Cecilie Wium

Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies

OBJECTIVE Fetuin A has been associated with insulin resistance and the metabolic syndrome. We therefore explored the role of fetuin A in nonalcoholic fatty liver disease (NAFLD). DESIGN Cross-sectional and intervention studies. METHODS We included 111 subjects with histologically proven NAFLD of whom 44 participated in a randomized, controlled trial with metformin. One hundred and thirty-one healthy subjects and 13 subjects undergoing hepatic surgery for metastatic cancer served as controls. Main outcome variables were circulating levels of fetuin A according to the presence of NAFLD, hepatic gene expression of fetuin A and key enzymes in glucose and lipid metabolism, and the effect of metformin on fetuin A levels in vivo and in vitro (HepG2 cells). RESULTS Fetuin A levels were significantly higher in NAFLD patients compared with controls (324 ± 98 vs 225 ± 75 mg/l, P<0.001). NAFLD was a significant predictor of elevated fetuin A levels (β=174 (95% confidence interval: 110-234)) independent of body mass index, age, sex, fasting glucose, and triglycerides. Hepatic fetuin A mRNA levels correlated significantly with hepatic mRNA levels of key enzymes in lipid (sterol regulatory element-binding protein 1c, carnitine palmitoyltransferase 1) and glucose (phosphoenol pyruvate kinase 1, glucose-6-phosphatase) metabolism. Plasma fetuin A levels decreased significantly after metformin treatment compared with placebo (-40 ± 47 vs 15 ± 82 mg/l, P = 0.008). Metformin induced a dose-dependent decrease in fetuin A secretion in vitro. CONCLUSIONS Fetuin A levels were elevated in NAFLD. Hepatic expression of fetuin A correlated with key enzymes in glucose and lipid metabolism. Metformin decreased fetuin A levels in vitro.

Characteristics of glucose metabolism in Nordic and South Asian subjects with type 2 diabetes.

Background Insulin resistance and type 2 diabetes are more prevalent in people of South Asian ethnicity than in people of Western European origin. To investigate the source of these differences, we compared insulin sensitivity, insulin secretion, glucose and lipid metabolism in South Asian and Nordic subjects with type 2 diabetes. Methods Forty-three Nordic and 19 South Asian subjects with type 2 diabetes were examined with intra-venous glucose tolerance test, euglycemic clamp including measurement of endogenous glucose production, indirect calorimetry measuring glucose and lipid oxidation, and dual x-ray absorptiometry measuring body composition. Results Despite younger mean ± SD age (49.7±9.4 vs 58.3±8.3 years, p = 0.001), subjects of South Asian ethnicity had the same diabetes duration (9.3±5.5 vs 9.6±7.0 years, p = 0.86), significantly higher median [inter-quartile range] HbA1c (8.5 [1.6] vs 7.3 [1.6] %, p = 0.024) and lower BMI (28.7±4.0 vs 33.2±4.7 kg/m2, p<0.001). The South Asian group exhibited significantly higher basal endogenous glucose production (19.1 [9.1] vs 14.4 [6.8] µmol/kgFFM⋅min, p = 0.003). There were no significant differences between the groups in total glucose disposal (39.1±20.4 vs 39.2±17.6 µmol/kgFFM⋅min, p = 0.99) or first phase insulin secretion (AUC0–8 min: 220 [302] vs 124 [275] pM, p = 0.35). In South Asian subjects there was a tendency towards positive correlations between endogenous glucose production and resting and clamp energy expenditure. Conclusions Subjects of South Asian ethnicity with type 2 diabetes, despite being younger and leaner, had higher basal endogenous glucose production, indicating higher hepatic insulin resistance, and a trend towards higher use of carbohydrates as fasting energy substrate compared to Nordic subjects. These findings may contribute to the understanding of the observed differences in prevalence of type 2 diabetes between the ethnic groups.

LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro.

Aims/hypothesisActivation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus.MethodsPlasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro.ResultsOur major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR).Conclusions/interpretationOur findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Insulin Secretion in Subjects With Type 2 Diabetes and Vitamin D Deficiency: A Randomized Controlled Trial.

OBJECTIVE In observational studies, low vitamin D levels are associated with type 2 diabetes (T2D), impaired glucose metabolism, insulin sensitivity, and insulin secretion. We evaluated the efficacy of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with T2D and low vitamin D (25-hydroxyvitamin D [25(OH)D] <50 nmol/L). RESEARCH DESIGN AND METHODS Sixty-two men and women with T2D and vitamin D deficiency participated in a 6-month randomized, double-blind, placebo-controlled trial. Participants received a single dose of 400,000 IU oral vitamin D3 or placebo, and the vitamin D group received an additional 200,000 IU D3 if serum 25(OH)D was <100 nmol/L after 4 weeks. Primary end points were total Rd by euglycemic clamp with assessment of endogenous glucose production and first-phase insulin secretion by intravenous glucose tolerance test. RESULTS In the vitamin D group, the mean ± SD baseline serum 25(OH)D of 38.0 ± 12.6 nmol/L increased to 96.9 ± 18.3 nmol/L after 4 weeks, 73.2 ± 13.7 nmol/L after 3 months, and 53.7 ± 9.2 nmol/L after 6 months. The total exposure to 25(OH)D during 6 months (area under the curve) was 1,870 ± 192 and 1,090 ± 377 nmol/L per week in the vitamin D and placebo groups, respectively (P < 0.001). Insulin sensitivity, endogenous glucose production, and glycemic control did not differ between or within groups after treatment (P = 0.52). First-phase insulin secretion did not change significantly after treatment (P = 0.10). CONCLUSIONS Replenishment with a large dose of vitamin D3 to patients with T2D and vitamin D deficiency did not change insulin sensitivity or insulin secretion. These findings do not support such use of therapeutic vitamin D3 supplementation to improve glucose homeostasis in patients with T2D.

Adipose tissue distribution in relation to insulin sensitivity and inflammation in Pakistani and Norwegian subjects with type 2 diabetes

Abstract Immigrants from South Asia to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) associated with obesity. We investigated the relationship between diabetes and adipose tissue distribution in a group of younger T2DM subjects from Norway and Pakistan. Eighteen immigrant Pakistani and 21 Norwegian T2DM subjects (age 29–45, 49% men) were included. They underwent anthropometrical measurements including bioelectrical impedance analysis, CT scans measuring fatty infiltration in liver and adipose and muscle tissue compartments in mid-abdomen and thigh, a euglycemic clamp, and blood samples for serum insulin and plasma glucose, adipokines and inflammation markers. Adipose tissue distribution was similar in Norwegians and Pakistanis. Pakistanis, but not Norwegians, showed a negative correlation between insulin sensitivity and visceral adipose tissue (VAT, rs = − 0.704, p = 0.003). Subcutaneous adipose tissue (SAT) correlated to leptin in both Pakistanis and Norwegians (rs = 0.88, p < 0.001 and 0.67, p = 0.001). SAT also correlated to C-reactive protein (CRP) in the Pakistanis only (rs = 0.55, p = 0.03), and superficial SAT to Interleukin-1 receptor antagonist (IL-1RA) in Norwegians only (rs = 0.47, p = 0.04). In conclusion, despite similar adipose tissue distribution in the two groups Pakistanis were more insulin resistant, with a negative correlation of VAT to insulin sensitivity, not present in Norwegians. The correlation of adipose tissue to Leptin, CRP and IL-1RA showed ethnic differences.

Vitamin D and Insulin Action and Secretion - An Overview of Current Understanding and Future Perspectives

Impaired vitamin D status has been linked to the development of type 2 diabetes. This review summarises the current knowledge of the effects of vitamin D on insulin action and secretion. Animal and in vitro studies suggest an effect of vitamin D on insulin action and secretion. The effects of vitamin D status in humans are not as clear, however, and cross-sectional data on insulin sensitivity and secretion are inconclusive. Intervention studies are few and often suffer from inadequate design including short duration, low sample power, low dose of vitamin D or use of indirect measures of insulin sensitivity and secretion. Despite some plausible biological mechanisms for an effect of vitamin D on both insulin secretion and action, more evidence is needed to decide whether vitamin D plays an important role in the pathophysiology of type 2 diabetes.

Data on circulating leukocyte subpopulations and inflammatory proteins in children with familial hypercholesterolemia and healthy children

The data in this relies on a previous publication: “Altered leukocyte distribution under hypercholesterolemia: a cross-sectional study in children with familial hypercholesterolemia” (Christensen et al. 2016) [1]. In the present paper, whole blood leukocyte distribution and plasma inflammatory proteins were measured for association with cholesterol concentration and CRP in children with familial hypercholesterolemia (FH) and healthy children.

The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and negative subjects: A post-hoc analysis of the ORIGIN trial

We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti‐glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti‐GAD measured at baseline and 267 were anti‐GAD positive. The effects of insulin glargine versus standard care and of n‐3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti‐GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti‐GAD positive and anti‐GAD negative subjects. The incidence of the composite of cardiovascular death, non‐fatal myocardial infarction, or non‐fatal stroke did not differ between anti‐GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44‐1.44) or in anti‐GAD negative participants with a HR of 1.07 (0.96‐1.20) (P for interaction = 0.20).

Authors ' response to letter: ' Proper assessment of leptin results with confounders '

SIR: We thank Sertoglu and Tapan for their interest in our recently published article on adipose tissue distribution in relation to insulin resistance and infl ammation in Pakistani and Norwegian subjects with type 2 diabetes [1]. We agree that gender, other hormones, medication and diet might infl uence leptin levels. However, as leptin was not the main topic of our article, we chose not to discuss this in the paper. We are nevertheless happy to attach a few comments here. Even though gender is an important determinant of leptin levels, our cohorts were sex-matched in both ethnicities. Due to a limited total number of patients we did not perform separate analyses in men and women. All measurements were performed under standardized conditions, as described in [1]. More Pakistanis than Norwegians were on insulin treatment, but patients had been without short acting and NPH insulin for at least 12 hours prior to all measurements. Long acting insulin analogs were not in use in this patient group at the time of the study. We found no signifi cant correlation between plasma leptin and serum insulin levels ( r s 0.06). None of the patients used systemic glucocorticoid treatment. Inhaled or nasal glucocorticoids were used by two subjects in the Norwegian group and fi ve subjects in the Pakistani group; however we believe the confounding effect of this to be negligible. Inhaled beta adrenergic agonists were used by one Norwegian and two Pakistani patients. Unfortunately, we do not have suffi ciently detailed dietary data on our patients to allow analysis for fatty acid/ omega-3 consumption. We agree that the lack of signifi cant correlation between adipose tissue and Il-6 could have been discussed. We did not fi nd a signifi cant correlation between IL-6 and adipose tissue, although Spearman correlation coeffi cients in the range of 0.30 – 0.45 in the Pakistani group could indicate that this might have been due to lack of power. Leptin as a predictor of Il-6 levels as described by Stelzer et al. [2] was shown in adolescents under the age of 18, not in adults, and thought to be involved in the induction of obesity-related infl ammation. Our cohort is older, more obese and with established type 2 diabetes, which might explain the lack of correlation between leptin and Il-6.