Decrease of dipeptidyl peptidase 4 activity is associated with weight loss after bariatric surgery.

PURPOSE: Dipeptidyl peptidase 4 (DPP4) is expressed and secreted by adipocytes. DPP4 induces insulin resistance independently of its effect on glucagon-like peptide 1, thus it is conceivable that DPP4 directly contributes to metabolic dysfunction in patients with morbid obesity. The aim of this study was to investigate the impact of weight loss induced by bariatric surgery on DPP4 activity, and whether these changes are associated with improvements in markers of metabolic dysfunction and fatty liver disease. MATERIALS AND METHODS: We included 68 non-diabetic patients who underwent bariatric surgery. Serum DPP4 activity was measured using a fluorogenic substrate before and after surgery. RESULTS: Results: After a median follow-up period of 12 (IQR 11-17) months, median serum DPP4 activity decreased from 230 (IQR: 194-273) to 193 (164-252) pmol/min (p=0.012). The decrease in DPP4 activity was significantly correlated with decreases in BMI, improved cholesterol levels, reduced hepatic injury markers as well as improved post-prandial insulin sensitivity. After multivariable adjustment, ΔDPP4 activity remained significantly associated with Δcholesterol (beta=0.341, p=0.025), ΔLDL cholesterol (beta=0.350, p=0.019), Δgamma-glutamyltransferase (beta=0.323, p=0.040) and ΔMatsuda index (beta=-0.386, p=0.045). CONCLUSION: We demonstrated that weight loss induced by bariatric surgery results in decreased circulating DPP4 activity beyond the initial phase of weight loss. The associations between decreased DPP4 activity and improved cholesterol levels as well as hepatic injury markers point towards pleiotropic effects of DPP4 beyond glucose metabolism which warrant further investigation.

The right place for metformin today.

Metformin is the most widely used glucose lowering drug worldwide in the treatment of patients with type 2 diabetes, since we have experience with this drug for more than 60 years about the efficacy and safety. Metformin is very effective in HbA1c lowering associated with some weight loss, but does not increase risk for hypoglycemia. At the moment all guidelines in the world recommend to use metformin in monotherapy in patients with newly diagnosed diabetes or in combination with other antidiabetic drugs with documented CV (and renal) benefit in cardiovascular outcome trials (CVOT). Although a randomized placebo controlled CVOT with metformin is lacking, many observational studies in patients with coronary heart disease, heart failure and chronic kidney disease have demonstrated consistent beneficial effects. A recent metanalysis of 26 observational studies including 815 839 patients showed that metformin use was associated with a significantly lower rate of all-cause mortality (HR: 0.74; 95% CI: 0.68-0.81). Whether this very consistent reduction of all-cause mortality is related to the incidence/outcome of several cancers has still to be investigated. In the future early combination therapy of metformin e.g. with SGLT-2 inhibitors should be more often used.

Albuminuria in Patients with Morbid Obesity and the Effect of Weight Loss Following Bariatric Surgery.

BACKGROUND AND OBJECTIVES: Patients with morbid obesity are at an increased risk for cardiovascular and renal complications, which are not only linked to traditional cardiovascular risk factors. Thus, we evaluated (a) the prevalence of albuminuria in non-diabetic and diabetic morbidly obese patients and (b) the effect of weight loss following bariatric surgery. MATERIAL AND METHODS: We included 1307 patients (77% women, mean age 40 ± 12 years, BMI 45.6 ± 6.6 kg/m2) in a cross-sectional study. A subgroup (n = 318) was followed up for 2 years after bariatric surgery. Weight, cardiovascular risk markers and a 75-g glucose tolerance test were determined. Albuminuria was assessed by collecting 24-h urine on three consecutive days. RESULTS: In the cross-sectional study, the prevalence of microalbuminuria was 16.0% (n = 209), of macroalbuminuria 3.1% (n = 41). The chi-square for the association of albuminuria and diabetes was 31.937 (p < 0.001). Of all patients with albuminuria, 42.0% exhibited normal glucose tolerance. In a multivariate regression analysis, systolic blood pressure (beta = 0.236; p < 0.001), log fasting insulin (beta = 0.309; p < 0.001) and log 2-h postprandial insulin (beta = - 0.173; p = 0.033) were predictive risk factors for albuminuria. Longitudinally, albumin excretion decreased significantly from 11.1 (6.4, 18.4 mg/24 h) to 7.8 mg/24 h (4.9, 13.0 mg/24 h; p < 0.001). In the group with albuminuria preoperatively, albumin excretion decreased from 65.7 (38.2, 147.1 mg/24 h) to 13.5 mg/24 h (8.4, 36.8 mg/24 h; p < 0.001). After adjusting for age, sex and baseline albuminuria, patients with lower creatinine clearance showed a smaller decrease of albuminuria (beta = 0.117; p = 0.021). CONCLUSION: A substantial portion of patients with morbid obesity exhibits microalbuminuria, nearly half of those present with normal glucose tolerance. After weight loss, we found a significant decrease of albuminuria, potentially indicating or even contributing to the known reduction of cardiovascular mortality after bariatric surgery.

Frequency of Hypoglycaemia after Different Bariatric Surgical Procedures.

OBJECTIVES: The frequency of postprandial hypoglycaemia after different operative procedures of bariatric surgery (BS) is unknown, although this complication is potentially dangerous. Predictors and severity of hypoglycaemia after Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, and gastric banding were investigated in a large prospective study. METHODS: This study was performed at an excellence centre for BS at a tertiary care institution. Data of 333 patients (mean BMI: 44.9 ± 9.6 kg/m2; mean age: 40 ± 10 years; 80.7% women) were analysed in a prospective study with a 2-year observation period after BS. All patients underwent a 2-hour oral glucose tolerance test (OGTT) with measurements of blood glucose (BG) and insulin. For the purpose of this study, hypoglycaemia was defined as a post-challenge BG <2.8 mmol/L during the OGTT. RESULTS: 72 (25.6%) of 281 patients showed post-challenge hypoglycaemia after surgery. Hypoglycaemia was different after various procedures: 32.6% of patients after RYGB, 22.6% after sleeve gastrectomy, but only 2.3% after gastric banding had hypoglycaemia. In the whole group, patients with hypoglycaemia had lost more weight (p = 0.013), had a slightly greater decrease in BMI (p = 0.037), a greater change in 2-hour post-challenge BG (p = 0.001), and a smaller change in 1-hour post-challenge insulin (p = 0.004) compared to patients without hypoglycaemia. CONCLUSION: This prospective study shows a higher prevalence of severe hypoglycaemia (25.6%) after BS than anticipated from retrospective registers. A systematic evaluation of glucose and insulin levels by OGTT 2 years post-surgery may help to identify patients at increased risk for symptomatic and asymptomatic hypoglycaemia.

Unrecognised cardiovascular disease in type 2 diabetes: is it time to act earlier?

Cardiovascular disease (CVD) is the most significant prognostic factor in individuals with type 2 diabetes (T2D). However, a significant number of individuals may develop CVD that does not present with the classic angina-related or heart failure symptoms. In these cases, CVD may seem to be 'silent' or 'asymptomatic', but may be more accurately characterised as unrecognised diabetic cardiac impairment. An initial step to raise awareness of unrecognised CVD in individuals with T2D would be to reach a consensus regarding the terminology used to describe this phenomenon. By standardising the terminologies, and agreeing on the implementation of an efficient screening program, it is anticipated that patients will receive an earlier diagnosis and appropriate and timely treatment. Given the availability of anti-diabetic medications that have been shown to concomitantly reduce CV risk and mortality, it is imperative to improve early identification and initiate treatment as soon as possible in order to enable as many patients with T2D as possible to benefit.

Diabetes in the older patient: heterogeneity requires individualisation of therapeutic strategies.

Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.

Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery.

BACKGROUND: Postoperative micronutrient deficiency is a known side effect of bariatric surgery. In this study, we examined the prevalence of micronutrient deficiency in patients with morbid obesity (MO) preoperatively. METHODS: A total of 1732 patients with MO wishing to undergo bariatric surgery (age: 40 ± 12 years, mean BMI: 44 ± 9 kg/m2, means ± SD, 77.3% female) were analyzed in this cross-sectional examination. Iron state, vitamin B12, folic acid, 25hydroxy(OH)-vitamin D, PTH, vitamin A, and vitamin E levels were determined. Subsequently, patients underwent nutritional counseling and were substituted accordingly. RESULTS: A total of 63.2% (n = 1094) of the patients had a deficit in folic acid (< 5.3 ng/ml), 97.5% (n = 1689) in 25OHvitamin D (< 75 nmol/l), and 30.2% (n = 523) had a PTH elevation (> 56.9 pg/ml). A total of 5.1% (n = 88) of the patients presented with a deficit in vitamin B12 (< 188 pg/ml) and 6.2% (n = 107) in vitamin A (< 1.05 µmol/l). A total of 9.6% (n = 166) exhibited iron deficiency (ferritin < 15 µg/l). None of the patients had a deficit in vitamin E. There were no gender differences except for ferritin deficiency (women 11.8% vs. men 1.5%, p < 0.001). Patients in the highest BMI tertile had significantly more often a deficit in vitamin D (p = 0.033) and folic acid (p < 0.001). Patients in the lowest age tertile had significantly more often a deficit in folic acid (p < 0.001). CONCLUSIONS: Our data show a high prevalence of micronutrient deficiency in patients with morbid obesity preoperatively and emphasize the importance of exact preoperative evaluation and adequate substitution as well as postoperative surveillance.

Variability in and predictors of glycaemic responses after 24 weeks of treatment with exenatide twice daily and exenatide once weekly.

The range of glycated haemoglobin (HbA1c) responses and characteristics associated with above-average response to exenatide twice daily and once weekly were examined. Data were pooled from 8 exenatide-twice-daily and 5 exenatide-once-weekly studies. A baseline HbA1c-corrected measure of change in HbA1c after 24 weeks identified high, average and low responses. Multiple linear regression and multivariate generalized estimating equation models identified factors associated with high response. Among 2355 participants (exenatide twice daily, n = 1414; exenatide once weekly, n = 941), baseline HbA1c correlated with change in HbA1c (P < .0001). Across baseline HbA1c levels, the 25th to 75th percentile of HbA1c change ranged from -0.3% to -3.2% with exenatide twice daily and from -0.5% to -3.6% with exenatide once weekly. Asian ethnicity and older age were significantly associated with high response to exenatide twice daily; no factors were significantly associated with response to exenatide once weekly. These data provide clinically useful information for estimating the likelihood that, depending on baseline HbA1c, an individual can achieve HbA1c goals. The association between Asian ethnicity, age and high response to exenatide twice daily may relate to the specific effects of exenatide twice daily on postprandial glucose.

Inverse Relationship Between Organ-Specific Autoantibodies and Systemic Immune Mediators in Type 1 Diabetes and Type 2 Diabetes: Action LADA 11.

OBJECTIVE: We related organ-specific autoantibodies, including diabetes-associated autoantibodies (DAAs) and non-DAAs to systemic cytokines/chemokines in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: From the European Action LADA (latent autoimmune diabetes in adults) cohort, patients with adult-onset type 1 diabetes (n = 80, of whom 50 had LADA and 30 had classic type 1 diabetes) and type 2 diabetes (n = 626) were analyzed for DAAs (GAD antibody [GADA], IA-2 antigen, islet cell antibody, and zinc transporter T8), non-DAAs (transglutaminase, thyroid peroxide autoantibodies, parietal cell antibodies), and 10 immune mediator concentrations (measured by LUMINEX). RESULTS: Type 1 diabetes patients (whether having classic type 1 diabetes or LADA), apart from their clinical phenotype, could not be distinguished by either autoantibodies (both DAAs and non-DAAs) or immune mediators. In type 1 diabetes, most immune mediators (9 of 10) were negatively correlated with DAA titers. Type 2 diabetes patients, who by definition were without DAAs, had fewer non-DAAs (P < 0.0005), but had higher levels of proinflammatory immune mediators, especially compared with patients with type 1 diabetes who had high GADA titers (interleukin [IL]-6 [P < 0.001], soluble E-selectin [P < 0.01], and IL-1 receptor antagonist [P = 0.052], for trend). CONCLUSIONS: Patients with type 1 diabetes had more DAAs and non-DAAs than did those with type 2 diabetes, whereas the frequency and nature of these autoantibodies was broadly similar in classic type 1 diabetes and LADA. Systemic immune mediator levels, in the main, were negatively correlated with DAA titers, and, for some, were higher in patients with type 2 diabetes, especially when compared with patients who had high GADA titers. Differences in the clinical classification of diabetes are associated with graded differences in adaptive and innate immune reactivity.

Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study.

OBJECTIVE: The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated. RESULTS: Over 36 months, twice-daily exenatide was associated with improved body weight (-3.9 kg), waist circumference (-3.6 cm), systolic/diastolic BP (-2.5/-2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (-0.2 mmol/L), and hsCRP (-1.7 mg/L). Heart rate did not increase (-0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4%; P = 0.026) or lipid-lowering medication (8.4 vs 12.8%; P = 0.025). CONCLUSIONS: Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride. CLINICAL TRIAL REGISTRATION: NCT00359762, http://www.ClinicalTrials.gov.

The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway.

Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. METHODS: We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA(1c)) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886. FINDINGS: Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA(1c) was greater in patients in the liraglutide group (-1·48%, SE 0·05; n=386) than in those in the exenatide group (-1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08-0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. INTERPRETATION: Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes. FUNDING: Eli Lilly and Company and Amylin Pharmaceuticals LLC.

Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial.

BACKGROUND: Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. METHODS: We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762. FINDINGS: We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. INTERPRETATION: These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. FUNDING: Eli Lilly and Company; Amylin Pharmaceuticals.

Circulating angiopoietic cells and diabetic retinopathy in type 2 diabetes mellitus, with or without macrovascular disease.

PURPOSE: To investigate different types of circulating angiopoietic cells, such as vasculogenic circulating progenitor cells (CPCs), endothelial progenitor cells (EPCs), and mature EPCs (matEPCs) in patients with type 2 diabetes mellitus (T2DM), with or without diabetic retinopathy (DR) and with or without macrovascular disease (MVD). METHODS: One hundred twenty-six patients with T2DM-66 with MVD and 60 without MVD-were enrolled in a case-control study. MVD comprised coronary heart disease, peripheral arterial disease, stroke, or various combinations of those conditions. By a modified Early Treatment of Diabetic Retinopathy Study (ETDRS) classification, 55 patients were classified without DR (CO), 19 with mild nonproliferative DR (mNPDR), 16 with moderate-severe NPDR (msNPDR), 19 with early proliferative diabetic retinopathy (ePDR), and 17 with high-risk PDR (hrPDR). CPCs (CD34/CD133), EPCs (CD34/CD133/CD30), and matEPCs (CD34/CD133/CD309/CD31) were enumerated by flow cytometry. RESULTS: Patients with MVD CPCs, EPCs, and matEPCs showed a significant, stepwise decline with advancing stages of retinopathy. In contrast, in the patients without MVD, EPCs and matEPCs reached up to 56% of CPCs and 37% of EPCs. On the other hand, the percentage of EPCs and matEPCs was reduced to 5% of CPCs and EPCs each in MVD patients. Thus, the percentage of EPCs and matEPCs in comparison with that of CPCs and EPCs represented an 11- and 7-fold difference. CONCLUSIONS: The circulating angiopoietic CPCs, EPCs, and matEPCs in T2DM patients with DR had a different regulations, with increasing relative differences occurring in proliferative DR, apparently depending on the macrovascular comorbidities. Patients with MVD showed a strong retinopathy-stage-dependent depletion of all angiopoietic cells.

Elevated Fetuin-A concentrations in morbid obesity decrease after dramatic weight loss.

CONTEXT: Morbid obesity (MO) is a risk factor for cardiovascular morbidity, mortality, and diabetes, which can be effectively reduced by bariatric surgery. The liver-secreted protein Fetuin-A is elevated in insulin resistance, is an independent predictor of type 2 diabetes and is associated with atherosclerosis. OBJECTIVE: We studied Fetuin-A concentrations in patients with MO before and after weight loss induced by gastric bypass. DESIGN: We conducted a cross-sectional study and a 16-month longitudinal study. SETTING: This study was performed in secondary care. PATIENTS, SUBJECTS, AND INTERVENTION: We included 75 MO patients [65 women, body mass index (BMI) 45.6 ± 8.1 kg/m(2)] and 38 healthy controls (21 women, BMI 26.0 ± 5.5 kg/m(2)) in a cross-sectional study and investigated them before and about 16 months after gastric bypass surgery. MAIN OUTCOME MEASURES: Apart from measurements of blood pressure and routine laboratory parameters, a 75-g oral glucose tolerance test was performed. Insulin resistance was calculated by using homeostatic model assessment (HOMA). RESULTS: Fetuin-A levels were significantly higher in MO (877 ± 318 µg/ml) than in controls (295 ± 61 µg/ml; P < 0.001). After surgery-induced weight loss (BMI 31.6 ± 6.8 vs. 45.6 ± 8.1 kg/m(2); P < 0.001), HOMA (2.0 ± 1.2 vs. 6.6 ± 6.3; P < 0.001) and Fetuin-A (710 ± 350 vs. 877 ± 318 µg/ml; P < 0.001) decreased. Delta (Δ) Fetuin-A concentrations correlated with Δfasting insulin (r = 0.710; P = 0.001), Δ2-h insulin (r = 0.693; P = 0.005), and HOMA-insulin resistance (r = 0.684; P = 0.001). CONCLUSIONS: Fetuin-A is markedly increased in patients with MO. The reduction of Fetuin-A after weight loss could play an important role in the beneficial effects of gastric bypass surgery.

YKL-40 is elevated in morbidly obese patients and declines after weight loss.

BACKGROUND: Patients suffering from morbid obesity (MO) have an increased cardiovascular morbidity and mortality. This increased cardiovascular burden is believed to be caused by a sub-inflammatory state through an increased secretion of monocyte chemoattractant protein-1 (MCP-1) by the adipose tissue, resulting in insulin resistance (IR) and type 2 diabetes mellitus (T2DM). YKL-40, which is elevated in inflammatory processes in T2DM and IR and in ruptured plaques, might as well be involved in the increased cardiovascular burden of MO patients. The present study aims to study the level of YKL-40 in MO patients before and after weight loss as well as to investigate the relationship between YKL-40, IR, MCP-1, and obesity. METHODS: We investigated YKL-40 levels in serum samples of both 17 morbidly obese patients before and after bariatric surgery and 17 healthy controls. YKL-40 levels were determined in serum samples by enzyme-linked immunosorbent assay. RESULTS: After a mean follow-up of 17.4 months and a mean weight loss of 40 kg through bariatric surgery, YKL-40 levels declined by 30.5% (p = 0.027). Multiple linear regression analysis revealed that only preoperative MCP-1 values remained independently and significantly (p = 0.001) associated with preoperative YKL-40 levels. Moreover, delta (change) homeostasis model assessment of insulin resistance (HOMA-IR) values remained independently and significantly (p = 0.002) associated with delta YKL-40 levels. CONCLUSIONS: We show for the first time that elevated levels of YKL-40 in MO patients decreased after massive weight loss via bariatric surgery. YKL-40 was correlated with HOMA-IR and fasting insulin levels, indicating a role in developing processes of IR and T2DM. The tight association of MCP-1 (plaque development) and YKL-40 (plaque rupture) points to a central role of both proteins, contributing to the increased cardiovascular mortality in MO patients.

Increase of osteopontin plasma concentrations after bariatric surgery independent from inflammation and insulin resistance.

BACKGROUND: Osteopontin (OPN) is a multifunctional matrix glycoprotein associated with bone metabolism and has been linked to chronic inflammation, insulin resistance, and atherosclerosis. Diet-induced weight loss decreases elevated OPN concentrations in obese patients. The aim of the current study was to investigate the role of OPN after bariatric surgery, where not only improvements of chronic inflammation, insulin resistance and comorbidities, but also malabsorption and altered bone metabolism have been reported. METHODS: OPN plasma concentrations were determined in 31 morbidly obese patients (5 men, 26 women, BMI 46.2+/-7.1 kg/m2, age 41+/-11 years; mean+/-SD) before and 18 months after bariatric surgery, together with parameters of bone metabolism and inflammation. RESULTS: OPN concentrations increased by +20.3+/-26.6 ng/ml (mean+/-SD, p<0.01), concomitant to a weight loss of -38+/-22 kg, and a decrease in BMI by -13.1+/-7.7 kg/m2 (both p<0.01). HOMA-index improved from 5.2+/-3.4 to 1.5+/-1.0 (p<0.01). Calcium concentrations slightly decreased, and phosphate increased (-0.06+/-0.13 mmol/l and +0.08+/-0.16 mmol/l, respectively; both p<0.05), while 25-OH-Vitamin D3 remained unchanged and PTH tended to increase (+5.1+/-14.0 pg/ml, p=0.054). Monocyte chemoattractant protein 1 and interleukin 18 were significantly decreased and associated with HOMA both before and after bariatric surgery. DeltaOPN was correlated with DeltaPTH, but not with other parameters. CONCLUSIONS: OPN plasma concentrations increased concomitant to weight loss after bariatric surgery, which was independent from an improvement of insulin sensitivity and a decrease of inflammatory markers. Further studies are needed to differentiate whether these changes in bone metabolism after bariatric surgery are secondary to calcium deficiency or an adaptation to weight loss.

Ghrelin and obestatin levels in severely obese women before and after weight loss after Roux-en-Y gastric bypass surgery.

BACKGROUND: Ghrelin and obestatin are derived from the same gene but have different effects: Ghrelin stimulates appetite, and previous-albeit inconsistent-data show that obestatin may be involved in satiety. The present study was designed to test the hypothesis that Roux-en-Y gastric bypass (RYGB) surgery and/or the weight loss that reliably results from this procedure would alter levels of ghrelin and obestatin and ghrelin/obestatin ratios in a cohort of morbidly obese women. METHODS: This is a longitudinal follow-up study in 18 morbidly obese women (mean weight 131.2 kg, mean body mass index [BMI] 47.4). Clinical parameters and fasting serum concentrations of ghrelin, obestatin, triglycerides, low-density lipoprotein cholesterol, glucose, and insulin were measured before and 2 years after RYGB surgery, which was associated with body weight reductions of 41.5 +/- 11.6 kg (mean 62.5% excess weight loss). RESULTS: Ghrelin concentrations (-12%, p = 0.022) and ghrelin/obestatin ratios (-14%, p = 0.017) were lower after surgery than before, while obestatin levels did not change. Changes in ghrelin concentrations correlated with changes in insulin levels (r = 0.45, p = 0.011). Most cardiovascular risk factors studied improved postsurgically (p < 0.01). CONCLUSION: In contrast to previous weight loss studies involving gastric banding, ghrelin levels decreased and obestatin levels remained stable after massive weight loss in long-term follow-up. The favorable gastrointestinal hormone profiles observed are likely to contribute to the long-term weight loss success rate attributed to RYGB.

Correlation of different circulating endothelial progenitor cells to stages of diabetic retinopathy: first in vivo data.

PURPOSE: To investigate vasculogenic circulating progenitor cells (CPCs), endothelial progenitor cells (EPCs), and mature EPCs in patients with type 1 diabetes mellitus (T1DM) with or without diabetic retinopathy (DR). METHODS: A case-control study comparing 90 patients with T1DM with and without DR was performed. Patients were studied and staged for retinopathy according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. Ninety patients were included: 30 without DR (control [CO]), 30 with mild nonproliferative DR (mNPDR), 10 with moderate-severe NPDR (msNPDR), 10 with mild-moderate proliferative diabetic retinopathy (mmPDR), and 10 with high-risk PDR (hrPDR). CPCs (CD34/CD133), EPCs (CD34/CD133/CD309), and mature EPCs (CD34/CD133/CD309/CD31) were enumerated by flow cytometry. RESULTS: EPCs were reduced in mNPDR (114 +/- 66; P < 0.001) and msNPDR (77 +/- 40; P = 0.042) compared with CO (244 +/- 115). In contrast, EPCs were unchanged in mmPDR (248 +/- 155) compared with CO. Strikingly, EPCs were augmented in hrPDR (389 +/- 124) compared with all other stages. Numbers of undifferentiated progenitor cells (CPCs) did not differ among CO, mmPDR, and hrPDR. Augmentation (3x) of mature EPCs in hrPDR (325 +/- 118; P < 0.001) compared with CO (100 +/- 49) but against all other stages of DR was observed. The percentage of mature EPCs/EPCs was augmented in an ETDRS classification-dependent manner. CONCLUSIONS: In patients with T1DM with DR, EPCs undergo stage-related regulation. In nonproliferative retinopathy, a reduction of EPCs was observed, and in proliferative retinopathy, a dramatic increase of mature EPCs was observed.