A systematic review: the appraisal of the effects of metformin on lipoprotein modification and function.

AIMS: Metformin is a commonly prescribed anti-hyperglycaemic pharmacological agent, and it remains a staple in the management of type II diabetes. In addition to metformin's glucose lowering effects, research has indicated that metformin inhibits glycation-mediated and oxidative modification of lipoprotein residues. The purpose was to discuss the effects of metformin as it relates to high-density lipoprotein (HDL) and low-density lipoprotein (LDL) modification. MATERIALS AND METHODS: The purpose was to conduct a narrative and pragmatic review on the effects of metformin as it pertains to HDL and LDL modification. RESULTS: High-density lipoprotein (HDL) concentration is a quantitative measure and therefore does not provide insight into its function, which is a qualitative property. Dysfunctional HDLs are unable to carry out functions normally associated with HDL because they can be modified by glycating agents. Metformin may counteract HDL dysfunction by abating HDL modification. Reductions in HDL modification may improve reverse cholesterol transport ability and thus possibly diminish cardiovascular risk. Similarly, metformin-mediated attenuations in LDL modification may reduce their atherogenic potency. CONCLUSION: Metformin may partially ameliorate HDL dysfunction and reduce LDL modification by inhibiting alpha-dicarbonyl-mediated modification of apolipoprotein residues; consequently, the results are salient because cardiovascular disease incidence may be reduced given that reverse cholesterol transport activity predicts risk, and modified LDL are proatherogenic.

How safe is metabolic/diabetes surgery?

Although recent studies have shown the impressive antidiabetic effects of laparoscopic Roux-en-Y gastric bypass (LRYGB), the safety profile of metabolic/diabetes surgery has been a matter of concern among patients and physicians. Data on patients with type 2 diabetes who underwent LRYGB or one of seven other procedures between January 2007 and December 2012 were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database and compared. Of the 66 678 patients included, 16 509 underwent LRYGB. The composite complication rate of 3.4% after LRYGB was similar to those of laparoscopic cholecystectomy and hysterectomy. The mortality rate for LRYGB (0.3%) was similar to that of knee arthroplasty. Patients who underwent LRYGB had significantly better short-term outcomes in all examined variables than patients who underwent coronary bypass, infra-inguinal revascularization and laparoscopic colectomy. In conclusion, LRYGB can be considered a safe procedure in people with diabetes, with similar short-term morbidity to that of common procedures such as cholecystectomy and appendectomy and a mortality rate similar to that of knee arthroplasty. The mortality risk for LRYGB is one-tenth that of cardiovascular surgery and earlier intervention with metabolic surgery to treat diabetes may eliminate the need for some later higher-risk procedures to treat diabetes complications.

Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non-remission status after bariatric surgery.

AIM: To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months. METHODS: A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed. RESULTS: At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and ß-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced ß-cell function, lower triglyceride levels and fat loss. CONCLUSIONS: Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.

Gender-specific effects of oral hypoglycaemic agents on cancer risk in type 2 diabetes mellitus.

AIMS: To analyse the association between cancer incidence and oral diabetes therapy (biguanide, sulphonylurea, thiazolidinedione and meglitinide) in men and women with type 2 diabetes mellitus. METHODS: A retrospective analysis of the electronic health record-based Cleveland Clinic Diabetes Registry (25 613 patients) was cross-indexed with the histology-based tumour registry (48 051 cancer occurrences) over an 8-year period (1998-2006). Multiple imputations were used to account for missing data. Cox regression with propensity scores was used to model time for the development of incident cancer in each of the imputed datasets and the results were pooled. RESULTS: During 51 994 person follow-up years, 892 incident cancer cases were identified; prostate (14.5%) and breast (11.7%) malignancies were most frequent. In women, thiazolidinedione use was associated with a 32% decreased cancer risk compared with sulphonylurea use [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.48-0.97, in the adjusted analysis]. Comparison of insulin secretagogues (sulphonylurea and meglitinide) versus insulin sensitizers (biguanide and thiazolidinedione) demonstrated a 21% decreased cancer risk in insulin sensitizers [HR 0.79 (95% CI 0.64-0.98) in the adjusted analysis]. Oral diabetes therapy showed no significant difference in men. Adjustments were made for age, body mass index (BMI), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, coronary heart disease (CHD), diabetes oral monotherapy, race, gender, haemoglobin A1c, statin use, income, insulin use, glomerular filtration rate (GFR), new diabetes status, prior cancer, prior cerebrovascular accident (stroke or transient ischaemic event), systolic/diastolic blood pressure, tobacco use (ever/never) and the propensity score for receiving a biguanide. CONCLUSIONS: Oral insulin sensitizers, particularly thiazolidinedione, are associated with decreased malignancy risk in women with type 2 diabetes mellitus.

Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN: STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS: Fifty-three (body mass index: 36±3 kg m(-2), age: 49±9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7±2%) were randomized to IMT, IMT+RYGB or IMT+SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS: RYGB and SG reduced body fat comparably (15-23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P<0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P=0.32). Fasting AG was reduced fourfold following SG (P<0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P=0.01 vs SG, P=0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r=-0.32, P<0.02) and decreased android fat (r=0.38; P<0.006). CONCLUSIONS: Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery.

Ghrelin suppression is associated with weight loss and insulin action following gastric bypass surgery at 12 months in obese adults with type 2 diabetes.

Roux-en-Y gastric bypass (RYGB) surgery reverses type 2 diabetes mellitus (T2DM) in approximately 80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB surgery. Changes in ghrelin, body weight, glucagon-like polypeptide-1 (GLP-1, glucose tolerance and insulin sensitivity (IS) were measured. At 1 month, body weight, glycaemia and IS were improved, while ghrelin concentrations were reduced (p < 0.05). After 12 months, body weight and fasting glucose were reduced (30 and 16%, respectively; p < 0.05) and IS was enhanced (threefold; p < 0.05). Ghrelin suppression improved by 32% at 12 months (p < 0.05), and this was associated with weight loss (r = 0.72, p = 0.03), enhanced IS (r = -0.78, p = 0.01) and peak postprandial GLP-1 (r = -0.73, p = 0.03). These data suggest that postprandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.

Clinical considerations for the management of residual diabetes following bariatric surgery.

Residual diabetes following bariatric surgery is increasingly recognized despite initial weight loss. It occurs more commonly following banding and sleeve gastrectomy procedures than with gastric bypass, is associated with long duration and advanced stages of diabetes and is exacerbated by weight regain. Long-term diabetes management following various gastric restrictive surgery (i.e. lap banding) requires targeting weight loss, insulin resistance and insulin secretion defects with antidiabetic agents that have weight negative or neutral effects. In contrast, re-emergence of hyperglycaemia following gastric bypass may require targeting ß-cell failure with insulin analogues. Revisional bariatric surgery is also a consideration. On the basis of our experience, we propose a clinical approach for long-term management of diabetes following various bariatric procedures in the presence and absence of weight regain that is based on recognized pathophysiological effects of these procedures on diabetes remission.

Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes.

CONTEXT: Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear. OBJECTIVE: To examine glucose metabolism and beta-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery. DESIGN: Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial. PATIENTS: In all, 16 T2DM patients (9 males and 7 females, 52+/-14 years, 47+/-9 kg m(-2), HbA1c 7.2+/-1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery. OUTCOME MEASURES: Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery. RESULTS: At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95+/-3 mg 100 ml(-1)). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and beta-cell sensitivity to glucose only after RYGB (P<0.05). CONCLUSION: RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and beta-cell responsiveness to glucose, in part because of an incretin effect.

All-cause mortality risk predictors in a preventive cardiology clinic cohort-examining diabetes and individual metabolic syndrome criteria: a PRECIS database study.

AIM: It is unclear if metabolic syndrome (MS) is equal to type 2 diabetes mellitus (DM) in predicting cardiovascular disease (CVD) risk and mortality, and its prognostic value compared to Framingham risk model is controversial. We assessed mortality, CVD risk and prevalence in patients with DM and those without DM who met National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) MS criteria compared to patients without DM or MS. We analysed which component(s) of NCEP MS criteria had greatest predictive value for mortality. METHODS: Retrospective cohort analysis of 1189 DM, 1241 MS (fasting glucose < 126 mg/dl and > or =3 components NCEP-ATP III criteria) and 3023 non-DM/non-MS patients presented for baseline visit to Preventive Cardiology clinic between 1995 and 2006, whose subsequent vital status was determined for a median of 5.2 years. The association with mortality was determined by Cox proportional hazards models. The incremental predictive value of MS components was performed by concordance indexes. RESULTS AND CONCLUSION: DM group had highest mortality and CVD prevalence vs. MS and non-DM/non-MS groups respectively (all p < or = 0.001). Patients with MS criteria had increased CVD prevalence and 1.5-fold increased mortality vs. non-DM/non-MS group (all p < 0.02). In NCEP MS criteria, only fasting glucose significantly predicted mortality in MS group (p = 0.05). MS criteria predicted CVD prevalence in a parallel manner to Framingham risk score assessment. In a cohort of patients at high risk for CVD whose risk factors are being treated, presence of diabetes in addition to plasma glucose within NCEP MS criteria strongly predicts all-cause mortality.

Serum uric acid, mortality and glucose control in patients with Type 2 diabetes mellitus: a PreCIS database study.

AIMS: To determine the association of serum uric acid with all-cause mortality and hyperglycaemia in patients with Type 2 diabetes. METHODS: Retrospective cohort analysis of 535 consecutive patients who had uric acid determinations between 1998 and 2004 and whose subsequent vital status was determined at a median of 4.5 years. The association with mortality was analysed with Cox proportional hazards models. The incremental predictive value of uric acid was examined with concordance indexes. The proportional risk of mortality was represented with the Kaplan-Meier survival curves by uric acid quartiles. RESULTS: We studied 370 men and 165 women aged 59.3 +/- 11.5 years. Mean uric acid was 371.7 +/- 106.2 micromol/l. Patients with glycated haemoglobin (HbA(1c)) > or = 9% had lower uric acid vs. the rest (342.2 +/- 112.1 vs. 383.5 +/- 106.2, P = 0.002). Overall mortality was 10.8%. For each 59 micromol/l increase in uric acid there was a 41% increase in risk of death (unadjusted analysis). The association of uric acid with mortality remained after adjustment for covariates (hazard ratio = 1.21, 95% confidence interval 1.07-1.45) and after gender subanalyses. Uric acid increased the accuracy of prediction when added to a model including Framingham risk factors, components of metabolic syndrome and fibrinogen (P = 0.03). Mortality was higher in patients taking diuretics vs. the rest (15.9 vs. 7.3%), but uric acid predicted mortality in both subgroups. CONCLUSIONS: Serum uric acid predicts mortality in Type 2 diabetic patients regardless of gender, HbA(1c), renal function and diuretic use. Intervention studies should determine whether uric acid is a potential therapeutic target or only a marker of mortality risk.