Preoperative use of incretins is associated with increased diabetes remission after RYGB surgery among patients taking insulin: a retrospective cohort analysis.

OBJECTIVE: The main goal of this study was 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 disease with 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.

Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity.

OBJECTIVES: Genome-wide association studies (GWAS) have led to the identification of single nucleotide polymorphisms in or near several loci that are associated with the risk of obesity and nonalcoholic fatty liver disease (NAFLD). We hypothesized that missense variants in GWAS and related candidate genes may underlie cases of extreme obesity and NAFLD-related cirrhosis, an extreme manifestation of NAFLD. METHODS: We performed whole-exome sequencing on 6 Caucasian patients with extreme obesity [mean body mass index (BMI) 84.4] and 4 obese Caucasian patients (mean BMI 57.0) with NAFLD-related cirrhosis. RESULTS: Sequence analysis was performed on 24 replicated GWAS and selected candidate obesity genes and 5 loci associated with NAFLD. No missense variants were identified in 19 of the 29 genes analyzed, although all patients carried at least 2 missense variants in the remaining genes without excess homozygosity. One patient with extreme obesity carried 2 novel damaging mutations in BBS1 and was homozygous for benign and damaging MC3R variants. In addition, 1 patient with NAFLD-related cirrhosis was compound heterozygous for rare damaging mutations in PNPLA3. CONCLUSIONS: These results indicate that analyzing candidate loci previously identified by GWAS analyses using whole-exome sequencing is an effective strategy to identify potentially causative missense variants underlying extreme obesity and NAFLD-related cirrhosis.

Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation.

Oncogenic ras is known to inhibit cell death and growth inhibitory genes and activate prosurvival genes. Proapoptotic gene PAR-4, has been found to be downregulated by oncogenic ras. Since pancreatic tumors harbor a high incidence of K-ras point mutations, we hypothesized that oncogenic K-ras might influence the function and expression of PAR-4. PAR-4 expression levels were analyzed in 4 established pancreatic tumor cell lines, 10 normal pancreatic tissues, 44 frozen tumor tissues and 25 paraffin-embedded pancreatic adenocarcinoma samples by Real Time RT-PCR, Western blot analysis and immunohistochemistry. K-ras mutational status was analyzed by allele-specific oligonucleotide-hybridization. Expression levels of PAR-4 were correlated with the K-ras mutational status and clinical characteristics. Further, modulation of endogenous PAR-4 was tested by transiently expressing oncogenic ras in a wild-type K-ras pancreatic cancer cell line, BxPC-3. Three cell lines with K-ras mutations showed low levels of PAR-4 when compared to a normal pancreatic tissue. Of 44 frozen tumors, 16 showed appreciable upregulation of Par mRNA and 27 showed significant downregulation of PAR-4 mRNA when compared to normal pancreatic tissue and 1 had levels equivalent to normal pancreatic tissue. Of 25 paraffin-embedded tumors, 9 showed downregulation of PAR-4 protein and this downregulation of PAR-4 correlated significantly with K-ras mutational status (p < 0.00002). In addition, the presence of PAR-4 mRNA or protein expression in pancreatic tumors correlated with prolonged survival. Transient overexpression of oncogenic ras in wild-type K-ras BxPC-3 cells significantly downregulated the endogenous PAR-4 protein levels and conferred accelerated growth. Thus, downregulation or loss of PAR-4 expression by oncogenic ras may provide a selective survival advantage for pancreatic tumors, through inhibition of proapoptotic pathway mediated by PAR-4.

All-Cause and Specific-Cause Mortality Risk After Roux-en-Y Gastric Bypass in Patients With and Without Diabetes.

OBJECTIVE: This study assessed all-cause and specific-cause mortality after Roux-en-Y gastric bypass (RYGB) and in matched control subjects, stratified by diabetes status. RESEARCH DESIGN AND METHODS: RYGB patients were matched by age, BMI, sex, and diabetes status at time of surgery to nonsurgical control subjects using data from the electronic health record. Kaplan-Meier curves and Cox regression were used to assess differences in all-cause and specific-cause mortality between RYGB patients and control subjects with and without diabetes. RESULTS: Of the 3,242 eligible RYGB patients enrolled from January 2004 to December 2015, control subjects were identified for 2,428 (n = 625 with diabetes and n = 1,803 without diabetes). Median postoperative follow-up was 5.8 years for patients with diabetes and 6.7 years for patients without diabetes. All-cause mortality was reduced in RYGB patients compared with control subjects only for those with diabetes at the time of surgery (adjusted hazard ratio 0.44; P < 0.0001). Mortality was not significantly improved in RYGB patients without diabetes compared with control subjects without diabetes (adjusted hazard ratio 0.84; P = 0.37). Deaths from cardiovascular diseases (P = 0.011), respiratory conditions (P = 0.017), and diabetes P = 0.011) were more frequent in control subjects with diabetes than in RYGB patients with diabetes. RYGB patients without diabetes were less likely to die of cancer (P = 0.0038) and respiratory diseases (P = 0.046) than control subjects without diabetes but were at higher risk of death from external causes (P = 0.012), including intentional self-harm (P = 0.025), than control subjects without diabetes. CONCLUSIONS: All-cause mortality benefits of RYGB are driven predominantly by patients with diabetes at the time of surgery. RYGB patients with diabetes were less likely to die of cardiovascular diseases, diabetes, and respiratory conditions than their counterparts without RYGB.

Feasibility and impact of an evidence-based program for gastric bypass surgery.

BACKGROUND: Health care in the United States is expensive and quality is variable. The aim of this study was to investigate whether our integrated health system, composed of academic hospitals, a practice plan, and a managed care payer, could reliably implement an evidence-based program for gastric bypass surgery. A secondary aim was to evaluate the impact of the program on clinical outcomes. STUDY DESIGN: A standardized program for delivery of clinical best-practice elements for patients undergoing initial open or laparoscopic Roux-en-Y gastric bypass was implemented in 2008. Best-practice elements were embedded into the workflow. The best-practice elements were refined after reviewing failures observed during the early implementation period. The study period was divided into 3 groups: group α = year preceding program implementation (control), group ß = first year of implementation (unreliable), and group Ω = 2nd to 4th years of implementation (reliable). Outcomes data were collected for all patients who had undergone Roux-en-Y gastric bypass between May 2008 and April 2012 and were compared with a control group from the preceding year using multiple logistic regression analysis. RESULTS: Two thousand and sixty-one patients were studied, with no significant demographic differences between study groups. Best-practice elements delivery was 40% in group ß, but was >90% for group Ω (p < 0.001). Length of stay for group α was 3.5 days and improved to 2.2 days (p < 0.001) for group Ω. Complications and readmission rates improved considerably with reliable delivery of best-practice elements. CONCLUSIONS: Standardization of evidence-based care delivery for Roux-en-Y gastric bypass was feasible and reliable delivery of this pathway improved clinical outcomes.

Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common in adults with extreme obesity and can impact long-term health and survival. Liver biopsy is the only accurate test for diagnosis and staging, but is invasive and costly. Non-invasive testing offers an attractive alternate, but the overall accuracy remains a significant issue. This study was conducted to determine the accuracy and clinical utility of pre-operative ultrasound and liver transaminase levels, as well as intra-operative hepatic visual inspection, for assessing presence of NAFLD as confirmed by hepatic histology. METHODS: Data was collected prospectively from 580 morbidly obese adult patients who underwent Roux-en-Y gastric bypass surgery with intraoperative wedge biopsy between January 2004 and February 2009. Complete data for ultrasound, ALT and AST levels, and documented visual inspection was available for 513 patients. RESULTS: The prevalence of NAFLD was 69 % and that of NASH was 32 %. The individual non-invasive clinical assessments demonstrated low sensitivity, specificity, and accuracy for detecting the presence of steatosis, steatohepatitis, or fibrosis. The combination of normal or abnormal results for all tests improved predictive utility. Abnormal tests with all three assessments had a sensitivity of 95-98 % and a specificity of 28-48 % for major histologic findings in NAFLD/NASH. Normal tests with all three assessments had a sensitivity of 12-22 % and a specificity of 89-97 % for major histologic findings in NAFLD/NASH. CONCLUSIONS: Although individual clinical tests for NAFLD have limited accuracy, the use of combined clinical tests may prove useful.

Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes.

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, ß-Klotho, FGFR4, HNF4α, 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.

Laparoscopic cholecystectomy for elderly patients: gold standard for golden years?

HYPOTHESIS: Laparoscopic cholecystectomy (LC) has known physiological benefits and positive socioeconomic effects over the open procedure. Although recent studies have questioned the technique's efficacy in elderly patients (>65 years), we hypothesize that LC is safe and efficacious in that patient group. METHODS: Five thousand eight hundred eighty-four consecutive patients (mean age, 40 years; 26% male) underwent an attempted LC (conversion rate, 5.2%) from 1991 to 2001 at a teaching institution. Of these, 395 patients (6.7%) were older than 65 years. Analysis included patient age, sex, American Society of Anesthesiologists classification, conversion rate, morbidity, mortality, and assessment of results over time. RESULTS: Elderly patients were predominantly male (64%). Septuagenarians had a 40% incidence of complicated gallstone disease, such as acute cholecystitis, choledocholithiasis, or biliary pancreatitis, and octogenarians had a 55% incidence. Overall mortality was 1.4%. The conversion rate was 17% for the first 5 years of the study period and 7% for the second half. The conversion rate was 22% for patients with complicated disease and 2.5% for patients with chronic cholecystitis. Average hospital stay decreased from 10.2 days to 4.6 days during the first and second half of the study period, respectively. CONCLUSIONS: The results of LC in patients aged 65 to 69 years are comparable with those previously reported in younger patients. Patients older than 70 years had a 2-fold increase in complicated biliary tract disease and conversion rates, but a low mortality rate (2%) compared with results of other authors (12%), despite an increase in American Society of Anesthesiologists classification. Increased technical experience with LC favorably affected outcomes over time. Early diagnosis and treatment prior to onset of complications are necessary for further improvement in the outcomes of elderly patients undergoing LC.

Intraoperative parathyroid hormone assay: an accurate predictor of symptomatic hypocalcemia following thyroidectomy.

HYPOTHESIS: Intraoperative parathyroid hormone (IOPTH) assay is useful for predicting symptomatic hypocalcemia following total thyroidectomy. DESIGN: A prospective study of 30 patients undergoing total thyroidectomy with IOPTH levels obtained following skin closure and ionized calcium (Ca2+) levels obtained 6 hours postoperatively and on postoperative day 1. All patients were evaluated for symptoms of hypocalcemia. SETTING: University teaching hospital. MAIN OUTCOME MEASURES: Patients who developed symptomatic hypocalcemia were compared with asymptomatic patients in regard to age, diagnosis, thyroid weight, thyrotropin level, Ca2+ level, parathyroid status, and IOPTH level. RESULTS: The onset of symptomatic hypocalcemia ranged from 8 to 48 hours postoperatively (n = 10). One patient required readmission. Of 10 patients with symptoms, 5 developed tetany. There were no significant differences in age, diagnosis, thyroid weight, thyrotropin level, or the number of parathyroid glands preserved in patients with or without symptomatic hypocalcemia. All patients with an IOPTH level of less than 10 pg/mL (1.1 pmol/L) had symptoms (n = 8). The mean +/- SD IOPTH level (7.6 +/- 12.0 pg/mL [0.8 +/- 1.3 pmol/L]) in patients who developed symptomatic hypocalcemia was significantly lower than the mean IOPTH level (55.7 +/- 31.8 pg/mL [5.9 +/- 3.3 pmol/L]) in patients without symptoms (P =.001). The 6-hour and postoperative day 1 Ca2+ levels were significantly lower in patients with symptomatic hypocalcemia (P =.19 and P =.13, respectively). An IOPTH level of less than 10 pg/mL is 80% sensitive and 100% specific for the development of symptomatic hypocalcemia. CONCLUSION: The incorporation of the IOPTH assay in the management of thyroid disease is recommended to prevent and prospectively treat symptomatic hypocalcemia, thereby reducing readmissions following thyroidectomy.

Reasons for conversion from laparoscopic to open cholecystectomy: a 10-year review.

Laparoscopic cholecystectomy is now considered the "gold standard" operation for patients with gallstone disease. A number of patients require conversion to an open cholecystectomy for the safe completion of the procedure. This study investigates how the etiology and incidence of conversion from laparoscopic to open cholecystectomy has changed over time. All 5884 patients undergoing laparoscopic cholecystectomy between March 1991 and June 2001 were prospectively collected in a database. A total of 310 patients (5.2%) had had their cholecystectomies converted to an open procedure. The mortality rate for these patients was 0.7%. Causes for conversion were inability to correctly identify anatomy (50%), "other" indications (16%), bleeding (14%), suspected choledocholithiasis (11%), and suspected bile duct injury (8%). After an initial learning curve in thin patients with symptomatic cholelithiasis, inclusion of patients with acute cholecystitis, morbid obesity, or a prior celiotomy resulted in a peak conversion rate of 11% by 1994. From 1994 to the first half of 2001, the conversion rate has declined significantly for all patients (10% to 1%), as well as for patients with acute cholecystitis (26% to 1%). Although unclear anatomy secondary to inflammation remains the most common reason for conversion, the impact of acute cholecystitis on the operative outcome has decreased with time.

Is thyroid frozen section too much for too little?

BACKGROUND: The role of frozen section (FS) in thyroid disease is controversial. The goal of this study was to identify a cohort of patients who may or may not benefit from FS. METHODS: Two hundred thirty-one patients who underwent thyroidectomy were evaluated in regard to fine-needle aspiration (FNA), FS, and the extent of surgery. RESULTS: In all, 155 patients underwent FNA, 140 patients underwent FS, and 103 patients had both. A final diagnosis of malignancy was obtained in 47 of 231 patients. FNA had a sensitivity of 50% and a specificity of 99%, and FS had a sensitivity of 50% and a specificity of 100% for diagnosing malignancy. Accounting for the clinical findings and FNA results, FS results altered the extent of thyroidectomy in 1 of 103 patients. CONCLUSIONS: The increased costs for the operative time and the pathologists needed to obtain routine FS are not supported with any substantial benefit in patient outcome.

Identification of novel clinical factors associated with hepatic fat accumulation in extreme obesity.

OBJECTIVES: The accumulation of lipids stored as excess triglycerides in the liver (steatosis) is highly prevalent in obesity and has been associated with several clinical characteristics, but most studies have been based on relatively small sample sizes using a limited set of variables. We sought to identify clinical factors associated with liver fat accumulation in a large cohort of patients with extreme obesity. METHODS: We analyzed 2929 patients undergoing intraoperative liver biopsy during a primary bariatric surgery. Univariate and multivariate regression modeling was used to identify associations with over 200 clinical variables with the presence of any fat in the liver and with moderate to severe versus mild fat accumulation. RESULTS: A total of 19 data elements were associated with the presence of liver fat and 11 with severity of liver fat including ALT and AST, plasma lipid, glucose, and iron metabolism variables, several medications and laboratory measures, and sleep apnea. The accuracy of a multiple logistic regression model for presence of liver fat was 81% and for severity of liver fat accumulation was 77%. CONCLUSIONS: A limited set of clinical factors can be used to model hepatic fat accumulation with moderate accuracy and may provide potential mechanistic insights in the setting of extreme obesity.

Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study.

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 4·41­7·90; p<0·0001). Kaplan-Meier analysis showed that 88% (95% CI 83­92%) of patients who scored 0­2, 64% (58­71%) of those who scored 3­7, 23% (13­33%) of those who scored 8­12, 11% (6­16%) of those who scored 13­17, and 2% (0­5%) of those who scored 18­22 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.

A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass.

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 can 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 RYGB, lower FGF19 levels were significantly correlated with increased hepatic expression of the cholesterol 7alpha-hydroxylase 1 (CYP7A1) gene, which modulates BA production. Following RYGB surgery, 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.

High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery.

Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI.

Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2.

In this study, we investigated whether lack of transforming growth factor beta (TGF-beta) type II receptor (RII) expression and loss of TGF-beta signaling played a role in radiation resistance of pancreatic cancer cells MIA PaCa-2 that possess a mutated p53 gene. Transfection of this cell line with a RII cDNA led to a stimulation of the transcriptional activity of p3TP-Lux, a TGF-beta-responsive reporter construct. The RII transfectants (MIA PaCa-2/RII) showed a significant increase in sensitivity to radiation when compared with MIA PaCa-2/vector cells. The increase in sensitivity to radiation was reversed by neutralizing antibodies to TGF-beta, indicating that these changes were dependent on TGF-beta signaling. Compared with MIA PaCa-2/vector cells, MIA PaCa-2/RII cells showed a greater than 3-fold increase in apoptosis after radiation. Enhanced radiation sensitivity of MIA PaCa-2/RII cells was associated with an induction of Bax mRNA and protein that was followed by a release of cytochrome c and activation of caspase-3 and poly(ADP-ribose) polymerase cleavage after radiation exposure. Overexpression of Bcl-x(L) or treatment with antisense oligodeoxynucleotides targeted against Bax significantly inhibited radiation-induced apoptosis in MIA PaCa-2/RII but not in MIA PaCa-2/Vector cells, suggesting that Bax induction is necessary for radiation-induced TGF-beta signaling-mediated apoptosis. Thus, restoration of TGF-beta signaling sensitized these cells to ionizing radiation, although these cells possess a mutated p53 gene. In addition, disruption of RII function by dominant negative mutant of RII inhibited the radiation-induced TGF-beta signaling and apoptosis in primary cultures of mouse embryonic fibroblasts. Together, these observations imply that RII is an important component of radiation-induced TGF-beta signaling, and loss of function of RII may enhance resistance to radiation-induced apoptosis.