Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.

BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

Weight-Reduction Preferences Among OBSERVE Study Participants With Obesity or Overweight: Opportunities for Shared Decision-Making.

OBJECTIVE: Limited recent evidence exists regarding weight-reduction preferences among people with obesity in the United States (US). We assessed preferred magnitudes of weight reduction among adults with obesity and how these preferences differ by participant characteristics. METHODS: The Perceptions, Barriers, and Opportunities for Anti-obesity Medications in Obesity Care: A Survey of Patients, Providers and Employers was a cross-sectional study assessing perceptions of obesity and anti-obesity medications among people with obesity, healthcare providers, and employers in the US. Adults with obesity and overweight with obesity-related complications self-reported current weight and weight they associated with 5 preferences ("dream," "goal," "happy," "acceptable," and "disappointed.") Preferred percent weight reductions for each preference were calculated. Multivariable regression analyses were performed identifying associations between weight-reduction preferences and participant characteristics. RESULTS: The study included 1007 participants (women: 63.6%; White: 41.0%; Black or African American: 28.9%; Asian: 6.5%; Hispanic: 15.3%; and median body mass index (BMI): 34.2 kg/m2). Median preferred percent weight reductions were dream = 23.5%; goal = 16.7%; happy = 14.6%; acceptable = 10.3%; and disappointed = 4.8%. Women reported higher preferred weight reductions than men. Preferred weight reductions among Black/African American participants were lower than White participants. Regression analyses indicated significant associations, with higher preferred magnitudes of weight reduction within females, higher weight self-stigma, and BMI class in Hispanic participants compared to White. CONCLUSION: In this large, real-world study, preferred magnitudes of weight reduction exceeded outcomes typically achieved with established nonsurgical obesity treatments but may be attained with bariatric procedures and newer and emerging anti-obesity medications. Respecting patients' preferences for treatment goals with obesity management could help support shared decision-making. Evaluating for an individual's contributors to weight preferences, such as weight self-stigma, can further benefit holistic obesity care.

Safety and efficacy analyses across age and body mass index subgroups in East Asian participants with type 2 diabetes in the phase 3 tirzepatide studies (SURPASS programme).

AIM: To assess the safety and efficacy of tirzepatide in people of East Asian descent based on age and body mass index (BMI). MATERIALS AND METHODS: Data of participants enrolled in East Asian countries in the SURPASS-1, -3, -4, -5, J-mono and J-combo phase 3 clinical trials were included. Participants with type 2 diabetes with a baseline HbA1c of 7.0% up to 11.0% and a BMI of 23 kg/m2 or greater or 25 kg/m2 or greater were included. Participants treated with tirzepatide 5, 10 or 15 mg were evaluated to assess the safety and efficacy of tirzepatide in people of East Asian descent (94% from Japan) based on age (< 65 and ≥ 65 years) and BMI (< 25 and ≥ 25 kg/m2 ). Key safety and efficacy outcomes were assessed. RESULTS: At baseline, 73% of East Asian participants had a BMI of 25 kg/m2 or greater and 74% were younger than 65 years. At week 52, tirzepatide induced a similar dose-dependent reduction in HbA1c, waist circumference and BMI across subgroups. Across all BMI and age subgroups, mean absolute HbA1c reductions across the three doses ranged from 2.3% to 3.0%, and mean waist circumference reductions ranged from 4.3 to 9.8 cm. Improvements in absolute insulin sensitivity, assessed by homeostatic model assessment for insulin resistance, were greater in those with a baseline BMI of ≥ 25 kg/m2 . Improvements in lipid profiles were similar across subgroups. While the safety profile of tirzepatide was broadly similar across BMI and age subgroups, drug discontinuation because of adverse events was higher in participants with a baseline age of ≥ 65 years. CONCLUSIONS: This post hoc analysis showed that once-weekly tirzepatide had a similar safety and efficacy profile across BMI and age subgroups in East Asian participants.

Examining the evidence for weight management in individuals with type 2 diabetes.

The obesity epidemic has been linked to the worsening diabetes epidemic. Despite this, weight reduction for individuals with obesity is seen as a secondary, or even tertiary, consideration in the treatment of type 2 diabetes (T2D). The aim of this review is to examine the benefits of weight management in individuals with T2D. A literature review of current available published data on the benefits of weight reduction in individuals with T2D was conducted. In individuals with T2D who have obesity or overweight, modest and sustained weight reduction results in improvement in glycaemic control and decreased utilization of glucose-lowering medication. A total body weight loss of 5% or higher reduces HbA1c levels and contributes to mitigating risk factors of cardiovascular disease, such as hyperlipidaemia and hypertension, as well as other disease-related complications of obesity. Progressive improvements in glycaemic control and cardiometabolic risk factors can occur when the total body weight loss increases to 10% or more. In the approach to treating patients with T2D and obesity, prioritizing weight management and the use of therapeutics that offer glycaemic control as well as the additional weight loss should be emphasized given their potential to attenuate the progression and severity of T2D.

Weight reduction and the impact on apnea-hypopnea index: A systematic meta-analysis.

Obstructive sleep apnea (OSA) is strongly associated with obesity. While the relationship between weight reduction and apnea-hypopnea index improvement has been documented, to our knowledge, it has not been quantified adequately. Therefore, this study aimed to quantify the relationship between weight reduction and AHI change. METHODS: A systematic literature search was performed using meta-analyses (PRISMA) guidelines for studies reporting AHI and weight loss in people with obesity/overweight and OSA between 2000 and 2023. A linear and quadratic model (weighted by treatment arm sample size) predicted percent change from baseline AHI against mean percent change from baseline weight. The quadratic term was statistically significant (P < 0.05), so the quadratic model (with 95 % prediction interval) was used. RESULTS: The literature search identified 27 studies/32 treatment arms: 15 using bariatric surgery and lifestyle intervention each and 2 using pharmacological interventions. Included studies were ≥3 months with weight intervention and participants had AHI ≥15/h. Weight reduction in people with OSA and obesity was associated with improvements in the severity of OSA. BMI reduction of 20 % was associated with AHI reduction of 57 %, while further weight reduction beyond 20 % in BMI was associated with a smaller effect on AHI. As the prediction intervals are relatively wide, a precise relationship could not be conclusively established. CONCLUSION: The degree of AHI index improvement was associated with the magnitude of weight reduction. The model suggests that with progress in weight reduction beyond 20 %, the incremental decrease in BMI appeared to translate to a smaller additional effect on AHI.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.

Dorsal striatal response to taste is modified by obesity and insulin resistance.

OBJECTIVE: In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. METHODS: Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. RESULTS: The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. CONCLUSIONS: These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss.

Real-world primary nonadherence to antiobesity medications.

BACKGROUND: Primary nonadherence (PNA), when a medication is newly prescribed but not filled, has been identified as a major research gap potentially impacting the optimal treatment of patients with overweight and obesity who are newly prescribed antiobesity medications (AOMs). OBJECTIVES: To assess PNA among patients with newly prescribed AOMs and to examine factors associated with PNA to AOMs. METHODS: This was a retrospective study that used the Optum Integrated Clinical plus Claims database to identify individuals who had at least 1 prescription order for an AOM the US Food and Drug Administration approved for long-term use. Individuals with prescription orders between January 1, 2012, and February 28, 2019, were identified, and patient demographics, clinical characteristics, medication prescribed, baseline health care utilization, and obesity-related complications were described by PNA status. PNA was defined as no pharmacy claim for the AOM within 60 days of the date of the new prescription order as identified in electronic health record data. A multivariable logistic regression model was used to examine factors associated with PNA. RESULTS: The study sample included a total of 1,563 patients. The mean body mass index was 38.4 kg/m2; 10.7% were prescribed liraglutide 3.0 mg, 26.0% were prescribed lorcaserin, 36.3% of patients were prescribed naltrexone-bupropion, 5.4% were prescribed orlistat, and 21.6% were prescribed phentermine-topiramate. Most patients (91.1%) exhibited PNA, with only 8.9% filling their newly prescribed AOM within 60 days. Both the adherent and nonadherent groups were predominately female sex, White, and covered by commercial insurance. The mean age was similar between the 2 groups. Most obesity-related complications were less prevalent in the adherent group, although the Charlson comorbidity index score was similar between the 2 groups. After adjustment for patient demographics and clinical characteristics, there was not a statistically significant association between the specific AOM and PNA (P = 0.299). Patients with depression or living in the Midwest or South regions were at significantly increased risk of PNA. CONCLUSIONS: The rate of PNA to AOMs was very high, suggesting barriers in effective medical management of patients with overweight and obesity. Future research is warranted to understand reasons for PNA to AOMs and how to address these barriers. DISCLOSURES: Dr Kan, Dr Bae, Dr Dunn, and Dr Ahmad are employees of Eli Lilly and Company. Ms Buysman and Dr Gronroos are employees of Optum. Dr Swindle was an employee of Optum at the time the study was conducted and is currently employed at Evidera. Dr Bengtson is employed at Boehringer Ingelheim Pharmaceuticals, Inc. (Boehringer Ingelheim has no connection to this study), and during the conduct of this study was employed at Optum.

Weight management treatment modalities in patients with overweight or obesity: A retrospective cohort study of administrative claims data.

Background: The purpose of this study was to describe demographic and clinical characteristics among patients who have medical encounters for weight management treatments and to investigate the association of those characteristics with treatment modality. Methods: This was a retrospective database study using medical claims, pharmacy claims, and enrollment information from commercial and Medicare Advantage with Part D members in the Optum Research Database from 01/01/2011-2/29/2020. Adult patients with a claim for a weight management treatment from 01/01/2012-2/28/2019 were categorized into cohorts according to the highest intensity intervention received. To examine the association between patient characteristics and treatment modality received, a multinomial logit model was performed. Results: Cohorts by increasing intensity included lifestyle intervention (LSI, n = 67,679), weight reduction pharmacotherapy (WRRx) with an anti-obesity medication (AOM, n = 6,905), weight reduction procedure (WRP, n = 1,172), and weight reduction surgery (WRS, n = 18,036). Approximately 32.1% and 16.6% of patients who received WRS or WRP had an LSI during the 12-month baseline, and only 0.6% and 0.4% had treatment with long-term AOMs. In a multinomial logit model, patients with type 2 diabetes (not including WRRx cohort), respiratory disorders, cardiovascular risk factors, pain disorders, and mental health conditions had increased odds of treatment with higher intensity intervention versus LSI. Patients who were male, received an intervention more recently (2016-2019), or had a Charlson comorbidity score of 1 (compared to 0) had decreased odds of treatment with higher intensity interventions. Conclusion: In this study, age, sex, body mass index, obesity-related complications, and Charlson comorbidity score appeared to influence the type of weight management treatment modality received. This study improves understanding of weight management treatment utilization and identifies gaps and opportunities to improve obesity care with the appropriate use of different treatment modalities.

Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery.

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB (P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery (P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB (P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time (P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.

Striatal Dopamine Responses to Feeding are Altered in People with Obesity.

OBJECTIVE: This study determined whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than in the fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after consuming a meal to satiation and after fasting overnight as well as in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight by using positron emission tomography with [11 C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (P < 0.05), but there was no difference in the magnitude of the response between fasting and fed conditions. CONCLUSIONS: People with obesity and prediabetes do not increase striatal DA release after eating a meal to satiation compared with fasting overnight and fail to inhibit DA release in response to high-calorie food stimuli after eating a meal to satiation. These data suggest that impaired DA signaling contributes to greater energy intake during meals in this population.

Brief communication: ß-cell function influences dopamine receptor availability.

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a ß-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for ß-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity. Clinical Trial Registration Number: NCT00802204.

Predictors and Outcomes Associated With Adherence to Weekly Alendronate in US Military Veterans: Clinical Research Study.

Background: Poor adherence to oral bisphosphonates is a challenge to treatment and prevention of osteoporosis. The Veterans Health Administration (VA) operates the largest integrated health care system in the United States and offers certain advantages to possibly improve medication adherence. We aimed to determine adherence to weekly alendronate for osteoporosis in Veterans, and investigate predictors and outcomes related to adherence. Methods: A retrospective study cohort was generated from VA databases selecting Veterans who were treated with weekly alendronate. Adherence was measured by medication possession ratio (MPR) and persistence. Two groups were defined as low and high adherence based on MPR <80% or ≥80%, respectively. Regression models were used to investigate predictors of adherence and included clinically relevant covariates. Further regressions were used to investigate the impact of adherence on change in bone mineral density measured by dual energy X-ray absorptiometry and incident fracture. Results: In a cohort of 913 (female/male, 207/706) Veterans, 48% had high adherence in year 1. Distribution for gender, race, and age were similar between the 2 groups, MPR <80% or MPR ≥80%. Baseline fracture [odds ratio OR: 0.64, 95%CI: (0.41, 0.98)], alcohol abuse [0.40 (0.21, 0.74)] and tobacco use [0.44 (0.31, 0.63)] were associated with low adherence in the unadjusted analyses, but only tobacco use [0.45 (0.30, 0.67)] was associated with low adherence after adjustment. Among males, tobacco use was associated with low adherence while prostate cancer predicted high adherence in adjusted models. High adherence was associated with a 30% [hazard ratio HR: 0.70, 95% CI: (0.47, 1.03)] decreased risk of incident fracture in the whole cohort, and a 40% [0.60 (0.38, 0.95)] decrease risk in males. Conclusion: Year one adherence to weekly alendronate was a relevant determinant to long-term clinical outcomes including changes in bone mineral density and incident fracture in Veterans.

The Rising Cost of Diabetes: Can DiRECT Tip the Scales?

The cost of treating diabetes mellitus has risen sharply in recent years because of an increasing number of patients with type 2 diabetes and obesity and a rapidly expanding repertoire of expensive nongeneric medications. Despite the call for a new treatment paradigm by the American Diabetes Association to mitigate this cost, recent Medicare Part D expenditure data show that this call remains unanswered. The Diabetes Remission Clinical Trial, published in The Lancet, adds support to a different path, demonstrating success with intensive lifestyle intervention followed by structured support for long-term weight loss maintenance. Nearly half of patients enrolled were able to achieve remission of their diabetes with hemoglobin A1c < 6.5% and an improvement of their quality of life. Although only from one trial, and of limited duration, these results should provide optimism for providers and patients alike and support future work toward an evidence base for non-medication-based management of diabetes.

Caloric Restriction-Induced Decreases in Dopamine Receptor Availability are Associated with Leptin Concentration.

OBJECTIVE: It has been previously reported that early after Roux-en-Y-gastric bypass, dopamine (DA) type 2 and 3 receptor (D2/3R) binding potential (BPND ) was decreased from preoperative levels. The current study aimed to determine whether calorie restriction without weight loss modifies D2/3R BPND and whether such changes are explained by neuroendocrine regulation. METHODS: Fifteen females with obesity (BMI = 39 ± 6 kg/m2 ) were studied before and after ∼10 days of a very-low-calorie-diet (VLCD). Outcome measures included fasting insulin, leptin, acyl ghrelin, and glucose, and insulin sensitivity and disposition index were estimated using the oral-minimal model (OMM) method. Participants underwent positron emission tomography scanning with the displaceable radioligand [18 F]fallypride to estimate available regional D2/3R levels. Regions of interest included the caudate, putamen, ventral striatum, hypothalamus, and substantia nigra (SN). RESULTS: With the VLCD, weight decreased slightly (-3 kg). Insulin, glucose, and leptin decreased significantly, but there was no change in acyl ghrelin or measures from OMM. SN D2/3R BPND decreased significantly, with trends toward decreased levels in the remaining regions. The decrease in leptin concentration strongly predicted the change in D2/3R BPND in all regions (all P ≤ 0.004). CONCLUSIONS: In obesity, reductions in regional D2/3R availability after VLCD are suggestive of increased endogenous DA competing with the radioligand. Changes in regional D2/3R availability were associated with decreases in leptin concentrations that occurred before clinically significant weight loss.

Regulation of novelty seeking by midbrain dopamine D2/D3 signaling and ghrelin is altered in obesity.

OBJECTIVE: To investigate the relationship of novelty seeking traits (NS) with midbrain dopamine (DA) receptors and acyl ghrelin levels (AG) in normal weight (NW) and obese females.NS predict addictive behaviors and are hypothesized to contribute to eating behaviors. In healthy, NS are negatively associated with DA receptors in the substantia nigra (SN). The influence of obesity on the regulation of NS by DA signaling and AG was hypothesized. METHODS: PET scanning to measure DA type 2/type 3 receptor (D2/D3R) binding potential (BPND ) in the SN was used. Participants completed Tridimensional Personality Questionnaire-Novelty-Seeking Scale (TPQ-NS) and AG were measured. RESULTS: In eight NW and 19 obese (BMI 22 vs 38 kg/m(2) ), TPQ-NS (16 vs 15) and SN D2/D3R BPND (2.48 vs 2.66) were similar, while AG higher (256 vs 60, P < 0.01), respectively. D2/D3R BPND and TPQ-NS had a negative relationship in NW (r = -0.7) but not in obese (P > 0.10). AG and TPQ-NS were positively correlated in NW (r = 0.9) but not in obese (P > 0.10). D2R BPND and AG were negatively correlated in NW (r = -0.8) but positively in obese (r = 0.6). CONCLUSION: Obese do not maintain posited regulatory relationships for NS to either midbrain D2/D3R availability or AG present in NW. Also opposite relationships exist for NW and obese between SN D2/D3R availability and AG. The altered regulation of NS in obesity needs to be further explored.

Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity.

OBJECTIVE: Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity. RESEARCH DESIGN AND METHODS: We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test. RESULTS: Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand. CONCLUSIONS: Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy.

OBJECTIVE: Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB. RESEARCH DESIGN AND METHODS: We studied 40 obese (BMI 48 ± 8 kg/m(2)) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity. RESULTS: Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP. CONCLUSIONS: Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.

Advanced neuroimaging in obesity.

The Obesity Society, founded in 1982, conducts the most comprehensive annual scientific meeting on obesity in North America. Annually, the meeting brings together over 2000 scientists and healthcare professionals of various specialties to allow a multidisciplinary forum on this burdensome disease. Numerous basic science presentations addressed the importance of the brain's role in obesity. Investigating the role of the human brain in obesity has been limited until more recent advances in biomedical imaging. This review details the symposium that was held at this year's annual meeting of The Obesity Society on 'Neuroimaging in obesity', bringing together current leader's in this emerging field.

The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery.

OBJECTIVE: Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB. RESEARCH METHODS AND DESIGN: A mixed meal was administered to nine subjects before and after RYGB (average 4 +/- 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet. RESULTS: Weight loss in both groups was minimal; the RYGB subjects lost 1.4 +/- 5.3 kg (P = 0.46) vs. 2.2 +/- 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 +/- 3.1 to 3.3 +/- 2.1; P = 0.03) and caloric restriction (4.8 +/- 4.1 to 3.6 +/- 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 +/- 67 to 65 +/- 33 and 85 +/- 59 to 65 +/- 56 nmol x l(-1) x min(-1), respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 +/- 8.6 to 12.2 +/- 5.5 pg x l(-1) x min(-1); P = 0.04) and peaked higher (45.2 +/- 37.3 to 84.8 +/- 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction. CONCLUSIONS: These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.