Insulin-Like Growth Factor 1 Predicts Post-Load Hypoglycemia following Bariatric Surgery: A Prospective Cohort Study

<div><p>Postprandial hypoglycemia is a complication following gastric bypass surgery, which frequently remains undetected. Severe hypoglycemic episodes, however, put patients at risk, e.g., for syncope. A major cause of hypoglycemia following gastric bypass is hyperinsulinemic nesidioblastosis. Since pancreatic islets in nesidioblastosis overexpress insulin-like growth factor 1 (IGF-1) receptor α and administration of recombinant IGF-1 provokes hypoglycemia, our main objective was to investigate the occurrence of post-load hypoglycemia one year after bariatric surgery and its relation to pre- and post-operative IGF-1 serum concentrations. We evaluated metabolic parameters including 2 h 75 g oral glucose tolerance test (OGTT) and measured IGF-1 serum concentration in thirty-six non-diabetic patients (29 f/7 m), aged 41.3±2.0 y with a median (IQR) BMI of 30.9 kg/m² (27.5–34.3 kg/m²), who underwent elective bariatric surgery (predominantly gastric bypass, 83%) at our hospital. Post-load hypoglycemia as defined by a 2 h glucose concentration <60 mg/dl was detected in 50% of patients. Serum insulin and C-peptide concentration during the OGTT and HOMA-IR (homeostatic model assessment–insulin resistance) were similar in hypoglycemic and euglycemic patients. Strikingly, pre- and post-operative serum IGF-1 concentrations were significantly higher in hypoglycemic patients (p = 0.012 and p = 0.007 respectively). IGF-1 serum concentration before surgery negatively correlated with 2 h glucose concentration during the OGTT (rho = −0.58, p = 0.0003). Finally, IGF-1 serum concentrations before and after surgery significantly predicted post-load hypoglycemia with odds ratios of 1.28 (95%CI:1.03–1.55, p = 0.029) and 1.18 (95%CI:1.03–1.33, p = 0.015), respectively, for each 10 ng/ml increment. IGF-1 serum concentration could be a valuable biomarker to identify patients at risk for hypoglycemia following bariatric surgery independently of a diagnostic OGTT. Thus, IGF-1 testing could help to prevent a significant complication of gastric bypass surgery.</p></div

Post-operative OGTT glucose, insulin and C-peptide concentration in patients with euglycemia and hypoglycemia.

<p>(A) Glucose, (B) insulin and (C) C-peptide concentrations during the course of the post-operative 2 h OGTT in patients with euglycemia (n = 17, full lines) and patients with post-load hypoglycemia (n = 18, dashed lines). Differences between pre and post-operative values were calculated with paired t-test. Differences between patients with euglycemia and hypoglycemia were calculated by unpaired student's t-test.*p<0.05.</p

Characteristics of obese patients before and one year after bariatric surgery.

a<p>Metabolic syndrome was defined according to IDF criteria;</p><p>ALT, alanine transaminase; BP, blood pressure; FLI, fatty liver index; GGT, gamma-glutamyl-transferase; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol, WHR, waist to hip ratio.</p

Glucose, insulin and C-peptide concentration during pre-operative and post-operative OGTT.

<p>(A) Glucose concentrations during the course of the pre-operative 2 h OGTT (n = 35, full lines) compared to the post-operative OGTT (n = 35, dashed lines). (B) Histogram of post-operative 2 h glucose concentrations during the OGTT (n = 35). Post-load hypoglycemia was defined by a 2 h glucose concentration<60 mg/dl. (C) Insulin and (D) C-peptide concentrations during the course of the pre-operative 2 h OGTT (n = 35, full lines) compared to the post-operative OGTT (n = 35, dashed lines).</p

IGF-1 in patients with euglycemia and post-load hypoglycemia at 2 h during the post-operative OGTT.

<p>(A) Box-plots of pre- and post-operative serum IGF-1 concentrations in patients with euglycemia (n = 17, black bars) and post-load hypoglycemia (n = 18, white bars). Outliers are represented by dots. (B) Pre-operative serum IGF-1 concentration plotted against 2 h glucose concentration during the post-operative OGTT (n = 35). (C) Post-operative serum IGF-1 concentration plotted against 2 h glucose concentration during the post-operative OGTT (n = 35). (D) ROC-AUC curve for detecting post-load hypoglycemia according to pre-operative IGF-1 concentration (n = 35). Differences between IGF-1 concentrations between the two groups were calculated by unpaired student's t-test. The association between pre- and post-operative serum IGF-1 concentration and post-operative 2 h glucose concentration during the OGTT was analyzed using Spearman's rank correlation,*p<0.05.</p

Treatment with n-3 Polyunsaturated Fatty Acids Overcomes the Inverse Association of Vitamin D Deficiency with Inflammation in Severely Obese Patients: A Randomized Controlled Trial

<div><p>Obesity affects the vitamin D status in humans. Vitamin D and long-chain n-3 polyunsaturated fatty acids (PUFA) provide benefit for the prevention of fractures and cardiovascular events, respectively, and both are involved in controlling inflammatory and immune responses. However, published epidemiological data suggest a potential interference of n-3 PUFA supplementation with vitamin D status. Therefore, we aimed to investigate in a randomized controlled clinical trial whether treatment with long chain n-3 PUFA affects vitamin D status in severely obese patients and potential interrelations of vitamin D and PUFA treatment with inflammatory parameters. Fifty-four severely obese (BMI≥40 kg/m2) non-diabetic patients were treated for eight weeks with either 3.36 g/d EPA and DHA or the same amount of butter fat as control. Changes in serum 25-hydroxy-vitamin D [25(OH)D] concentrations, plasma fatty acid profiles and circulating inflammatory marker concentrations from baseline to end of treatment were assessed. At baseline 43/54 patients were vitamin D deficient (serum 25(OH)D concentration <50 nmol/l). Treatment with n-3 PUFA did not affect vitamin D status (<em>P</em> = 0.91). Serum 25(OH)D concentration correlated negatively with both IL-6 (<em>P</em> = 0.02) and hsCRP serum concentration (<em>P</em> = 0.03) at baseline. Strikingly, the negative correlations of 25(OH)D with IL-6 and hsCRP were lost after n-3 PUFA treatment. In conclusion, vitamin D status of severely obese patients remained unaffected by n-3 PUFA treatment. However, abrogation of the inverse association of 25(OH)D concentration with inflammatory markers indicated that n-3 PUFA treatment could compensate for some detrimental consequences of vitamin D deficiency.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/show/NCT00760760">NCT00760760</a></p> </div

Characteristics of vitamin D-deficient and non-deficient study subjects at baseline.

1<p>Data presented as mean ± SEM for normally distributed data, otherwise median (IQR). No statistical significant differences between the analyzed parameters in vitamin D deficient and non-deficient patients were found, except for age plasma interleukin-6 concentration, indicated by asterisk.</p>*<p>(both <i>P</i> = 0.04, calculated by ANOVA and Mann-Whitney-U Test).</p><p>BMI, body mass index; hsCRP, high sensitive C-reactive protein; PTH, parathyroid hormone; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; MUFA, sum of all detected monounsaturated fatty acids; VDBP, vitamin D binding protein.</p

CONSORT flowchart, adapted from [21].

<p>CONSORT flowchart, adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054634#pone.0054634-Itariu1" target="_blank">[21]</a>.</p

Vitamin D, n-3 PUFA and inflammation.

<p>A, B. Correlations of serum 25(OH)D concentrations with IL-6 and EPA in severely obese patients at baseline. Serum 25(OH)D concentrations of obese patients (n = 54), plotted against (A) plasma IL-6 concentration and (B) eicosapentaenoic acid (EPA) in plasma phospholipids at baseline. Statistical analysis was performed by Spearman's rank correlation test. C. The effect of long chain n-3 PUFA treatment on serum 25(OH)D concentrations. The difference (Δ) between serum 25(OH)D concentration at the end of treatment vs. its baseline value in both n-3 PUFA treated patients (n = 26) and controls (n = 28) was not statistically significant (<i>P</i> = 0.58 in ANOVA). D, E. Correlation of serum 25(OH)D concentrations with IL-6 in severely obese n-3 PUFA and control treated patients at study end. Serum 25(OH)D concentration of (D) n-3 PUFA treated patients (n = 26) and (E) controls (n = 28) plotted against plasma IL-6 concentration at the end of the intervention. Statistical analysis was performed by Spearman's rank correlation.</p

Selective targeting OPN fragments with antibodies.

<p>(A) ELISA data of mAb 21–5 (white bars) and mAb 9–3 (hatched bars) against flOPN, mOPN, and tOPN. OPN bound antibodies were detected with HRP-labeled anti-mouse antibodies. OD405 nm represents the ABTS substrate consumption after incubating 30 minutes in arbitrary units. Depicted are the means ± SD of duplicates of a repeated experiment. (B) Cellular adhesion in percent of HEK 293 cells at 10 and 30 nM coated recombinant OPN form. Plates were preincubated either with 5 μg/ml isotype control (black bars), mAb 21–5 (white bars) or mAb 9–3 (hatched bars) antibodies. Depicted are the means ± SEMs of 3 independent experiments with triplicates. * indicates significant reduction of cellular adhesion in comparison to the isotype control.</p