Danville, PA, United States
Danville, PA, United States

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Wood G.C.,Institute of Obesity | Gerhard G.S.,Institute of Obesity | Gerhard G.S.,Pennsylvania State University | Benotti P.,Institute of Obesity | And 8 more authors.
Annals of Surgery | Year: 2015

Objective: Themain goal of this studywas to determine the effects of incretins on type 2 diabetes (T2D) remission after Roux-en-Y gastric bypass (RYGB) surgery for patients taking insulin. Background: Type 2 diabetes is a chronic diseasewith potentially debilitating consequences. RYGB surgery is one of the few interventions that can remit T2D. Preoperative use of insulin, however, predisposes to significantly lower T2D remission rates. Methods: A retrospective cohort of 690 T2D patients with at least 12 months follow-up and available electronic medical records was used to identify 37 T2D patients who were actively using a Glucagon-like peptide 1 (GLP-1) agonist in addition to another antidiabetic medication, during the preoperative period. Results: Here, we report that use of insulin, along with other antidiabetic medications, significantly diminished overall T2D remission rates 14 months after RYGB surgery (9%) compared with patients not taking insulin (56%). Addition of the GLP-1 agonist, however, increased significantly T2D early remission rates (22%), compared with patients not taking the GLP-1 agonist (4%). Moreover, the 6-year remission rates were also significantly higher for the former group of patients. The GLP-1 agonist did not improve the remission rates of diabetic patients not taking insulin as part of their pharmacotherapy. Conclusions: Preoperative use of antidiabetic medication, coupled with an incretin agonist, could significantly improve the odds of T2D remission after RYGB surgery in patients also using insulin. Copyright © 2014 by Lippincott Williams & Wilkins.


Gerhard G.S.,Weis Center for Research | Gerhard G.S.,Institute of Obesity | Styer A.M.,Weis Center for Research | Wood G.C.,Institute of Obesity | And 7 more authors.
Diabetes Care | Year: 2013

OBJECTIVE - Roux-en-Y gastric bypass (RYGB) in humans can remit type 2 diabetes, but the operative mechanism is not completely understood. In mice, fibroblast growth factor (FGF) 15 (FGF19 in humans) regulates hepatic bile acid (BA) production and an also resolve diabetes. In this study, we tested the hypothesis that the FGF19-BA pathway plays a role in the remission of human diabetes after RYGB surgery. RESEARCH DESIGN AND METHODS - Cohorts of diabetic and nondiabetic individuals of various body weights were used. In addition, RYGB patients without diabetes (No- Diabetes), RYGB patients with diabetes who experienced remission for at least 12 months after surgery (Diabetes-R), and RYGB patients with diabetes who did not go into remission after surgery (Diabetes-NoR) were studied. Circulating FGF19 and BA levels, hepatic glycogen content, and expression levels of genes regulating the FGF19-BA pathway were compared among these Groups of patients using pre- and postoperative serum samples and intraoperative liver biopsies. RESULTS - Preoperatively, patients with diabetes had lower FGF19 and higher BA levels than nondiabetic patients, irrespective of body weight. In diabetic patients undergoing YGB, lower FGF19 levels were significantly correlated with increased hepatic expression of the cholesterol 7alpha-hydroxylase 1 (CYP7A1) gene, which modulates BA production. Following RYGB urgery, however, FGF19 and BA levels (particularly cholic and deoxycholic acids) exhibited larger increases in Diabetic-R patients compared with nondiabetic and Diabetic-NoR patients. CONCLUSIONS - Taken together, the baseline and postoperative data implicate the FGF19-CYP7A1-BA pathway in the etiology and remission of type 2 diabetes following RYGB surgery. © 2013 by the American Diabetes Association.


Still C.D.,Institute of Obesity | Still C.D.,Geisinger Health System | Wood G.C.,Institute of Obesity | Benotti P.,Institute of Obesity | And 16 more authors.
The Lancet Diabetes and Endocrinology | Year: 2014

Background: About 60% of patients with type 2 diabetes achieve remission after Roux-en-Y gastric bypass (RYGB) surgery. No accurate method is available to preoperatively predict the probability of remission. Our goal was to develop a way to predict probability of diabetes remission after RYGB surgery on the basis of preoperative clinical criteria. Methods: In a retrospective cohort study, we identified individuals with type 2 diabetes for whom electronic medical records were available from a primary cohort of 2300 patients who underwent RYGB surgery at the Geisinger Health System (Danville, PA, USA) between Jan 1, 2004, and Feb 15, 2011. Partial and complete remission were defined according to the American Diabetes Association criteria. We examined 259 clinical variables for our algorithm and used multiple logistic regression models to identify independent predictors of early remission (beginning within first 2 months after surgery and lasting at least 12 months) or late remission (beginning more than 2 months after surgery and lasting at least 12 months). We assessed a final Cox regression model with a consistent subset of variables that predicted remission, and used the resulting hazard ratios (HRs) to guide creation of a weighting system to produce a score (DiaRem) to predict probability of diabetes remission within 5 years. We assessed the validity of the DiaRem score with data from two additional cohorts. Findings: Electronic medical records were available for 690 patients in the primary cohort, of whom 463 (63%) had achieved partial or complete remission. Four preoperative clinical variables were included in the final Cox regression model: insulin use, age, HbA1c concentration, and type of antidiabetic drugs. We developed a DiaRem score that ranges from 0 to 22, with the greatest weight given to insulin use before surgery (adding ten to the score; HR 5·90, 95% CI 4·41-7·90; p<0·0001). Kaplan-Meier analysis showed that 88% (95% CI 83-92%) of patients who scored 0-2, 64% (58-71%) of those who scored 3-7, 23% (13-33%) of those who scored 8-12, 11% (6-16%) of those who scored 13-17, and 2% (0-5%) of those who scored 18-22 achieved early remission (partial or complete). As in the primary cohort, the proportion of patients achieving remission in the replication cohorts was highest for the lowest scores, and lowest for the highest scores. Interpretation: The DiaRem score is a novel preoperative method to predict the probability of remission of type 2 diabetes after RYGB surgery. Funding: Geisinger Health System and the US National Institutes of Health. © 2014 Elsevier Ltd.


Gerhard G.S.,Weis Center for Research | Gerhard G.S.,Pennsylvania State University | Styer A.M.,Weis Center for Research | Strodel W.E.,Geisinger Medical Center | And 13 more authors.
International Journal of Obesity | Year: 2014

Objective:The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals.Design:Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism.Subjects and methods:Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR.Results:The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable.Conclusions:These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated. © 2014 Macmillan Publishers Limited.


PubMed | Institute of Obesity and University of Alabama at Birmingham
Type: | Journal: Frontiers in genetics | Year: 2014

Whole Genome Prediction (WGP) jointly fits thousands of SNPs into a regression model to yield estimates for the contribution of markers to the overall variance of a particular trait, and for their associations with that trait. To date, WGP has offered only modest prediction accuracy, but in some cases even modest prediction accuracy may be useful. We provide an illustration of this using a theoretical simulation that used WGP to predict weight loss after bariatric surgery with moderate accuracy (R (2) = 0.07) to assess the clinical utility of WGP despite these limitations. Prevention of Type 2 Diabetes (T2DM) post-surgery was considered the major outcome. Treating only patients above predefined threshold of predicted weight loss in our simulation, in the realistic context of finite resources for the surgery, significantly reduced lifetime risk of T2DM in the treatable population by selecting those most likely to succeed. Thus, our example illustrates how WGP may be clinically useful in some situations, and even with moderate accuracy, may provide a clear path for turning personalized medicine from theory to reality.


Buyken A.E.,Westmead Millennium Institute | Buyken A.E.,Institute of Obesity | Buyken A.E.,University of Sydney | Buyken A.E.,University of Bonn | And 5 more authors.
Journal of Nutrition | Year: 2010

Prospective evidence on the extent to which serum lipid concentrations in older persons respond to dietary modification is scarce. It is not clear whether such behavioral changes are relevant in the context of more commonly initiated treatments with lipid-lowering drugs. We therefore examined whether individual changes in the consumption of dietary fatty acids or main food sources were associated with changes in the serum lipid profile of older Australians. A total of 903 participants (≥49 y) in the Blue Mountains Eye Study had complete data on fasting lipids and dietary intake from a validated FFQ at baseline (1992-1994) and 5- and 10-y follow-up examinations. Decreasing consumption of SFA and butter during the 10-y period were associated with moderate decreases in serum total cholesterol independently of initiation of lipid-lowering drug treatment [adjusted estimates were 0.018 ± 0.007 mmol/(L x % energy (%en) from SFA (P = 0.01) and 0.055 ± 0.015 mmol/(L x 5 g butter) (P = 0.0003), respectively]. Increased consumption of (n-3) fatty acids and fish was independently related to modest increases in serum HDL-cholesterol [0.067 ± 0.026 mmol/(L x %en from (n-3) fatty acids) (P = 0.01) and 0.010 ± 0.004 mmol/(L x 20 g fish) (P = 0.02)] and decreases in log-transformed serum triglyceride concentrations [P = 0.02 for (n-3) fatty acids and P = 0.02 for fish intake]. Hence, 10-y changes in the intake of dietary fatty acids and their food sources appear to have contributed to concurrent improvements in the serum lipid profile of older Australians, independent of concomitantly initiated lipid-lowering drug treatment. © 2010 American Society for Nutrition.


Roesch S.L.,Institute of Obesity | Styer A.M.,Institute of Obesity | Wood G.C.,Institute of Obesity | Kosak Z.,Institute of Obesity | And 9 more authors.
PLoS ONE | Year: 2015

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have been implicated, independently, in type 2 diabetes (T2D) but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB), and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA) in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, β-Klotho, FGFR4, HNF4 α, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were < 200 mg/mL and FGF21 > 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes. © 2015 Roesch et al.


PubMed | Pennsylvania State University, Geisinger Health System and Institute of Obesity
Type: Journal Article | Journal: PloS one | Year: 2015

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have been implicated, independently, in type 2 diabetes (T2D) but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB), and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA) in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, -Klotho, FGFR4, HNF4, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were < 200 mg/mL and FGF21 > 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

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