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Peripheral nerve function: metabolic features, clinical assessment, and heat shock protein 27
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peripheral neuropathy is a common complication among patients with diabetes mellitus, but whether peripheral neuropathy is present in individuals with impaired glucose tolerance (IGT) is debatable. In order to identify and diagnose peripheral neuropathy correctly, it is important to evaluate diagnostic tools that can be implemented in routine health care to assess both large and small nerve fibre function. There is currently limited knowledge about neuroprotective factors that could be useful for measuring peripheral nerve function in individuals at risk of developing neuropathy such as those with diabetes mellitus. Thus, studies are needed to investigate potential neuroprotective factors in relation to peripheral nerve function in humans.

Objectives: The overall goal of this thesis was to study the metabolic features and clinical assessment of peripheral nerve function and the potential relationship between the neuroprotective factor heat shock protein 27 (HSP27) and peripheral nerve function.

Methods: Thirty-nine participants with normal glucose tolerance (NGT) and 29 participants with IGT were recruited from the population-based Västerbotten Intervention Programme in 2003–2004. Patients with type 2 diabetes mellitus (T2DM, n = 51) were recruited from primary health care centres. NGT and IGT individuals underwent two separate oral glucose tolerance tests to verify their glucose status. The peripheral nerve function in the lower limb was assessed by nerve conduction studies, neuropathy disability scoring, quantitative sensory tests, and skin biopsies with subsequent quantification of intraepidermal nerve fibre density (IENFD). The concentrations of HSP27 in serum were determined in the NGT, IGT, and T2DM individuals. Patients with type 1 diabetes mellitus (T1DM) were recruited from the Diabetes Clinic, Skåne University Hospital in Malmö, Sweden (n = 27) in 1992 and were followed-up in 2005. Baseline and follow-up concentrations of HSP27 were determined in T1DM patients as well as in healthy non-diabetic controls (n = 397). The T1DM patients underwent nerve conduction studies and thermal and vibration perception threshold tests at baseline and at follow-up. Delta changes in HSP27 concentrations and small and large nerve fibre function were calculated.

Results: There was no difference between IGT and NGT in sural nerve conduction, intraepidermal nerve fibre density, or thermal thresholds. The biothesiometer had a sensitivity of 82% and a specificity of 72% in identifying peripheral neuropathy with a cut-off value of ≥24.5 V at the medial malleolus. Adding the quantification of IENFD to the combination of the tuning fork and biothesiometer increased the diagnostic sensitivity from 81% to 95%, the negative predictive value from 87% to 94%, and the positive likelihood ratio from 1.8 to 1.9 when identifying small nerve fibre dysfunction. T2DM patients had lower HSP27 concentrations (mean HSP27 = 412 pg/mL, 95% CI 284–598 pg/mL) than NGT (mean HSP27 = 722 pg/mL, 95% CI 564–922 pg/mL) and IGT (mean HSP27 = 1010 pg/mL, 95% CI 638–1300 pg/mL) individuals (p <0.05 for both comparisons). T1DM patients had lower HSP27 concentrations at baseline (mean HSP27 = 547 pg/mL, 95% CI 421–711 pg/mL) and at follow-up (mean HSP27 = 538 pg/mL, 95% CI 417–693 pg/mL) compared to healthy controls (mean HSP27 = 785 pg/mL, 95% CI 732–842 pg/mL), p <0.05 for both comparisons). High concentrations of HSP27 were associated with better large nerve fibre function (Odds ratio = 2.51, 95% CI 1.25–5.05, p <0.05). Deteriorating large nerve fibre function correlated with decreasing HSP27 concentrations over time in T1DM patients (r = 0.50, p = 0.01).

Conclusions: Measures of large and small nerve fibre function in IGT individuals do not differ significantly from NGT individuals. The existence of peripheral neuropathy as a consequence of IGT is not likely, and extensive control of neuropathy in IGT individuals is not advocated by this thesis. The biothesiometer is a useful clinical tool to identify peripheral neuropathy in routine health care. Quantification of IENFD using skin biopsies in combination with methods measuring vibrotactile sense, such as the biothesiometer and the tuning fork, increase the diagnostic usefulness of identifying small nerve fibre dysfunction. High HSP27 concentrations are associated with better peripheral large nerve fibre function. Patients with diabetes mellitus have lower HSP27 concentrations than healthy non-diabetic controls, and deterioration of large nerve fibre function correlates with a decrease in HSP27 concentrations over time in T1DM. This could be indicative of insufficient neuroprotection in patients with diabetes mellitus.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 77 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1589
National Category
Clinical Medicine Family Medicine Endocrinology and Diabetes Neurology
Identifiers
URN: urn:nbn:se:umu:diva-79469ISBN: 978-91-7459-692-2 (print)OAI: oai:DiVA.org:umu-79469DiVA: diva2:641895
Public defence
2013-09-12, Sal 135, byggnad 9A, ingång X1, Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-08-22 Created: 2013-08-19 Last updated: 2013-08-22Bibliographically approved
List of papers
1. No difference in small or large nerve fiber function between individuals with normal glucose tolerance and impaired glucose tolerance
Open this publication in new window or tab >>No difference in small or large nerve fiber function between individuals with normal glucose tolerance and impaired glucose tolerance
2013 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 4, 962-964 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

RESULTS There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [Interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

CONCLUSIONS Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.

Place, publisher, year, edition, pages
American Diabetes Association, 2013
National Category
Family Medicine Neurology Endocrinology and Diabetes Clinical Medicine
Research subject
Family Medicine; Neurology; Medicine
Identifiers
urn:nbn:se:umu:diva-66432 (URN)10.2337/dc12-1331 (DOI)
Available from: 2013-02-19 Created: 2013-02-19 Last updated: 2017-12-06Bibliographically approved
2. Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy
Open this publication in new window or tab >>Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy
2014 (English)In: Primary care diabetes, ISSN 1878-0210, Vol. 8, no 1, 77-84 p.Article in journal (Refereed) Published
Abstract [en]

AIMS: To compare the diagnostic usefulness of tuning fork, monofilament, biothesiometer and skin biopsies in peripheral neuropathy in individuals with varying glucose metabolism.

METHODS: Normoglycaemic, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) individuals were recruited. Nerve conduction studies (NCS) and thermal threshold tests were performed. Vibrotactile sense was tested with a biothesiometer and a 128-Hz tuning fork. Touch/pressure perception was examined with a 10-g monofilament. Skin biopsies were performed and intraepidermal nerve fibres were quantified. Distal symmetric polyneuropathy (DSPN) was defined as neuropathy disability score ≥2 and abnormal NCS. Thermal threshold tests were used to define small nerve fibre neuropathy (sDSPN) in cases where NCS (large nerve fibres) were normal.

RESULTS: The prevalence of DSPN and sDSPN in the whole group (n=119) was 18% and 23%, respectively. For the biothesiometer, a cut-off of ≥24.5V had a sensitivity of 82% and specificity of 70% (AUC=0.81, 95% CI 0.71-0.91) when evaluating DSPN. An intraepidermal nerve fibre density cut-off of ≤3.39fibres/mm showed a sensitivity of 74% and specificity of 70% in the detection of sDSPN, whereas the sensitivity of the tuning fork and the biothesiometer were relatively low, 46% and 67%, respectively. When combining skin biopsies with the tuning fork, 10 more sDSPN cases were identified. Adding skin biopsy to the combination of the tuning fork and biothesiometer increased the sensitivity of finding sDSPN cases, but not DSPN, from 81% to 93%.

CONCLUSION: Using a biothesiometer in clinical routine might be a sensitive method to detect large nerve fibre dysfunction in the lower extremity, whereas skin biopsies in combination with methods measuring vibrotactile sense could increase the diagnostic sensitivity of detecting peripheral neuropathy at an early stage.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
Biothesiometer, Diabetes mellitus, Nerve fibres, Neuropathy, Skin biopsy
National Category
Clinical Medicine Family Medicine Neurology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-79157 (URN)10.1016/j.pcd.2013.04.004 (DOI)000334086600011 ()23664849 (PubMedID)
Available from: 2013-08-10 Created: 2013-08-10 Last updated: 2014-05-16Bibliographically approved
3. Heat shock protein 27 is associated with better nerve function and fewer signs of neuropathy
Open this publication in new window or tab >>Heat shock protein 27 is associated with better nerve function and fewer signs of neuropathy
2011 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 12, 3143-3149 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis High levels of serum heat shock protein 27 (sHSP27) have been associated with distal symmetric polyneuropathy in patients with type 1 diabetes. Our objective was to investigate the association between sHSP27, neuropathic signs and nerve function in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes.

Methods Participants were recruited consecutively from the population-based Vasterbotten Intervention Program (NGT, n=39, IGT, n=29, and type 2 diabetes, n=51) and were matched for age and sex. sHSP27 levels were measured and nerve conduction studies were performed (peroneal and sural nerves). z Scores for each nerve conduction measure were calculated and compiled into a composite z score for the leg. Neuropathy disability score (NDS) was used to assess neuropathic signs.

Results Patients with diabetes had significantly lower sHSP27 levels (geometric mean sHSP27 206 pg/ml, 95% CI 142, 299) than those with IGT (geometric mean sHSP27 455 pg/ml, 95% CI 319, 650, p<0.05) and controls (geometric mean sHSP27 361 pg/ml, 95% CI 282, 461, p<0.05). Participants with few signs of neuropathy (first tertile, NDS <= 2) had significantly higher sHSP27 levels (geometric mean sHSP27 401 pg/ml, 95% CI 310, 520) than participants with many signs (third tertile, NDS >= 7) (geometric mean sHSP27 192 pg/ml, 95% CI 128, 288, p=0.007). The highest sHSP27 tertile was associated with better nerve function, adjusted for age, sex, statin medication and HbA(1c) (OR 2.51, 95% CI 1.25, 5.05, p<0.05).

Conclusions/interpretation High sHSP27 levels were associated with better nerve function and fewer neuropathic signs in NGT, IGT and type 2 diabetes.

Place, publisher, year, edition, pages
Springer, 2011
Keyword
Complications, Diabetes mellitus, Heat shock protein, Metabolism, Neuropathy
National Category
Endocrinology and Diabetes Family Medicine Neurology
Identifiers
urn:nbn:se:umu:diva-50929 (URN)10.1007/s00125-011-2303-5 (DOI)000297740000022 ()
Available from: 2012-01-17 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
4. Heat shock protein 27 concentrations are lower in patientswith type 1 diabetes mellitus than in healthy controls andcorrelates with large nerve fibre dysfunction
Open this publication in new window or tab >>Heat shock protein 27 concentrations are lower in patientswith type 1 diabetes mellitus than in healthy controls andcorrelates with large nerve fibre dysfunction
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective Heat shock protein 27 (HSP27) may contribute to the survival of neurons. Our aims were to study whether HSP27 concentrations differ between individuals with and without type 1 diabetes, and evaluate the relationship between the progression of peripheral nerve dysfunction and HSP27 concentrations.

Research Design and Methods Type 1 diabetes patients (n=27, 41% women; mean age 41±8 years) were recruited in 1992 with a follow-up in 2005; serum HSP27 concentrations were determined in baseline and follow-up samples and compared to non-diabetic controls (n=397, 34% women; mean age 43±14 years). The type 1 diabetes patients underwent nerve conduction studies and thermal and vibration perception threshold tests at baseline and at follow-up. Reference data was used to standardise results for age, height and sex by calculating the Z-scores. Delta changes in HSP27 (follow-up HSP27 – baseline HSP27) and small and large nerve fibre function were used for correlation analyses.

Results Type 1 diabetes patients had lower HSP27 concentrations at baseline (mean HSP27547 pg/ml, 95% CI 421, 711) and at follow-up (mean HSP27 538 pg/ml, 95% CI 417,693) compared to healthy controls (mean HSP27 785 pg/ml, 95% CI 732, 842; p<0.05 for both comparisons). Deteriorating large nerve fibre function correlated with delta HSP27 concentrations in type 1 diabetes (r=0.50, p=0.01).

Conclusions Patients with type 1 diabetes had lower HSP27 concentrations than non-diabetic controls and progression of large nerve fibre dysfunction correlated with decreasing HSP27 concentrations during the follow-up period. This could be indicative ofinsufficient neuroprotection in type 1 diabetes.

National Category
Clinical Medicine Family Medicine Endocrinology and Diabetes Neurology
Identifiers
urn:nbn:se:umu:diva-79468 (URN)
Available from: 2013-08-19 Created: 2013-08-19 Last updated: 2013-08-22Bibliographically approved

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