetic rats. Endocrinology. 1985;116(6):2483–8.

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):807–15.

Figure 4: Mean peak concentration of vitamin D3 in serum, 8–24 h after administration7

Treatment

Peanut oil capsules (fasting)

Medium chain triglyceride capsules

(fasting)

150

100

50

0

Vit

amin

D (n

mo

l/L) 116 ± 27

39 ± 11

D-CODE SERIES OVERVIEW

SR. NO.

TOPICS MONTH

1 Role of vitamin D in diabetic foot infection April

2 Role of vitamin D in diabetic patients with NAFLD May

3 Role of vitamin D in diabetic patients with obesity June

4 Role of vitamin D in diabetic nephropathy July

5 Role of vitamin D in diabetic hypertension August

6 Role of vitamin D in diabetic retinopathy September

7 Role of vitamin D in osteoporosis in diabetic patients October

8 Role of vitamin D in diabetic gastroparesis November

9 Role of vitamin D in diabetic neuropathy December

10 Vitamin D & immunity in diabetic patients January

11 Vitamin D in diabetic ketoacidosis February

12 Vitamin D in diabetic cardiomyopathy March

Thus, vitamin D supplementation may be an effective “analgesic” in relieving neuropathic pain.

Effect of Vitamin D Supplementation on Peripheral Neuropathy in T2DM14

• To assess the effi cacy of short-term oral vitamin D supplementation on peripheral neuropathy, a prospective, placebo-controlled study was conducted on 112 T2DM patients.

• Patients received either oral vitamin D3 (n = 57) or starch capsules (n = 55) once weekly for 8 weeks.

• 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).

• Serum 25(OH)D concentrations signifi cantly 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).

• Similarly, the improvement in NSS values was signifi cantly greater in the treatment group than in the placebo group (–1.49 ± 1.37 vs. –0.20 ± 0.59, p < 0.001).

7

Table 2: Characteristics, biochemistry, and pain scores at baseline and 3 months after treatment13

Variable Value

No. of subjects 51

Sex, No.

Female 37

Male 14

Age, ya 62 (13)

Weight, kga 79.7 (9.8)

BMIa 30.0 (2.3)

Serum 25D concentration at baseline, ng/mLa 18 (3)

Serum iPTH concentration at baseline, pg/mLa 32.2 (17.1)

VAS score for pain at baselinea 3.3 (0.7)

MPQ score at baselinea 32.1 (4.6)

Serum 25D concentration at 3 mo, ng/mLa 30 (5)

Serum iPTH concentration at 3 mo, pg/mLa 28.1 (10.0)

VAS score for pain at 3 moa 1.7 (0.8)

MPQ score at 3 moa 19.4 (7.4)

Change in serum 25D concentration, % +67.4b

Change in serum iPTH concentration, % −13.4

Change in VAS score, % −48.5b

Change in MPQ score, % −39.4b

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

6

Vitamin D Repletion: Improvement in Glycaemic Control12

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.

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.

• After vitamin D supplementation, raising her 25(OH)D level to 55 ng/mL, HbA1c levels decreased to 7.4%.

Case 2

• A 71-year-old female with type 2 diabetes had 25(OH)D level of 14 ng/mL and HbA1c level of 13.3%.

• Correction of vitamin D defi ciency and raising 25(OH)D level to 41 ng/mL resulted in a decline in HbA1c levels to 12.2%.

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.

• It was observed that serum vitamin D had an independent and inverse association with both diabetic neuropathy presence and severity.

• Also, reduced levels of circulating 25(OH)D may add to increased risk of large fi ber neuropathy in type 2 diabetic subjects.

• 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.

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 insuffi ciency (serum 25(OH)D concentration <24 ng/mL3).

• The study included patients with type 2 diabetes with typical neuropathic pain, including burning, tingling, numbness, and throbbing sensations.

• These patients also had fi ndings of reduced sensation to monofi lament on physical examination.

• Patients were supplemented with vitamin D3 tablets (mean dose, 2059 IU).

• 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.

• Vitamin D supplementation resulted in a signifi cant reduction in pain scores on both the VAS and MPQ at −48.5% and −39.4%, respectively (Table 2).

6

Over the past decades, numerous non-skeletal diseases are found to be associated with vitamin D defi ciency including type 2 diabetes mellitus (T2DM).1 Diabetic neuropathy is one such condition.

Around 60–70% 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 scientifi c input mainly focuses on the link between vitamin D defi ciency 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 defi ciency 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, classifi cation, and treatment of foot ulcers in diabetic patients. Clinical Diabetes. 2009;27(2):52−8.

6

Overview of diabetic neuropathy 1

Pathophysiology of diabetic neuropathy 1

Vitamin D defi ciency: A cause-effect relationship in diabetic neuropathy 2

Diagnosis of diabetic neuropathy 3

Incidence of diabetic neuropathy in vitamin D defi cient individuals 4

Need of vitamin D supplementation in diabetic neuropathy 4

Vitamin D supplements as an add-on treatment 5

Summary 8

1

2

3

4

5

7

8

• VDR expression was signifi cantly increased in diabetic subjects, which was observed in the cytoplasm, nuclei and cell membranes of neurons.

• VDR expression increase was observed in all types of neurons, most notable in the neurons of small diameter.

• Results suggested that vitamin D activates the expression of calcium-binding proteins and upregulates calcium-buffering 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.

VITAMIN D SUPPLEMENTS AS AN ADD-ON TREATMENT

Vitamin D Supplementation: Improvement in Insulin Resistance10

• 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.

• At the beginning and end of 12-week supplementation, serum levels of glucose, insulin, HbA1c and 25(OH)D were recorded.

• Signifi cant improvements were seen in HbA1c and HOMA-IR after supplementation (Table 1).

Vitamin D Supplementation: Improvement in HbA1c11

• A study examined the long-term effects of vitamin D supplementation on serum HbA1c as part of drug regimen over a 3-year continuum.

• Pearson correlations were used for the assessment.

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

• Signifi cant improvements in HbA1c were obtained with vitamin D supplementation as part of drug regimen over time.

55

Table 1: Signifi cant decrease in HOMA-IR on vitamin D supplementation after stratifying by different baseline serum levels of 25(OH)D

Decrease in HOMA-IR Intervention Control P- value

<20 ng/mL group 6 ± 3 5 ± 3 P < 0.05

20–30 ng/mL group 6 ± 3 5 ± 3 P < 0.05

>30 ng/mL group 5 ± 3 4 ± 3 P < 0.05

INCIDENCE OF DIABETIC NEUROPATHY IN VITAMIN D DEFICIENT INDIVIDUALS

Study 18

• Type 2 diabetics were enrolled in a trial conducted to assess the correlations between neuropathy and vitamin D defi ciency.

• Eighty-seven patients with neuropathy (signifi cantly longer duration of diabetes and higher HbA1c) and 123 patients without neuropathy were included.

• Among the diabetic patients having neuropathy, the average serum 25(OH)D concentration was signifi cantly lower as compared to those without diabetes.

• Vitamin D defi ciency was found in >81% of the patients with diabetic neuropathy.

Study 26

• The frequency of low 25(OH)D levels among 111 diabetics suffering from peripheral neuropathy was evaluated in a study.

• Neuropathy was confi rmed in 55.8% of type 2 diabetic patients.

• Vitamin D defi ciency incidence proved to be signifi cantly higher in the group of patients with neuropathy as compared to the diabetic group not suffering from neuropathy.

4

NEED OF VITAMIN D SUPPLEMENTATION IN DIABETIC NEUROPATHY

With numerous evidences suggesting vitamin D defi ciency 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

Vitamin D: Role in Improvement of Glucose Homeostasis9

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 calcium-dependent endopeptidases produce the cleavage of C-peptide, which facilitates the conversion of proinsulin to insulin.

Following are the other proposed mechanisms:

• Stimulation of insulin synthesis by activating protein biosynthesis in pancreatic islets

• Increased insulin secretion through direct modulation of -cell growth

Vitamin D: Protective for Neurons6

• A study conducted to assess the role of vitamin D in vitamin D receptor (VDR) signalling in diabetic neuropathy.

OVERVIEW 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

• There have been recent speculations that circulating 25-hydroxyvitamin D (25(OH)-D) could be involved in diabetic neuropathy development and progression.1

• It develops with longstanding hyperglycaemia, associated with metabolic derangements:2

Increased polyol fl ux

Accumulation of advanced glycation end products

Oxidative stress

Lipid alterations

Cardiovascular risk factors

• Alterations of microvessels are found to be associated with the pathologic alterations of nerves.2

• The neuropathies developing in diabetic patients vary by their symptoms, pattern of neurologic involvement, course, risk covariates, pathologic alterations, and underlying mechanisms.2

PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY

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

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

In addition, there is depletion of nicotinamide adenine dinucleotide phosphate stores, which are necessary for the detoxifi cation of reactive oxygen species and for the synthesis of the vasodilator nitric oxide.3

The resultant increase in oxidative stress on the nerve cell promotes nerve cell injury and death.3

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).

1

VITAMIN D DEFICIENCY: A CAUSE-EFFECT RELATIONSHIP IN DIABETIC NEUROPATHY

Vitamin D Defi ciency: Effect on Glucose Homeostasis

• A direct relation between insulin sensitivity and 25(OH)D level was found in a study, showing vitamin D defi ciency having a negative effect on -cell function in pancreatic -cells.5

• 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

• 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

2

Figure 1: Pathophysiology of diabetic neuropathy4

Hyperglycaemia

AGEsOxidative stress

AGE formation

RAGE activation

Sugar + ROSs carbonyls

Carbonyls + proteins or lipids glycoxidation or

lipoxidation products

Increased extracellular protein glycation

Increased intracellular glucose in nerve and vascular tissue

Increased glycolysis and TCA cycle activity

Increased diacylglycerol

Microvascular vasoconstriction, capillary basement membrane thickening, endothelial hyperplasia, haemologic abnormalities

Neural hypoperfusion and ischaemia

Polyol pathway fl ux

Redox reaction: glucose sorbitol fructose

Nerve dysfunction and death

Reduced NADPH + glutathione, NADH:NAD+ misbalance

Protein + glucose

Increased superoxide

Protein kinase C

Mitochondrial dysfunction

Vitamin D Defi ciency: Effects on Nervous System

• Vitamin D defi ciency has been the causative factor in the pathogenesis of several neurological diseases:6

Sclerosis multiplex Schizophrenia Parkinson’s disease Dementia

• In neurodegenerative disorders, role of vitamin D defi ciency as a risk factor has also been proven.6

• Soderstrom et al. evaluated relationship between vitamin D defi ciency and the symptoms of neuropathy.7

• Vitamin D insuffi ciency was present in 81% of the diabetics, which was associated with self-reported peripheral neuropathy symptoms (Figure 2).7

Thus, vitamin D defi ciency in diabetics could be a prelude to the development of diabetic neuropathy.

VITAMIN D LEVELS: A PREDICTOR OF DIABETIC NEUROPATHY

• An association between insuffi cient vitamin D and self-reported 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

• So, this indicates that a threshold effect for vitamin D in diabetics exists at a level ≥30 ng/mL.7

• The relationship between 25(OH)D levels and microvascular complications in diabetic patients was evaluated in a clinical study using UK screening score.6

• Mean 25(OH)D levels were lower in subjects with diabetic neuropathy compared to those without diabetic neuropathy.6

• Diabetic neuropathy was more prevalent in subjects with vitamin D defi ciency, using a cut-off value 20 ng/mL, than those with 25(OH)D levels ≥20 ng/mL.6

• Thus, 25(OH)D levels may prove to be signifi cant predictors of diabetic neuropathy.6

3

Figure 2: Associated of self-reported peripheral neuropathy symptoms with vitamin D insuffi ciency in terms of patient percentage7

Pat

ient

s (%

)

Neuropathy symptoms

60

50

40

30

20

10

0Paresthesia Tingling Numbness Insensitive feet

50

37 38

8