Lars Kärvestedt

Peripheral Sensory Neuropathy Associates With Micro- or Macroangiopathy: Results from a population-based study of type 2 diabetic patients in Sweden

OBJECTIVE—To assess associations between peripheral sensory neuropathy (PSN) and other diabetes-related complications. RESEARCH DESIGN AND METHOD—In an area-based cohort of type 2 diabetic subjects, we investigated 156 subjects (age 61.7 ± 7.2 years and diabetes duration 7.0 ± 5.7 years) by questionnaires, clinical examinations, blood and urine sampling, and review of medical records. RESULTS—Prevalence of PSN, assessed by monofilament and neurothesiometer testing, increased with severity of retinopathy (50% frequency in moderate and 100% in severe or proliferative retinopathy; P = 0.02). Vibration perception threshold was higher in subjects with retinopathy (25.6 ± 8.9 vs. 20.5 ± 8.9 V; P = 0.007). PSN was more common in subjects with overt nephropathy, with higher vibration perception thresholds, than in subjects without overt nephropathy. Subjects with PSN but no retinopathy had twice the prevalence of peripheral vascular disease (PVD) (52%) as subjects with both PSN and retinopathy (19%; P = 0.05). In subjects with PSN alone, PVD was three times more likely (52%) than in subjects without PSN (16%; P = 0.001). In multivariate analysis, PSN was independently associated with PVD (odds ratio 2.31; P = 0.007), age (1.12; P = 0.008), male sex (2.01; P = 0.02), and HDL cholesterol (0.21; P < 0.05) and tended to be independently associated with IGF-1 binding protein (1.03; P = 0.05) but not with diabetes duration or A1C. CONCLUSIONS—In a representative population of type 2 diabetes, PSN is related to microvascular and macrovascular pathology. PSN is possibly affected by the IGF axis.

Peripheral sensory neuropathy associates with micro- or macroangiopathy. Results from a population based study of patients with type 2 diabetes in Sweden.

OBJECTIVE—To assess associations between peripheral sensory neuropathy (PSN) and other diabetes-related complications. RESEARCH DESIGN AND METHOD—In an area-based cohort of type 2 diabetic subjects, we investigated 156 subjects (age 61.7 ± 7.2 years and diabetes duration 7.0 ± 5.7 years) by questionnaires, clinical examinations, blood and urine sampling, and review of medical records. RESULTS—Prevalence of PSN, assessed by monofilament and neurothesiometer testing, increased with severity of retinopathy (50% frequency in moderate and 100% in severe or proliferative retinopathy; P = 0.02). Vibration perception threshold was higher in subjects with retinopathy (25.6 ± 8.9 vs. 20.5 ± 8.9 V; P = 0.007). PSN was more common in subjects with overt nephropathy, with higher vibration perception thresholds, than in subjects without overt nephropathy. Subjects with PSN but no retinopathy had twice the prevalence of peripheral vascular disease (PVD) (52%) as subjects with both PSN and retinopathy (19%; P = 0.05). In subjects with PSN alone, PVD was three times more likely (52%) than in subjects without PSN (16%; P = 0.001). In multivariate analysis, PSN was independently associated with PVD (odds ratio 2.31; P = 0.007), age (1.12; P = 0.008), male sex (2.01; P = 0.02), and HDL cholesterol (0.21; P < 0.05) and tended to be independently associated with IGF-1 binding protein (1.03; P = 0.05) but not with diabetes duration or A1C. CONCLUSIONS—In a representative population of type 2 diabetes, PSN is related to microvascular and macrovascular pathology. PSN is possibly affected by the IGF axis.

The prevalence of peripheral neuropathy in a population-based study of patients with type 2 diabetes in Sweden☆

AIMS To assess peripheral neuropathy following a standardized foot examination protocol in a representative population-based cohort of subjects with type 2 diabetes. METHODS In a geographically defined population, aged 40-70 years with diabetes prevalence of 3.5% according to medical records, we investigated 156 type 2 diabetic subjects, 95% Caucasian, mean age 61.7±7.2 years, duration of diabetes 7.0±5.7 years, and HbA(1c) 7.3±2.4% (6.4% Mono-S), by questionnaires, clinical examinations, blood sampling, and review of medical records. Foot examination included clinical signs of peripheral neuropathy and tests of sensibility with monofilament, tuning fork, and assessments of the vibration perception thresholds (VPT). RESULTS Peripheral autonomic neuropathy (PAN) as judged by two or more signs of dysfunction was the most common and affected 43%. The prevalence of peripheral sensory neuropathy (PSN) was 15% by monofilament, 24% by tuning fork, and 28% by VPT expressed as ZscoreVPT ≥2.0 S.D. Twenty-nine percent had a VPT ≥25 V. Signs of peripheral motor neuropathy (PMN) affected 15%. Peripheral neuropathy, at least one variable, affected 67%, whereas 25% were affected by more than one variable of neuropathy, i.e., polyneuropathy. Exclusion of other identified causes for neuropathy than diabetes reduced the prevalence of diabetic polyneuropathy to 23%. Concurrent diabetic complications were 29% for retinopathy, 14% for incipient nephropathy, and 8% for overt nephropathy. The prevalence of macrovascular complications was 62% for CVD, 26% for PVD, and 11% for cerebrovascular lesion (CVL). CONCLUSION Peripheral neuropathy was common in this representative type 2 diabetes population. Clinical signs of PAN were the most frequent followed by diminished perception of vibration and touch.

Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes

BackgroundInsulin-like growth factor-binding protein 7 (IGFBP-7) is able to interact with insulin-like growth factor 1 (IGF-1) as well as insulin. Previous studies have suggested that serum IGFBP-7 levels may be associated with insulin resistance in type 2 diabetes (T2D). This study aimed to evaluate IGFBP-7 serum protein and IGFBP7 DNA methylation levels in the subjects with and without T2D.ResultsA total of 340 Swedish subjects including 100 newly diagnosed T2D patients (50 women/50 men), 100 age-matched nondiabetic control subjects (50/50) and 140 treated T2D patients (54/86) were studied. Serum IGFBP-7 levels were measured with a novel ELISA. IGF1, IGFBP-1, and insulin were determined by in-house radioimmunoassays. DNA methylation levels in the IGFBP7 gene were analyzed with a bisulfite-pyrosequencing technique. Serum IGFBP-7 protein levels were similar among nondiabetic subjects, newly diagnosed, and treated T2D patients and were not correlated with IGFBP7 DNA methylation. However, IGFBP7 DNA methylation was increased in men with newly diagnosed T2D compared with nondiabetic controls (17.6% vs. 12.5%, P < 0.01). Serum IGFBP-7 levels correlated (r = 0.331, P = 0.019) with serum IGFBP-1 levels, a marker of insulin production, in men but not women with newly diagnosed T2D.ConclusionsThis study demonstrates for the first time that IGFBP7 DNA methylation levels are increased in Swedish men with newly diagnosed T2D. The correlation between IGFBP-7 and IGFBP-1 suggests that low IGFBP-7 may be associated with insulin resistance in T2D.

Coenzyme Q10 and oxidative stress, the association with peripheral sensory neuropathy and cardiovascular disease in type 2 diabetes mellitus

OBJECTIVE Our study aimed to explore associations between metabolic control, oxidative stress and coenzyme Q10 (CoQ10) in relation to diabetes complications in a representative population of type 2 diabetes. RESEARCH DESIGN AND METHODS A geographic cohort of 156 subjects was recruited. Serum concentrations of CoQ10 and vitamin E were measured by HPLC. ROS was determined by free oxygen radicals testing (FORT). Glutaredoxin (Grx) activity, oxidized LDL cholesterol (oxLDLc), high sensitive CRP (hsCRP), HbA1c, urine albumin, serum creatinine, serum cystatin C, and plasma lipids were assayed with routine laboratory protocols. RESULTS Serum CoQ10 was higher than in nondiabetics. HbA1c, fP-glucose, hyperlipidemia, inflammation (hsCRP), and increased BMI were associated with signs of oxidative stress as increased levels of FORT, Grx activity and/or increased levels of oxLDLc Oxidative stress was found to be strongly correlated with prevalence of cardiovascular disease (CVD) and peripheral sensory neuropathy (PSN). In both gender groups there were positive correlations between CoQ10 and oxLDLc, and between BMI and the ratio CoQ10/chol. Grx activity was inversely correlated to oxLDLc and CoQ10. Women with CVD and PSN had higher waist index, oxLDLc, and FORT levels compared to men but lower CoQ10 levels. Men had worse kidney function and lower vitamin E. Multiple regression analysis showed increased levels of CoQ10 to be significantly correlated with increased levels of cholesterol, triglycerides, vitamin E, fB-glucose and BMI. CONCLUSIONS Hyperlipidemia, hyperglycemia and inflammation were associated with oxidative stress, which was correlated to the prevalence of diabetes complications. CoQ10 was increased in response to oxidative stress. There were gender differences in the risk factors associated with diabetes complications.

P03-16 Correlations of adiponectin with IGFBP-1 in Swedish men with and without type 2 diabetes

P03-16 Correlations of adiponectin with IGFBP-1 in Swedish men with and without type 2 diabetes H.F. Gu, T. Gu, A. Hilding, L. Karvestedt, A. Flyvbjerg, J. Frystyk, C.-G. Ostenson, K. Brismar. Karolinska Institutet, Molecular Medicine and Surgery, Stockholm, Sweden; Stockholm Sjukhem, Stockholm, Sweden; Aarhus University Hospital, Medical Research Laboratories, Institute of Clinical Medicine & Department of Endocrinology and Internal Medicine, Aarhus, Denmark

Evaluation of Sox2 genetic effect on the development of type 2 diabetes.

Sox2 is a transcription factor, which plays an important role in the induction of pluripotent stem cells from somatic cells. The Sox2 gene is located in chromosome 3q26.33 and resides in a linkage region of diabetes. In the present study, we attempted to evaluate the genetic effect of Sox2 in the development of type 2 diabetes (T2D). A total of 1598 Swedish subjects of T2D, pre-diabetes and non-diabetic control subjects were enrolled in the present study. Genotyping experiments for allelic discrimination of SNP rs11915160 were performed with TaqMan allelic discrimination. Sox2 mRNA expression levels in pancreatic islets of T2D patients (n=16) and control subjects (n=8) were detected by using real time RT-PCR. Among the non-diabetic control subjects with and without family history of diabetes (FHD, i.e. at least one first degree relative with diabetes or at least two second degree relatives with diabetes), the A allele frequency in Sox2 rs11915160 were 12.3% and 12.9%. This allele frequency was increased to 13.4% in T2D patients with FHD selected from SDPP and 17.9% in the patients with FHD from Kronan study, while the patients without FHD had the allele frequency at 12.4%. The difference of mRNA expression levels of the Sox2 gene in pancreatic islets between T2D patients and controls was not statistically significant. The present study thus suggests that Sox2 is unlikely to exert the genetic effect on the development of T2D.