Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger functional ovarian reserve. Hormonal regulation in the aetiology of this condition, through metabolic and reproductive features, was emphasised. The proteomic analysis highlighted perturbations of metabolically-related biology that are typical in women with PCOS. A PCOS polygenic risk score was associated with adverse cardio-metabolic outcomes, with differing contributions of testosterone and BMI in women and men. Finally, while oligo- and anovulatory infertility are characteristic features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Journal Article Accepted manuscript Response to Letter to the Editor from Rosenfield, et al: Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome Get access Helena Teede, Helena Teede Monash Centre of Health Research and Implementation, Monash University, Melbourne Australia Corresponding author: Helena Teede - Helena.teede@monash.edu. https://orcid.org/0000-0001-7609-577X Search for other works by this author on: Oxford Academic Google Scholar Chau Tay, Chau Tay Monash Centre of Health Research and Implementation, Monash University, Melbourne Australia Search for other works by this author on: Oxford Academic Google Scholar Ricardo Azziz Ricardo Azziz University of Alabama, Women and Infants Center, Birmingham, Alabama, USA Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, dgae370, https://doi.org/10.1210/clinem/dgae370 Published: 29 May 2024 Article history Received: 03 May 2024 Revision received: 21 May 2024 Editorial decision: 24 May 2024 Accepted: 28 May 2024 Published: 29 May 2024

Abstract Disclosure: R. Bauer: None. L. Gorsic: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility among reproductive age women. In addition to experiencing reproductive symptoms, women with PCOS are at elevated risk of developing obesity, insulin resistance (IR), and type 2 diabetes. Familial partial lipodystrophy type 2 (FPLD2) is a disorder of lipid storage and insulin resistance caused by dominant missense alleles in the gene encoding the intermediate filaments lamin A/C (LMNA). Women with this Mendelian disorder of IR also experience symptoms of PCOS such as amenorrhea and hyperandrogenism. We, therefore, hypothesize that genetic variation in LMNA also contributes to PCOS, which is a common form of IR. In other words, we hypothesize that PCOS falls into the phenotypic spectrum of disorders caused by variation in LMNA.Objective: We aim to identify and evaluate variation in LMNA that underlies PCOS pathogenesis. Methods: To test our hypothesis, we sequenced the LMNA gene in 602 women with PCOS and 125 reproductively healthy women. We comprehensively screened LMNA for genetic variation that is likely to alter the lamin A/C proteins, including missense, nonsense, splicing or frameshift variants. We identified 7 missense variants in 8 cases and no variants in reproductively healthy controls (χ2= 3.1, p=0.081, OR > 1.78, with study controls; χ2= 46.8, p<1x10-8, OR= 8.5 with gnomAD non-Finnish European cohort population controls). To determine which of these variants are pathogenic, we systematically evaluated them according to criteria outlined by the American College of Medical Genetics (ACMG). These guidelines evaluate pathogenicity of variants through multiple lines of evidence, including population data, computational predictions, and functional studies. Results: We identified 5 pathogenic variants in LMNA and 2 that are likely pathogenic. When assessed individually, 6 of the 7 variants are significantly enriched in our cohort when compared to gnomAD non-Finnish European population controls (OR > 5.0). All of the LMNA variants are likely damaging as predicted by 3 computational methods: CADD score ≥ 15, FATHMM prediction of “Damaging”, and MutationTaster classification as “disease causing.” Additionally, many of the variants have previously been identified in individuals with lipodystrophy. Conclusion: Together with previous identification of LMNA variants in women with PCOS by our lab (Urbanek et al. 2009 JCEM) and others (Crespo et al. 2022 JES), this work further establishes LMNA variation as a pathogenic mechanism for PCOS. Presentation Date: Friday, June 16, 2023

Poor sleep may be associated with reduced β-cell response or decreased insulin sensitivity in youth. We explored whether sleep duration, sleep quality or obstructive sleep apnea (OSA) risk factors were associated with measures of β-cell response or insulin sensitivity in youth. At baseline, 88 youth (10-19 yrs of age) with recently diagnosed T2D or prediabetes completed validated questionnaires (Sleep Disturbances Scale and Cleveland Adolescent Sleepiness) in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps measured insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide response to glucose (ACPRg), steady-state C-peptide at a glucose of 11.1 mmol/L (SSCP), and arginine-stimulated maximum C-peptide responses at glucose >25 mmol/L (ACPRmax). Linear regression models explored the independent association between sleep variables and clamp measures, adjusted for age, race/ethnicity, sex, Tanner stage, metformin use and BMI. Models including β-cell responses were adjusted for M/I to account for the role of insulin sensitivity in β-cell function. The cohort was 70% female, 28% white, 25% black, 36% Hispanic; age 14.3±2.0 yrs and BMI 36.9±6.4 kg/m2 (mean±SD). Using ADA criteria, 60% had prediabetes and 40% had T2D; 27% reported metformin use. Sleep duration <8 h was reported in 59%; 57% reported daytime sleepiness; 28% reported poor sleep quality; 29% had high risk for OSA. Low sleep duration (<8 h) was associated with a trend for lower ACPRg (p=0.069). No sleep variables (sleep duration or quality, OSA risk) were associated with clamp-derived outcomes in unadjusted or adjusted linear regression models. In youth with prediabetes or T2D, subjective measures of sleep quantity, sleep quality and OSA risk were not independently associated with β-cell response or insulin sensitivity. Further research using objective measures of sleep may better delineate the relationship between sleep and β-cell function in youth. Disclosure K.A.Temple: None. A.H.Tjaden: None. S.Manchanda: Advisory Panel; Inspire. D.Ehrmann: None. K.J.Nadeau: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. B.Mokhlesi: None. Rise consortium: n/a. Funding American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute

Poor sleep and obstructive sleep apnea (OSA) have both been associated with worsening neurocognitive function. In the Restoring Insulin Secretion (RISE) Study, we assessed the relationship between presence and severity of OSA and cognition in treatment-naïve adults (n=179) with prediabetes or early T2D. A cognitive battery (CogState™ and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Wrist accelerometers worn for 7 days measured average sleep duration and efficiency. Other sleep outcomes were measured during one night of laboratory polysomnography. Linear regression models were fit to assess independent relationships between cognition and sleep measures. The cohort consisted of 44% females, 56% males; 53% white, 33% black, 6% Hispanic; age 54.7±8.9 years and BMI 34.7±5.4 kg/m2 (mean±SD). Based on ADA criteria, 73% had prediabetes and 27% had T2D. Sleep duration was 6.5±1.0 h; sleep efficiency was 85.9±7.5%; 26% had moderate OSA, 40% had severe OSA. After adjustment for age, sex, race/ethnicity, education, and BMI, higher sleep efficiency was associated with better visual pattern separation (as measured by the One Card Learning Test; p=0.039) but not with any other neurocognitive assessment. In the RISE cohort, measures of OSA severity (apnea-hypopnea index, oxygen desaturation index, sleep duration below 90% oxygen saturation, microarousal index) were not associated with baseline cognition. This cross-sectional analysis shows a high prevalence of moderate/severe OSA in treatment-naïve adults with prediabetes or early T2D. Although higher sleep efficiency was associated with better visual pattern separation, it was not associated with other measures of cognitive function. Further, OSA severity was not associated with measures of neurocognition. Disclosure K.A.Temple: None. A.H.Tjaden: None. D.Ehrmann: None. S.Manchanda: Advisory Panel; Inspire. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.Craft: None. B.Mokhlesi: None. Rise consortium: n/a. Funding American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; U.S. Department of Veterans Affairs; Kaiser Permanente Southern California

Disproportionately increased proinsulin (PI) relative to C-peptide (CP) is a marker of inefficient β cell PI processing. To determine whether PI processing differs between youth (Y) and adults (A) with impaired glucose tolerance (IGT) and drug naïve T2D, we measured PI and CP in 58 Y (81% IGT, 69% female, 26% white, 22% black, 40% Hispanic, BMI=37±6 kg/m2) and 322 A (71% IGT, 52% female, 47% white, 28% black, 19% Hispanic, BMI=35±5 kg/m2) in the Restoring Insulin Secretion (RISE) Study. We assessed fasting PI, CP, PI/CP, and acute PI (API) and CP (ACP) responses to glucose (Rg) (APIRg, ACPRg, APIRg/ACPRg) and arginine at maximal (Rmax) glycemic potentiation (APIRmax, ACPRmax, APIRmax/ACPRmax) during a hyperglycemic clamp. Fasting PI, CP, and PI/CP were higher in Y vs. A, suggesting PI processing in the fasted state is lower in Y (Table) . APIRg and APCPg were higher in Y, and APIRg/ACPRg was similar. APIRmax, but not ACPRmax, was lower in Y. Thus, APIRmax/ACPmax was lower in Y, suggesting PI processing at maximal β cell stimulation is greater in Y. These results suggest that increased fasting β-cell secretory demand in Y may decrease the time available for PI processing and cause the release of more immature granules during fasting. Y may utilize a larger pool of granules in which PI processing is more complete when secretory demand is maximal. Disclosure T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. S.Sam: None. A.H.Tjaden: None. S.Edelstein: None. K.J.Nadeau: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. M.Cree-green: None. D.A.Ehrmann: None. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California

In the Restoring Insulin Secretion (RISE) Study, youth (Y) compared to adults (A) had enhanced β-cell (greater incremental C-peptide [CP] responses) and α-cell responsiveness (greater glucagon [GG] suppression) . As GLP-1 increases CP and decreases GG, we measured GLP-1 (Mercodia) during a 3-h oral glucose tolerance test (OGTT) in 65 Y (age: 14.2 y) and 65 A (51.0 y) to determine if greater GLP-1 release explained age-related differences in CP and GG responses. Groups were matched for sex (71% female) , race/ethnicity (29% white, 22% black, 37% Hispanic) and IGT/drug naïve T2D (80/20%) status and did not differ by BMI (36.7±6.0 vs. 35.3±4.1 kg/m2) . We calculated fasting, early (0-to-30 mins; ∆) and incremental area under the curve (iAUC) responses for G, CP and GLP-1, and decrements in GG (d∆; dAUC) . Y and A did not differ in fasting or OGTT glycemic responses, but Y had greater fasting CP, ∆CP and iAUC CP, more d∆GG suppression, and a trend for more diGG suppression, than A (Table) . Fasting GLP-1 was not different in Y vs. A, but stimulated GLP-1 was lower in Y throughout the OGTT. In conclusion, in Y higher CP and lower GG during an OGTT, paired with lower GLP-1 concentrations, suggest that the enhanced β- and α-cell responsiveness to GLP-1 could be due to increased sensitivity of the islet cells to the incretin, rather than a primary increase in GLP-1 release. Disclosure K.J.Nadeau: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. A.H.Tjaden: None. D.A.Ehrmann: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Caprio: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. K.A.Temple: None. A.Xiang: None. Funding American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California

Abstract Insulin resistance is common among women with PCOS independent of adiposity. However, the severity of insulin resistance in these women worsens with obesity especially in those who present with the classical phenotype of PCOS (NIH criteria) consisting of hyperandrogenism and menstrual irregularity. Hence, obese women with PCOS, especially those with the classic phenotype of PCOS, are at high risk for metabolic complications. These complications include type 2 diabetes (DM2), metabolic syndrome, dyslipidaemia and obstructive sleep apnoea (OSA). Additionally, these women are at increased risk for cardiovascular disease even though the exact risk for this complication is not established. Due to heightened risk for metabolic disorders, close screening and follow-up for development of glucose intolerance, metabolic syndrome, and OSA is essential and is supported by current guidelines. Management of women with PCOS is individualized and should depend on the patient’s symptoms as well as their risk for development of various complications.

OBJECTIVE:The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS:The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS:BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function. CONCLUSIONS:Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function.

Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea are frequently associated with polycystic ovary syndrome (PCOS) but remain underrecognized. Women with PCOS have a 2-4 times higher risk of NAFLD independent of body mass index than healthy weight-matched controls. Insulin resistance and hyperandrogenemia together play a central role in the pathogenesis of NAFLD. Timely diagnosis of NAFLD is important because its progression can lead to nonalcoholic steatohepatitis and/or advanced liver fibrosis that can eventually result in liver-related mortality. The presence of NAFLD has also been associated with increased risks of type 2 diabetes, cardiovascular events, overall mortality, and extrahepatic cancers. The treatment of NAFLD in PCOS should include lifestyle interventions. Glucagon-like peptide 1 receptor agonists have shown promising results in patients with PCOS and NAFLD, but future randomized trails are needed to confirm this benefit. Likewise, the use of combined oral estrogen-progestin contraceptives may provide a benefit by decreasing hyperandrogenemia. Sleep disordered breathing is common among women with PCOS and is responsible for a number of cardiometabolic derangements. Obstructive sleep apnea is most often found in overweight and obese women with PCOS, but as is the case with NAFLD, its prevalence exceeds that of women who are of similar weight without PCOS. Left untreated, obstructive sleep apnea can precipitate or exacerbate insulin resistance, glucose intolerance, and hypertension.

Objective: Identify predictorsof glycemic worsening among youth and adults with impaired glucose tolerance(IGT) or recently-diagnosed type 2 diabetes in the RISE Study. Research Design and Methods: Ninety-oneyouth (10-19 years) were randomized 1:1 to 12 months of metformin (MET), or 3months of glargine followed by 9 months of metformin (G-MET); 267 adults toMET, G-MET, liraglutide plus MET (LIRA+MET) or placebo for 12 months. Allparticipants underwent baseline hyperglycemic clamp and 3-h oral glucosetolerance test (OGTT) at baseline, month-6, month-12 and off treatment at month-15and month-21. Cox models identified baseline predictors of glycemic worsening (HbA1cincrease ≥0.5% from baseline). Results: Glycemic worseningoccurred in 17.8% of youth vs. 7.5% of adults at month-12 (p=0.008), and 36% ofyouth vs. 20% of adults at month-21 (p=0.002). In youth, glycemic worsening didnot differ by treatment. In adults, month-12 glycemic worsening was less on LIRA+METvs. placebo (HR 0.21, CI 0.05-0.96, p=0.044). In both age groups, lower baselineclamp-derived β-cell responses predicted month-12 and month-21 glycemicworsening (p<0.01); lower baseline OGTT-derived β-cell responses predicted month-21worsening (p<0.05). In youth, higher baseline HbA1c and 2-h glucose predictedmonth-12 and month-21 glycemic worsening and higher fasting glucose predicted month-21worsening (p<0.05). In adults, lower clamp and OGTT-derived insulinsensitivity predicted month-12 and month-21 worsening (p<0.05). Conclusions: Glycemicworsening was more common among youth than adults with IGT orrecently-diagnosed type 2 diabetes, predicted by lower baseline β-cell responsesin both groups, hyperglycemia in youth and insulin resistance in adults.

Insulin resistance is common among women with PCOS independent of adiposity. However, the severity of insulin resistance in these women worsens with obesity especially in those who present with the classical phenotype of PCOS (NIH criteria) consisting of hyperandrogenism and menstrual irregularity. Hence, obese women with PCOS, especially those with the classic phenotype of PCOS, are at high risk for metabolic complications. These complications include type 2 diabetes (DM2), metabolic syndrome, dyslipidaemia and obstructive sleep apnoea (OSA). Additionally, these women are at increased risk for cardiovascular disease even though the exact risk for this complication is not established. Due to heightened risk for metabolic disorders, close screening and follow-up for development of glucose intolerance, metabolic syndrome, and OSA is essential and is supported by current guidelines. Management of women with PCOS is individualized and should depend on the patient’s symptoms as well as their risk for development of various complications.

Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release. Research Design and Methods: In 66 youth and 350 adults with IGT or drug-naïve, recently diagnosed type 2 diabetes, we performed hyperglycemic clamps and OGTTs. From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L and arginine-stimulated glucagon (AGR) and C-peptide (ACPR) responses at glucose >25 mmol/L. Results: Fasting (7.63±3.47 vs 8.55±4.47 pmol/L; mean±SD; p=0.063) and steady-state glucagon (2.24±1.46 vs 2.49±1.96 pmol/L, p=0.234) were not different in youth and adults, while AGR was lower in youth (14.1±5.2 vs 16.8±8.8 pmol/L, p=0.001). Significant age group differences in M/I, fasting C-peptide, steady-state C-peptide and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults (r=0.133, p=0.012), and negatively correlated in youth (r= -0.143, p=0.251). In both age groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r=0.209, p=0.091; adults r=0.335, p<0.001) and lower M/I (youth r= -0.228, p=0.066; adults r= -0.324, p<0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth. Conclusions: Youth with IGT or drug-naïve, recently diagnosed type 2 diabetes have hyper-responsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared to adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults.

Objective: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet beta-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with beta-cell function in overweight/obese adults with prediabetes or recently-diagnosed, treatment-naïve type 2 diabetes. Research Design and Methods: 221 adults (57.5% men, age 54.5±8.7 years, BMI 35.1±5.5 kg/m2) completed one week of wrist actigraphy and one night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived and clamp-derived outcomes were evaluated with adjusted regression models. Results: Mean±SD objective sleep duration by actigraphy was 6.6±1.0 hours/night. OSA defined as an apnea-hypopnea index (AHI) ≥5 events per hour was present in 89% of the participants; 20% mild, 28% moderate and 41% severe. Higher AHI was associated with higher HbA1c (p =0.007). However, OSA severity, measured by either AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 h vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity or beta-cell responses. Conclusion: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently-diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or beta-cell responses.

ObjectiveThe aim of this study was to examine the relationship between changes in liver fat and changes in insulin sensitivity and β‐cell function 2 years after gastric banding surgery.MethodsData included 23 adults with the surgery who had prediabetes or type 2 diabetes for less than 1 year and BMI 30 to 40 kg/m2 at baseline. Body adiposity measures including liver fat content (LFC), insulin sensitivity (M/I), and β‐cell responses (acute, steady‐state, and arginine‐stimulated maximum C‐peptide) were assessed at baseline and 2 years after surgery. Regression models were used to assess associations adjusted for age and sex.ResultsTwo years after surgery, all measures of body adiposity, LFC, fasting and 2‐hour glucose, and hemoglobin A1c significantly decreased; M/I significantly increased; and β‐cell responses adjusted for M/I did not change significantly. Among adiposity measures, reduction in LFC had the strongest association with M/I increase (r = −0.61, P = 0.003). Among β‐cell measures, change in LFC was associated with change in acute C‐peptide response to arginine at maximal glycemic potentiation adjusted for M/I (r = 0.66, P = 0.007). Significant reductions in glycemic measures and increase in M/I were observed in individuals with LFC loss >2.5%.ConclusionsReduction in LFC after gastric banding surgery appears to be an important factor associated with long‐term improvements in insulin sensitivity and glycemic profiles in adults with obesity and prediabetes or early type 2 diabetes.

Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. Research Design and Methods: Glucagon was measured in three randomized, parallel, clinical studies: (1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; (2) 267 adults studied at the same timepoints and treated with MET, G/M, liraglutide plus metformin (L+M) or placebo (PLAC); and (3) 88 adults studied at baseline, and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). Results: No change in fasting glucagon, steady-state glucagon or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all p≤0.005), which was maintained three months after treatment withdrawal (all p<0.01). LB in adults also reduced fasting glucagon, steady-state glucagon and AGR at 12 and 24 months (p<0.05 for all, except AGR at 12 months [p=0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributed to weight loss in both interventions.

We compared 3-hr OGTT model-derived measures of insulin sensitivity and β-cell function after 12 mo treatment with placebo (PLAC), metformin (MET), liraglutide plus MET (L+M), 3 mo glargine followed by 9 mo MET (G/M) and gastric banding (GB) in adults with IGT or T2D in the Restoring Insulin Secretion (RISE) Study. Modeling parameters included insulin sensitivity (OGIS), insulin secretion rate (ISR) at reference glucose 6.5 mM (ISR@6.5), total integrated ISR (tISR), glucose sensitivity (GS: slope ISR vs. glucose concentration) and rate sensitivity (RS: ISR relative to glucose rate of change). Adjusted linear mixed models compared model parameters over time within and between each study arm. Results: Baseline model parameters did not differ by treatment arm. OGIS increased in all groups except PLAC. ISRs and GS increased in L+M but decreased or were unchanged in the other treatment arms. RS only increased in the G/M and GB arms. Treatment effects differed by arm. For L+M, GS and ISRs were increased vs. all other arms. For GB, RS was increased and tISR decreased vs. PLAC and GS was increased vs. MET. In summary, L+M augments insulin secretion and increases GS, while GB increases RS. Clinically, both L+M and GB appear to improve β-cell function at 12 mo and may benefit adults with IGT or recent-onset T2D while on treatment. Disclosure K. Utzschneider: Other Relationship; Self; Medtronic. L. El Ghormli: None. S. Sam: None. D.A. Ehrmann: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. E. Barengolts: None. T.S. Hannon: None. M. Tripputi: None. S. Edelstein: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. T. Consortium: None. Funding American Diabetes Association (1-14-RISE-01); National Institute of Diabetes and Digestive and Kidney Diseases