Sarah L. Prior

Does bariatric surgery adversely impact on diabetic retinopathy in persons with morbid obesity and type 2 diabetes? A pilot study

AIMS To assess the incidence and progression of diabetic retinopathy (DR) 12 months post bariatric surgery in persons with morbid obesity and type 2 diabetes. METHODS A retrospective pilot analysis of electronic hospital records between 1998 and 2012. RESULTS 40 of 148 subjects had pre- and post-surgery DR screening. Of those without DR pre-surgery 1.5% (n = 26) progressed to minimum background DR (BDR) post surgery. Those with minimum BDR (n = 9) pre-surgery revealed no progression, with 55.6% (n = 5) showing evidence of regression. One person with moderately severe BDR and two with pre-proliferative DR (PPDR) prior to surgery experienced progression. Two persons with PPDR prior to surgery remained under the hospital eye services and were therefore not eligible to be re-assessed by the screening service. CONCLUSIONS There was a low incidence of new DR and progression of DR in those either without evidence of retinopathy or with minimal BDR prior to surgery with some subjects showing evidence of regression. There was however a risk of progression of DR in those with moderate BDR or worse, and should therefore be monitored closely post-surgery.

Association between the rs4880 superoxide dismutase 2 (C>T) gene variant and coronary heart disease in diabetes mellitus.

Mitochondrial superoxide dismutase 2 (SOD2) is an endogenous anti-oxidant enzyme. The rs4880 gene variant results in a C>T substitution, influencing SOD enzymatic activity. This variant has been associated with micro- and macro-vascular complications in diabetes mellitus. Our aim was to examine the association between this variant and coronary heart disease (CHD) risk in a cross-sectional sample of subjects with diabetes. 776 Caucasian subjects with diabetes were genotyped. CHD risk, oxidised-LDL and plasma total anti-oxidant status (TAOS) were analysed in relation to genotype. In females, the TT genotype was associated with CHD (CC/CT/TT: No CHD vs. CHD: 22.4/56.0/21.6% vs. 12.0/50.0/38.0%, p=0.03; for CC/CT vs. TT, p=0.01). The odds ratio for CHD associated with the TT genotype compared to CC/CT was 2.22 [95%CI: 1.17-4.24], p=0.01. The TT genotype was also associated with significantly lower plasma TAOS. In males, no association was observed between genotype and CHD risk, but CHD was significantly associated with age, lower HDL, higher triglycerides, higher BMI and cigarette smoking. The TT genotype of this variant is associated with increased CHD risk and lower plasma anti-oxidant defences in females with diabetes. This modest genotype-effect is not apparent in males where traditional risk factors may play a greater role.

Adiponectin, total antioxidant status, and urine albumin excretion in the low-risk "Golden Years" type 1 diabetes mellitus cohort

Adiponectin is associated with inflammation and oxidative stress. Levels are reduced in type 2 diabetes mellitus and coronary heart disease. Conversely, levels are elevated in type 1 diabetes mellitus (T1DM) and associated with microalbuminuria and diabetic nephropathy. An explanation may be that elevated adiponectin in T1DM represents a beneficial counterregulatory response to disease. Our aim was to examine adiponectin in relation to urinary albumin excretion and plasma total antioxidant status (TAOS) in subjects with long-standing T1DM. Serum adiponectin and plasma TAOS were measured in 338 samples from the Golden Years cohort. These subjects have T1DM for at least 50 years and are at low risk of complications. Subjects were divided into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. Adiponectin was elevated in women (20.53 ± 5.94 vs 11.8 ± 3.6 mg/L, P < .001); therefore, the samples were sex stratified. Within men, adiponectin was higher in those with macroalbuminuria (normoalbuminuria vs microalbuminuria vs macroalbuminuria: 10.97 ± 3.26 vs 11.55 ± 3.50 vs 23.63 ± 7.07 mg/L, P = .002). In women, no difference was observed (20.48 ± 5.61 vs 20.75 ± 7.04 vs 29.62 ± 7.81 mg/L, respectively; P = .42). Plasma TAOS did not differ by groups. The correlation between adiponectin and TAOS showed a linear increase from normoalbuminuria, microalbuminuria, to macroalbuminuria in men (r = 0.33, P = .001; r = 0.48, P < .001; r = 0.59, P = .04) and women (r = 0.25, P = .01; r = 0.63, P < .001; r = 0.79, P = .08). Adiponectin was higher in women. Within men, levels were significantly higher in the presence of macroalbuminuria. In both sexes, adiponectin and TAOS were correlated, which was most marked with micro-/macroalbuminuria. The increase in adiponectin in the face of an insult may be a compensatory mechanism to reduce oxidative burden.

Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus

AIM To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin. METHODS A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F(2)-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)). RESULTS Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress. CONCLUSION Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress.

Temporal changes in glucose homeostasis and incretin hormone response at 1 and 6 months after laparoscopic sleeve gastrectomy

BACKGROUND Bariatric surgery is an effective treatment for morbid obesity. Current literature reports significant improvements in glucose homeostasis after malabsorptive surgery. There is limited evidence on the effects of laparoscopic sleeve gastrectomy (SG) on glucose-insulin homeostasis and postoperative incretin hormone response. The objective of this study was to examine the metabolic effects of SG on temporal changes in insulin and glucose homeostasis, incretin hormones and hepatic insulin clearance in patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM). METHODS A nonrandomized prospective study comprising 22 participants undergoing SG (body mass index [BMI] 50.1 kg/m(2), glycated hemoglobin [HbA1c] 53 mmol/mol) and 15 participants undergoing biliopancreatic diversion (BPD) (BMI 62.1 kg/m(2), HbA1c 58 mmol/mol). Serial measurements of glucose, insulin, C-peptide, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 minutes. RESULTS Within the SG group, significant improvements were observed respectively at 1 and 6 months in glucose control (HbA1c: -0.9%, -1.3%), measures of insulin sensitivity (fasting insulin: -4.8 mU/L, -8.5 mU/L; fasting C-peptide: -0.6 pmol/L, -1.1 pmol/L; Homeostasis Model Assessment [HOMA-IR]: -0.144, -0.174; HOMA %S:+29.6,+92.4), hepatic insulin clearance (+0.07,+0.13) and postprandial GLP-1 response (AUC0-30 pmol h L(-1):+300,+331, AUC0-60:+300,+294, AUC0-120:+316,+295). These results were comparable to the BPD group. CONCLUSIONS SG is associated with significant early improvements in insulin sensitivity and incretin hormone response and results in significant improvements in IGT/T2 DM.

Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes

BACKGROUND Bariatric surgery is an effective treatment for morbid obesity. Obesity and type 2 diabetes are associated with chronic inflammation. There is lack of data examining the effects of sleeve gastrectomy (SG) on inflammatory biomarkers. Our aim was to study the effects of SG on specific cytokines associated with obesity including interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, adiponectin, and C-reactive protein (CRP) preoperatively, 1 and 6 months after surgery. METHODS A nonrandomized prospective study comprising of 22 participants with impaired glucose homeostasis and type 2 diabetes undergoing SG (body mass index 50.1 kg/m(2), glycated hemoglobin [HbA1c] 53 mmol/mol). Serial measurements of IL-6, IL-10, leptin, adiponectin, and CRP were performed during oral glucose tolerance testing preoperatively, 1 and 6 months postoperatively. RESULTS We observed significant improvements at 1 and 6 months in leptin (P≤.001) and CRP (P = .003) after SG. We also observed a significant reduction in IL-6 at 6 months (P = .001). No statistically significant differences were observed for adiponectin and IL-10. CONCLUSION This study is the first to examine the detailed changes in the inflammatory cytokines after SG. Our study shows significant improvements in the inflammatory biomarkers after SG in patients with impaired glucose homeostasis and type 2 diabetes.

Use of a patient linked data warehouse to facilitate diabetes trial recruitment from primary care

Recruitment into clinical trials from primary care may be difficult. Our aim was to use the Secure Anonymised Information Linkage (SAIL) databank to identify potential participants for two factitious trials. We identified 284 and 711 participants for each study (population=250,086). This method appears promising in identifying trial participants.

Association between the adiponectin promoter rs266729 gene variant and oxidative stress in patients with diabetes mellitus

AIMS Low levels of adiponectin are associated with type 2 diabetes and coronary heart disease (CHD). Recent evidence also suggests that low levels of adiponectin are associated with increased oxidative stress. Our aim was to examine the association between the rs266729 promoter gene variant (-11377C > G) and plasma markers of oxidative stress in diabetes subjects. METHODS AND RESULTS Seven hundred and sixty-seven Caucasian subjects with diabetes were successfully genotyped (CC/CG/GG). Genotype data were analysed in relation to plasma total antioxidant status (TAOS) and Oxidized-LDL (Ox-LDL). Plasma adiponectin measurements were available in 206 samples. There was a significant association between genotype and plasma TAOS (CC: 42.1 +/- 13.4% vs. CG: 42.0 +/- 12.0% vs. GG: 47.9 +/- 12.0%, P = 0.02; for CC/CG vs. GG, P = 0.006). With respect to Ox-LDL, CC subjects had 8% higher plasma Ox-LDL compared with CG/GG [CC vs. CG vs. GG: 48.5 (36.3-60.2) U/L vs. 44.8 (35.6-54.1) U/L vs. 44.9 (41.2-49.1) U/L, for CC vs. CG/GG P = 0.03]. For plasma adiponectin, GG subjects had the highest levels [CC vs. CG vs. GG: 8.18 (5.69-15.38) microg/mL vs. 7.12 (5.34-12.97) microg/mL vs. 11.84 (6.98-25.25) microg/mL, P = 0.09; for CC/CG vs. GG, P = 0.05]. CONCLUSION This study shows an association between a promoter variant in the adiponectin gene and plasma markers of oxidative stress. In line with previous studies, this work supports an antioxidant role for adiponectin which may explain its cardioprotective effect. Further prospective study is necessary to explore the effect of this gene variant in diabetes in relation to CHD risk and oxidative stress.

A study of mitochondrial DNA D-loop mutations and p53 status in nonmelanoma skin cancer.

Background  Mitochondrial DNA (mtDNA) displacement‐loop (D‐loop) mutations have previously demonstrated potential as smoking‐induced biomarkers in oral squamous cell carcinoma (SCC). Additionally, they have been observed in SCC and basal cell carcinoma of nonmelanoma skin cancer (NMSC). However, they have not been examined in the SCC precursor lesions, Bowen disease or actinic keratosis.

Association of the adiponectin rs266729 C > G variant and coronary heart disease in the low risk ‘Golden Years’ type 1 diabetes cohort

The C-allele of rs266729 is associated with CHD, while the G-allele of rs17300539 is associated with metabolic traits. We examined these in type 1 diabetes. For rs266729, the C-allele was associated with 8-fold increase in CHD. For rs17300539, the G-allele was associated with increases in triglycerides and waist circumference.