Curr Diab Rep (2014) 14:537 DOI 10.1007/s11892-014-0537-6
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
Is There an Association Between Diabetic Neuropathy and Low Vitamin D Levels? Zsuzsanna Putz & Tímea Martos & Nóra Németh & Anna Erzsébet Körei & Orsolya Erzsébet Vági & Miklós Soma Kempler & Péter Kempler
# Springer Science+Business Media New York 2014
Abstract In the past few years, the effects of vitamin D that go beyond its relationship with bone metabolism have come into the focus of scientific attention. Research concerning diabetes and its complications has become a public health priority. An increasing number of reports link vitamin D deficiency to diabetes; however, so far, there has only been limited and contradictory data available on the correlation between diabetic peripheral neuropathy and vitamin D. Studies of people with type 2 diabetes confirmed the relationship between vitamin D deficiency and neuropathy incidence as well as the severity of the symptoms caused by neuropathy. The latest studies are also suggesting a relationship between the incidence of plantar ulcers and vitamin D deficiency.
Keywords Vitamin D . Diabetes mellitus . Neuropathy
Zs. Putz and T. Martos contributed equally to this study.
Introduction Today, the consequences of vitamin D deficiency are increasingly considered as a public health priority that needs to be tackled. An increasing quantity of evidence is being published about the widespread effects of vitamin D going beyond influencing bone and calcium homeostasis. Several studies have reported on the association of vitamin D deficiency with cardiovascular disease, tumours, autoimmune conditions and overall mortality. A recent meta-analysis of 73 cohort studies and 22 randomised controlled trials [1] that evaluate the correlation between vitamin D levels and the risk of cause-specific death showed a moderate, but significant, inverse association between circulating 25-hydroxyvitamin D (25OHD) concentrations and the risk of all-cause mortality. This association proved more specific for deaths due to coronary disease, lymphoma, upper digestive cancer and respiratory disorders. Low vitamin D levels may be associated with higher incidence of diabetes and neurodegenerative diseases as well.
This article is part of the Topical Collection on Microvascular Complications—Neuropathy Z. Putz (*) : T. Martos : N. Németh : A. E. Körei : O. E. Vági : M. S. Kempler : P. Kempler 1st Department of Internal Medicine, Faculty of Medicine, Semmelweis University, BudapestKorányi S. u. 2/a, 1089, Hungary e-mail: [email protected] T. Martos e-mail: [email protected] N. Németh e-mail: [email protected] A. E. Körei e-mail: [email protected] O. E. Vági e-mail: [email protected] P. Kempler e-mail: [email protected]
Vitamin D and Diabetes Diabetes-related research is of special importance, as authoritative forecasts indicate that the number of people with diabetes estimated at 382 million in 2013 will increase to 592 million by 2035 [2]. Numerous studies have implicated vitamin D in the pathophysiology of both type 1 and type 2 diabetes; however, conclusive causal proof is yet lacking. A recent study of Wolden-Kirk et al. [3] examined the molecular pathway of the protective effect of vitamin D against cytokine-induced inflammation in pancreatic cells. Human and mouse islets were exposed to IL-1β and interferon-γ in the presence or absence of active vitamin D. Cytokine exposure caused a significant increase in β-cell
537, Page 2 of 6
apoptosis, which was almost completely prevented by active vitamin D. In addition, vitamin D restored insulin secretion from cytokine-exposed islets. These effects may contribute to the beneficial effects of vitamin D against the induction of autoimmune diabetes. Vitamin D deficiency was examined in pre-type 1 diabetic children, following disease progression from autoantibody seroconversion until manifest diabetes [4]. 25OHD levels were lower in children with multiple islet antibodies and type 1 diabetic children, comparing to autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to diabetes in autoantibody-positive children. In the Third National Health and Nutrition Examination Survey (1988–1994), a cross-sectional survey of a nationally representative sample of the US population was analysed [5]. Vitamin D status was available from 6,228 adult people (2,766 non-Hispanic whites, 1,736 non-Hispanic blacks, and 1,726 Mexican Americans) with fasting and/or 2-h plasma glucose and serum insulin measurements. Adjusting for sex, age, BMI, leisure activity, and quarter of year, ethnicity-specific odds ratios for diabetes (fasting glucose ≥7.0 mmol/l) varied inversely across quartiles of 25OHD level in a dose-dependent pattern. In the highest 25OHD quartile (25OHD ≥81.0 nmol/l) compared with the lowest (25OHD ≤43.9 nmol/l), this inverse association was not observed in non-Hispanic blacks. Homeostasis model assessment of insulin resistance was inversely associated with serum 25OHD in Mexican Americans (p=0.0024) and non-Hispanic whites (p=0.058), adjusting for confounders.
Chronic Complications of Diabetes Mellitus Historically, chronic complications of diabetes mellitus have been divided into two categories on the basis of didactical considerations: microangiopathic and macroangiopathic complications. Within the group of microangiopathic complications, retinopathy, nephropathy and neuropathy are considered specific to the diabetic condition. These characteristic complications only occur in patients with diabetes. Macroangiopathy presents with the various forms of atherosclerosis, which (ischemic heart disease, stroke, peripheral vascular disease) are well known to develop also without any link to diabetes. Although the macroangiopathic complications occurring in diabetes do tend to show certain clinical characteristics in terms of their frequency, localisation, symptoms and course, they are not fundamentally different from the forms of their occurrence in patients without diabetes. Thus, the diseases that develop on the basis of macroangiopathy cannot be considered chronic complications specific to diabetes. Within the chronic complications that are specific to diabetes, neuropathy is of outstanding significance, as it tends to appear—as a complication of diabetes with a bad prognosis—
Curr Diab Rep (2014) 14:537
in over half of the patients with type 2 diabetes. The autonomic and sensory damage belongs to the progressive forms of neuropathy, the clinical and prognostic significance of which has only become clear in the past few decades. Follow-up studies conducted with diabetic patients confirmed that the existence of cardiovascular autonomic neuropathy increases mortality five times. Today, we consider sensory neuropathy to be the most important factor in the diabetic foot condition. Reduced or complete loss of pain, feeling and/or heat sensation plays a dominant role in the development of plantar (painless, neuropathic) ulcers. The fact that amputations of the lower leg are 15–45 times more frequent among people with diabetes than in the non-diabetic population should draw attention to the importance of this condition. In the developed industrial countries, nearly half of all lower-leg amputations of a non-traumatic origin are performed on patients with diabetes, while timely discovery and appropriate complex treatment could provide an opportunity to prevent primarily those of a neuropathic origin [6–8].
The Effects of Vitamin D on the Nervous System The role of vitamin D in preventing and treating various neurological diseases has been studied for several years. The effect of vitamin D is confirmed by VDR and CYP27B1 expression measureable in the nervous system, in the brain, in the nerve and in the glial cells [9]. The causal role of vitamin D deficiency has been considered in the pathomechanism of several neurological diseases (sclerosis multiplex, schizophrenia, Parkinson’s disease and dementia). It is a well-known fact that there is a link between the incidence of sclerosis multiplex and geography; the risk of sclerosis multiplex increases parallel to the increase in the distance from the Equator. Ample data confirm that lower serum 25OHD levels correlate with the incidence, relapses and mortality of sclerosis multiplex and with the active sclerosis multiplex lesions identified on MRI images of the brain [10–16]. Treatment involving high dosages of vitamin D slows down the progression of disability linked to multiple sclerosis [17]. However, the real therapeutic efficacy of vitamin D in the treatment of the disease will be revealed by the clinical trials that are currently under way [18]. The risk role of vitamin D deficiency has also been proven in the development of neurodegenerative diseases. In a follow-up study spanning nearly three decades, Finnish researchers found a link between higher 25OHD blood levels and a lower risk of Parkinson’s disease [19]. Another study examined the correlation between 25OHD levels and cognitive decline in 856 Italian individuals over the age of 65. In case of vitamin D deficiency, the risk of cognitive decline was proven to be 60 % higher [20]. The study of Ding et al. revealed an association between serum 25OHD and
Curr Diab Rep (2014) 14:537
Page 3 of 6, 537
Parkinson disease and suggests that thousands of patients with Parkinson’s disease in North America alone may be vitamin D deficient [20, 21].
The Role of Vitamin D in the Development of Neuropathy Notwithstanding the numerous publications on the relationship between diabetes and vitamin D deficiency, there are few— and only contradictory—data concerning the actual correlation between vitamin D deficiency and neuropathy (Table 1.). In vitro data and the outcomes of animal testing have both confirmed the role played by vitamin D analogues in stimulating and reducing the breakdown of the nerve growth factor that is crucial to the survival of sympathetic and sensory neurons. A
vitamin D derivative (CB1093) was examined in the study of Riaz et al. [28, 29]. In streptozotocin-diabetic rats, deficient nerve growth factor (NGF) causes impaired neurotrophic support in the muscle and skin. CB1093 stimulates the expression of NGF in both the skin and muscle of diabetic and control rats. In non-diabetic rats, CB1093 caused dose-dependent increases in nerve growth factor production (140 % in the soleus muscle and 190 % in the sciatic nerve) and a mechanical hyperalgesia in the foot. In sciatic nerves of diabetic rats, the depletions of nerve growth factor and its neuronal target gene products (substance P and CGRP) were prevented by CB1093. Correction of substance P and CGRP deficits by CB1093 is probably caused by the increase in NGF production and its collection by the peripheral projections of sciatic sensory neurones. These findings suggest that in animal models of
Table 1 The main outcomes of the relevant studies examining the relationship between vitamin D supply and neuropathy Authors
Type of study
Number of subjects included
Follow-up Main outcome periods
Result
Lee P et al. [22]
Observational
51
3 months
MPQ, 5-cm VAS, monofilament
Shebab D et al. [23]
Cross-sectional
210
NA
Valensi P et al. [24]
RCT
34
8 weeks
Neuropathy symptom score (NSS), neuropathy disability score (NDS), nerve conduction study (NCS) score Examination of the effect of QR 333 (vitamin D derivate), specific symptoms, VAS, QoL
Soderstrom LH et al. [25••]
Cross-sectional- unweighted n=591, representative weighted sample n=8.82 million
NA
Self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling, Semmes–Weinstein monofilament
Skalli S et al. [26]
Observational
111
NA
Ahmadieh K et al. [27]
Cross-sectional
136
NA
Patellar deep tendon reflexes, Achilles sensory loss. 128-Hz tuning fork and Semmes-Weinstein monofilament UK screening score
Vitamin D repletion resulted in a significant reduction in pain scores on both the VAS and MPQ at −48.5 and −39.4 %, respectively. 81.5 % of patients with diabetic neuropathy had vitamin D deficiency compared with 60.4 % of patients with no diabetic neuropathy (p=0.005) QR-333 reduced the severity of numbness (p=0038), jolting pain (p=0.0037) and irritation (p=0.048) from baseline values. Overall and specific quality-of-life measures were also improved. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95 % CI 1.17–3.85) and the adjusted numbness measure (odds ratio 2.04; 95 % CI 1.18–3.52). Serum 25-OH-vitamin D levels were significantly lower in the group with neuropathy, 24.6±11.98 vs. 34.74±17.26 nmol/l in the group without neuropathy (p
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
Is There an Association Between Diabetic Neuropathy and Low Vitamin D Levels? Zsuzsanna Putz & Tímea Martos & Nóra Németh & Anna Erzsébet Körei & Orsolya Erzsébet Vági & Miklós Soma Kempler & Péter Kempler
# Springer Science+Business Media New York 2014
Abstract In the past few years, the effects of vitamin D that go beyond its relationship with bone metabolism have come into the focus of scientific attention. Research concerning diabetes and its complications has become a public health priority. An increasing number of reports link vitamin D deficiency to diabetes; however, so far, there has only been limited and contradictory data available on the correlation between diabetic peripheral neuropathy and vitamin D. Studies of people with type 2 diabetes confirmed the relationship between vitamin D deficiency and neuropathy incidence as well as the severity of the symptoms caused by neuropathy. The latest studies are also suggesting a relationship between the incidence of plantar ulcers and vitamin D deficiency.
Keywords Vitamin D . Diabetes mellitus . Neuropathy
Zs. Putz and T. Martos contributed equally to this study.
Introduction Today, the consequences of vitamin D deficiency are increasingly considered as a public health priority that needs to be tackled. An increasing quantity of evidence is being published about the widespread effects of vitamin D going beyond influencing bone and calcium homeostasis. Several studies have reported on the association of vitamin D deficiency with cardiovascular disease, tumours, autoimmune conditions and overall mortality. A recent meta-analysis of 73 cohort studies and 22 randomised controlled trials [1] that evaluate the correlation between vitamin D levels and the risk of cause-specific death showed a moderate, but significant, inverse association between circulating 25-hydroxyvitamin D (25OHD) concentrations and the risk of all-cause mortality. This association proved more specific for deaths due to coronary disease, lymphoma, upper digestive cancer and respiratory disorders. Low vitamin D levels may be associated with higher incidence of diabetes and neurodegenerative diseases as well.
This article is part of the Topical Collection on Microvascular Complications—Neuropathy Z. Putz (*) : T. Martos : N. Németh : A. E. Körei : O. E. Vági : M. S. Kempler : P. Kempler 1st Department of Internal Medicine, Faculty of Medicine, Semmelweis University, BudapestKorányi S. u. 2/a, 1089, Hungary e-mail: [email protected] T. Martos e-mail: [email protected] N. Németh e-mail: [email protected] A. E. Körei e-mail: [email protected] O. E. Vági e-mail: [email protected] P. Kempler e-mail: [email protected]
Vitamin D and Diabetes Diabetes-related research is of special importance, as authoritative forecasts indicate that the number of people with diabetes estimated at 382 million in 2013 will increase to 592 million by 2035 [2]. Numerous studies have implicated vitamin D in the pathophysiology of both type 1 and type 2 diabetes; however, conclusive causal proof is yet lacking. A recent study of Wolden-Kirk et al. [3] examined the molecular pathway of the protective effect of vitamin D against cytokine-induced inflammation in pancreatic cells. Human and mouse islets were exposed to IL-1β and interferon-γ in the presence or absence of active vitamin D. Cytokine exposure caused a significant increase in β-cell
537, Page 2 of 6
apoptosis, which was almost completely prevented by active vitamin D. In addition, vitamin D restored insulin secretion from cytokine-exposed islets. These effects may contribute to the beneficial effects of vitamin D against the induction of autoimmune diabetes. Vitamin D deficiency was examined in pre-type 1 diabetic children, following disease progression from autoantibody seroconversion until manifest diabetes [4]. 25OHD levels were lower in children with multiple islet antibodies and type 1 diabetic children, comparing to autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to diabetes in autoantibody-positive children. In the Third National Health and Nutrition Examination Survey (1988–1994), a cross-sectional survey of a nationally representative sample of the US population was analysed [5]. Vitamin D status was available from 6,228 adult people (2,766 non-Hispanic whites, 1,736 non-Hispanic blacks, and 1,726 Mexican Americans) with fasting and/or 2-h plasma glucose and serum insulin measurements. Adjusting for sex, age, BMI, leisure activity, and quarter of year, ethnicity-specific odds ratios for diabetes (fasting glucose ≥7.0 mmol/l) varied inversely across quartiles of 25OHD level in a dose-dependent pattern. In the highest 25OHD quartile (25OHD ≥81.0 nmol/l) compared with the lowest (25OHD ≤43.9 nmol/l), this inverse association was not observed in non-Hispanic blacks. Homeostasis model assessment of insulin resistance was inversely associated with serum 25OHD in Mexican Americans (p=0.0024) and non-Hispanic whites (p=0.058), adjusting for confounders.
Chronic Complications of Diabetes Mellitus Historically, chronic complications of diabetes mellitus have been divided into two categories on the basis of didactical considerations: microangiopathic and macroangiopathic complications. Within the group of microangiopathic complications, retinopathy, nephropathy and neuropathy are considered specific to the diabetic condition. These characteristic complications only occur in patients with diabetes. Macroangiopathy presents with the various forms of atherosclerosis, which (ischemic heart disease, stroke, peripheral vascular disease) are well known to develop also without any link to diabetes. Although the macroangiopathic complications occurring in diabetes do tend to show certain clinical characteristics in terms of their frequency, localisation, symptoms and course, they are not fundamentally different from the forms of their occurrence in patients without diabetes. Thus, the diseases that develop on the basis of macroangiopathy cannot be considered chronic complications specific to diabetes. Within the chronic complications that are specific to diabetes, neuropathy is of outstanding significance, as it tends to appear—as a complication of diabetes with a bad prognosis—
Curr Diab Rep (2014) 14:537
in over half of the patients with type 2 diabetes. The autonomic and sensory damage belongs to the progressive forms of neuropathy, the clinical and prognostic significance of which has only become clear in the past few decades. Follow-up studies conducted with diabetic patients confirmed that the existence of cardiovascular autonomic neuropathy increases mortality five times. Today, we consider sensory neuropathy to be the most important factor in the diabetic foot condition. Reduced or complete loss of pain, feeling and/or heat sensation plays a dominant role in the development of plantar (painless, neuropathic) ulcers. The fact that amputations of the lower leg are 15–45 times more frequent among people with diabetes than in the non-diabetic population should draw attention to the importance of this condition. In the developed industrial countries, nearly half of all lower-leg amputations of a non-traumatic origin are performed on patients with diabetes, while timely discovery and appropriate complex treatment could provide an opportunity to prevent primarily those of a neuropathic origin [6–8].
The Effects of Vitamin D on the Nervous System The role of vitamin D in preventing and treating various neurological diseases has been studied for several years. The effect of vitamin D is confirmed by VDR and CYP27B1 expression measureable in the nervous system, in the brain, in the nerve and in the glial cells [9]. The causal role of vitamin D deficiency has been considered in the pathomechanism of several neurological diseases (sclerosis multiplex, schizophrenia, Parkinson’s disease and dementia). It is a well-known fact that there is a link between the incidence of sclerosis multiplex and geography; the risk of sclerosis multiplex increases parallel to the increase in the distance from the Equator. Ample data confirm that lower serum 25OHD levels correlate with the incidence, relapses and mortality of sclerosis multiplex and with the active sclerosis multiplex lesions identified on MRI images of the brain [10–16]. Treatment involving high dosages of vitamin D slows down the progression of disability linked to multiple sclerosis [17]. However, the real therapeutic efficacy of vitamin D in the treatment of the disease will be revealed by the clinical trials that are currently under way [18]. The risk role of vitamin D deficiency has also been proven in the development of neurodegenerative diseases. In a follow-up study spanning nearly three decades, Finnish researchers found a link between higher 25OHD blood levels and a lower risk of Parkinson’s disease [19]. Another study examined the correlation between 25OHD levels and cognitive decline in 856 Italian individuals over the age of 65. In case of vitamin D deficiency, the risk of cognitive decline was proven to be 60 % higher [20]. The study of Ding et al. revealed an association between serum 25OHD and
Curr Diab Rep (2014) 14:537
Page 3 of 6, 537
Parkinson disease and suggests that thousands of patients with Parkinson’s disease in North America alone may be vitamin D deficient [20, 21].
The Role of Vitamin D in the Development of Neuropathy Notwithstanding the numerous publications on the relationship between diabetes and vitamin D deficiency, there are few— and only contradictory—data concerning the actual correlation between vitamin D deficiency and neuropathy (Table 1.). In vitro data and the outcomes of animal testing have both confirmed the role played by vitamin D analogues in stimulating and reducing the breakdown of the nerve growth factor that is crucial to the survival of sympathetic and sensory neurons. A
vitamin D derivative (CB1093) was examined in the study of Riaz et al. [28, 29]. In streptozotocin-diabetic rats, deficient nerve growth factor (NGF) causes impaired neurotrophic support in the muscle and skin. CB1093 stimulates the expression of NGF in both the skin and muscle of diabetic and control rats. In non-diabetic rats, CB1093 caused dose-dependent increases in nerve growth factor production (140 % in the soleus muscle and 190 % in the sciatic nerve) and a mechanical hyperalgesia in the foot. In sciatic nerves of diabetic rats, the depletions of nerve growth factor and its neuronal target gene products (substance P and CGRP) were prevented by CB1093. Correction of substance P and CGRP deficits by CB1093 is probably caused by the increase in NGF production and its collection by the peripheral projections of sciatic sensory neurones. These findings suggest that in animal models of
Table 1 The main outcomes of the relevant studies examining the relationship between vitamin D supply and neuropathy Authors
Type of study
Number of subjects included
Follow-up Main outcome periods
Result
Lee P et al. [22]
Observational
51
3 months
MPQ, 5-cm VAS, monofilament
Shebab D et al. [23]
Cross-sectional
210
NA
Valensi P et al. [24]
RCT
34
8 weeks
Neuropathy symptom score (NSS), neuropathy disability score (NDS), nerve conduction study (NCS) score Examination of the effect of QR 333 (vitamin D derivate), specific symptoms, VAS, QoL
Soderstrom LH et al. [25••]
Cross-sectional- unweighted n=591, representative weighted sample n=8.82 million
NA
Self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling, Semmes–Weinstein monofilament
Skalli S et al. [26]
Observational
111
NA
Ahmadieh K et al. [27]
Cross-sectional
136
NA
Patellar deep tendon reflexes, Achilles sensory loss. 128-Hz tuning fork and Semmes-Weinstein monofilament UK screening score
Vitamin D repletion resulted in a significant reduction in pain scores on both the VAS and MPQ at −48.5 and −39.4 %, respectively. 81.5 % of patients with diabetic neuropathy had vitamin D deficiency compared with 60.4 % of patients with no diabetic neuropathy (p=0.005) QR-333 reduced the severity of numbness (p=0038), jolting pain (p=0.0037) and irritation (p=0.048) from baseline values. Overall and specific quality-of-life measures were also improved. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95 % CI 1.17–3.85) and the adjusted numbness measure (odds ratio 2.04; 95 % CI 1.18–3.52). Serum 25-OH-vitamin D levels were significantly lower in the group with neuropathy, 24.6±11.98 vs. 34.74±17.26 nmol/l in the group without neuropathy (p
