Suat Simsek

Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy

Aims/hypothesisIn addition to nephropathy, retinopathy and peripheral neuropathy, a microvascular complication of type 1 diabetes that may be tentatively referred to as ‘diabetic encephalopathy’ has gained increasing attention. There is growing evidence that lowered cognitive performance in patients with type 1 diabetes is related to chronic hyperglycaemia rather than recurrent episodes of severe hypoglycaemia, as previously speculated. The aim of our study was to use magnetic resonance imaging (MRI) to establish whether long-term hyperglycaemia, resulting in advanced retinopathy, contributes to structural changes in the brain (reduced grey matter).Subjects, materials and methodsWe applied voxel-based morphometry on magnetic resonance images to compare grey matter density (GMD) between three groups of participants. GMD is used as a marker of cortical atrophy. We compared 13 type 1 diabetic patients with a microvascular complication (i.e. proliferative retinopathy) with 18 type 1 diabetic patients who did not have retinopathy in order to assess the effects of microvascular changes on GMD. Both patient groups were compared with 21 healthy control subjects to assess the effect of diabetes in itself.ResultsPatients with diabetic retinopathy showed reduced GMD in the right inferior frontal gyrus and right occipital lobe compared both with patients without retinopathy and with healthy controls (p<0.05).Conclusions/interpretationOur data show that patients with type 1 diabetes, who, as a consequence of chronic hyperglycaemia, had developed advanced retinopathy, also showed increased focal cortical atrophy on brain MRI.

Vitamin D and gestational diabetes: A systematic review and meta-analysis

BACKGROUND Conflicting results currently exists on the association between vitamin D and glucose metabolism. The role of maternal vitamin D status in gestational diabetes mellitus (GDM) is not clear. This meta-analysis aimed to examine this role in women with GDM compared with normal glucose tolerance (NGT). METHODS We performed a systematic review and meta-analysis by searching MEDLINE database, the Cochrane library and Uptodate® Online for English-language literature up to September 2011. Summary odds ratios were calculated using a random-effects model meta-analysis. RESULTS Seven observational studies were eligible for the meta-analysis, including 2146 participants of whom 433 were diagnosed with GDM. Four studies reported a high incidence of vitamin D deficiency in pregnant women (>50%). Overall vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD)<50 nmol/l) in pregnancy was significantly related to the incidence of GDM with an odds ratio of 1.61 (95% CI 1.19-2.17; p=0.002). Serum 25OHD was significant lower in participants with GDM than in those with NGT (-5.33 nmol/l (95% CI -9.73 to -0.93; p=0.018). CONCLUSIONS This meta-analysis indicates a significant inverse relation of serum 25OHD and the incidence of GDM. However, it remains unclear whether this association is causal due to the observational study design of the studies. Clinical trials are needed to examine whether vitamin D supplementation will improve glycemic control in women with GDM.

Diabetic encephalopathy: a concept in need of a definition

Diabetes mellitus is associated with the occurrence of welldescribed microvascular complications, including retinopathy, nephropathy and peripheral neuropathy. The concept of central neuropathy has been controversial for more than 80 years now. As early as 1922 it was recognised that diabetes can lead to cognitive dysfunction [1]. The prevalence of cognitive dysfunction is difficult to estimate as it depends heavily on the way it is assessed. The reported prevalence is about 40% in long-standing or poorly controlled diabetes [2]. Cognitive dysfunction in diabetes is characterised by lowered performance on several cognitive domains, most notably slowing of mental speed and diminished flexibility [3]. The magnitude of these cognitive deficits appears mild to moderate, but can significantly hamper daily functioning, adversely affecting quality of life [4]. Cognitive decline in diabetic patients treated with insulin has so far largely been attributed to recurrent episodes of hypoglycaemia, rather than to hyperglycaemia, although there is little evidence to support this notion [5, 6]. In trying to describe cognitive impairment in diabetes as a complication of the disease, the term ‘diabetic encephalopathy’ was introduced in 1950 [7]. In 1965, rather characteristic pathological changes were found in brains from 16 long-term juvenile diabetic patients who had died from vascular complications of diabetes [8]: diffuse degenerative abnormalities, pseudocalcinosis, severe angiopathy of cerebral vessels, atrophy of the dentate nucleus, demyelinisation of cranial nerves and fibrosis of the leptomeninges. The authors stated that this histological pattern justifies the term ‘diabetic encephalopathy’, because it differs from that seen in any other clinical condition. However, for several reasons, the term ‘encephalopathy’ has not been widely accepted. Firstly, it has strong negative connotations and does not seem to match the mild cognitive problems usually seen in (nondemented) diabetic patients. Secondly, and most importantly, the diagnosis diabetic encephalopathy lacks clear criteria and is therefore difficult to ascertain. Historically, the term diabetic encephalopathy applies to type 1 diabetic patients only. Other terms found in the literature to describe cognitive dysfunction in diabetes include functional cerebral impairment and central neuropathy. To facilitate research into this area and to increase recognition of the disorder, we propose a new term—‘diabetes-associated cognitive decline’ (DACD). This term is not suggestive of a particular pathogenesis, but merely describes a state of mild to moderate cognitive impairment, in particular psychomotor slowing and reduced mental flexibility, not attributable to other causes. Pathogenic research should focus on type 1 diabetes patients first, as in type 2 diabetes bias is introduced by several coexistent risk factors for cognitive dysfunction other than hyperglycaemia (e.g. hypertension, hyperlipidaemia). For further validation of the term DACD, we propose the operational research criteria summarized in the text box. As the relation between cognitive complaints and objective dysfunction is weak, we do not regard subjective complaints about cognitive functioning as a prerequisite for diagnosis of DACD. As cognitive dysfunction in type 1 diabetes is usually mild to G. S. Mijnhout . M. Diamant . S. Simsek . R. J. Heine Department of Endocrinology and Diabetes, VU University Medical Centre, Amsterdam, The Netherlands

The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus.

Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes‐associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes‐associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high‐titre anti‐glutamic acid decarboxylase (GAD)—compared with single and low‐titre autoantibody—is associated with an early age of onset, low fasting C‐peptide values as a marker of reduced pancreatic B‐cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut‐off points of anti‐GAD for differentiating clinically relevant diabetes mellitus subgroups.

Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial

OBJECTIVE Low vitamin D status has been associated with impaired glycemic control in patients with type 2 diabetes. The purpose of our study was to evaluate the effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, placebo-controlled trial was conducted in 275 adult patients with type 2 diabetes without insulin treatment. Patients were randomly assigned to receive either vitamin D3 (50,000 IU/month) or placebo for 6 months. To assess the primary outcome of the study, change in HbA1c, we performed a linear regression analysis. RESULTS Mean baseline serum 25-hydroxyvitamin D [25(OH)D] increased from 60.6 ± 23.3 to 101.4 ± 27.6 nmol/L and 59.1 ± 23.2 to 59.8 ± 23.2 nmol/L in the vitamin D and placebo group, respectively. Mean baseline HbA1c was 6.8 ± 0.5% (51 ± 6 mmol/mol) in both groups. After 6 months, no effect was seen on HbA1c (mean difference: β = 0.4 [95% CI −0.6 to 1.5]; P = 0.42) and other indicators of glycemic control (HOMA of insulin resistance, fasting insulin, and glucose) in the entire study population. Subgroup analysis in patients with a serum 25(OH)D <50 nmol/L or an HbA1c level >7% (53 mmol/mol) did not differ the results. CONCLUSIONS In a well-controlled group of patients with type 2 diabetes, intermittent high-dose vitamin D supplementation did not improve glycemic control.

Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: Clinical and genetic characteristics

BACKGROUND Patients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. METHODS We studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. RESULTS Thirty-three percent of T1DM+CD patients reported CD related complaints for at least 5 years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45 years of age. Women were diagnosed with CD at a younger age than men (median 25 years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). CONCLUSION A delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5 years interval.

MANAGEMENT OF ENDOCRINE DISEASE: The effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

OBJECTIVE Epidemiologic studies suggest that vitamin D status plays a role in glycaemic control in patients with type 2 diabetes. However, intervention studies yielded inconsistent results. The aim of this study is to systematically review the effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes. METHODS Systematic review and meta-analysis. We searched Medline, Embase and the Cochrane Library for RCTs examining the effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes. A random-effects model meta-analysis was performed to obtain a summarized outcome of vitamin D supplementation on HbA1c, fasting glucose and homeostasis model assessment - insulin resistance (HOMA-IR). RESULTS Twenty-three RCTs were included in this systematic review representing a total of 1797 patients with type 2 diabetes. Mean (± s.d.) change in serum 25-hydroxyvitamin D varied from 1.8 ± 10.2 nmol/L to 80.1 ± 54.0 nmol/L. Nineteen studies included HbA1c as outcome variable. Combining these studies no significant effect in change of HbA1c was seen after vitamin D intervention compared with placebo. A significant effect of vitamin D supplementation was seen on fasting glucose in a subgroup of studies (n = 4) with a mean baseline HbA1c ≥ 8% (64 mmol/mol) (standardized difference in means: 0.36; 95% CI: 0.12-0.61, P = 0.003). CONCLUSIONS Current evidence of RCTs does not support short-term vitamin D supplementation in a heterogeneous population with type 2 diabetes. However, in patients with poorly controlled diabetes, a favourable effect of vitamin D is seen on fasting glucose.

Thyroid function and the metabolic syndrome in older persons: a population-based study

BACKGROUND Studies suggest an association between a high TSH and (individual components of) the metabolic syndrome. Only a few studies have been performed in the general older population. OBJECTIVE This study investigates the association between serum TSH and the metabolic syndrome in a representative sample of older persons in The Netherlands. DESIGN AND PATIENTS Data of the Longitudinal Aging Study Amsterdam were used, which is an ongoing cohort study in a representative sample of Dutch older persons. A total of 1187 subjects (590 men and 597 women) between the ages of 65 and 88 years participated in the study. MEASUREMENTS Metabolic syndrome (US National Cholesterol Education Program definition) and its individual components were assessed, as well as serum TSH levels. RESULTS Among the participants, the prevalence of the metabolic syndrome was 34.2%. The mean serum TSH was 1.9 mU/l. Subjects in the upper quartile with a serum TSH level above 2.28 mU/l (odds ratio (OR)=1.68; 95% confidence interval (CI) 1.19-2.37) had a significantly increased prevalence of metabolic syndrome compared with subjects in the lowest quartile with a serum TSH below 1.04 mU/l. After adjustment for confounders, age, sex, alcohol use, total physical activity, and smoking, the OR was 1.62 (95% CI 1.15-2.32). CONCLUSIONS Subjects with a serum TSH in the upper quartile have a higher prevalence of metabolic syndrome as compared with subjects with a serum TSH in the lowest quartile.

Increased Nepsilon-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus.

OBJECTIVE Non-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, Nepsilon-(carboxymethyl)-lysine (CML), in cerebral vessels. RESEARCH DESIGN AND METHODS Brain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels. RESULTS Staining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 0.85 (interquartile range (IQR) 0.66-1.52) vs 0.63 in the control group (IQR 0.44-0.70); P=0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm(2) in the diabetic group of 1.08 (IQR 0.73-1.43) vs 0.23 in the control group (IQR 0.12-0.43); P=0.003). CONCLUSIONS Accumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGE-blocking and/or breaking compounds is indicated.

Cross-sectional and longitudinal association between homocysteine, vitamin B12 and physical performance in older persons.

Background/Objectives:Decreases in physical performance are associated with multiple negative health outcomes. The objective of this study was to examine whether high plasma homocysteine and low serum vitamin B12 are independent risk factors for lower physical performance, both cross-sectionally and longitudinally.Subjects/Methods:This study was performed in persons aged ⩾65 years of the LASA (Longitudinal Aging Study Amsterdam), an ongoing cohort study. Blood was collected in 1995/1996 (n=1352). Physical performance was assessed in 1995/1996 and in 1998/1999 using three tests: the walking test, the chair stands test and the tandem stand (n=901–1155).Results:After adjustment for confounding, women in the highest quartile of homocysteine had a significantly lower physical performance than did those in the lowest quartile in the cross-sectional analyses (β=−0.93, s.e.=0.34, P<0.01). This association was borderline statistically significant in the longitudinal analyses (β=−0.69, s.e.=0.35, P=0.05). After additional adjustment for serum vitamin B12, both associations were statistically significant (P<0.05). For vitamin B12 in women, and for homocysteine and vitamin B12 in men, the observed associations were less consistent.Conclusions:High plasma homocysteine is an independent risk factor for lower physical performance in older women. The association between vitamin B12 and physical performance is less clear.