Background:Type 1 diabetes (T1D) results in the loss of endogenous production of insulin and C-peptide, which are co-secreted by pancreatic β cells. Serum C-peptide following mixed-meal tolerance tests is commonly used in T1D trials to assess residual insulin secretion. Urine C-peptide (UCP) offers a non-invasive alternative suitable for home collection. Here, we aimed to optimize urine handling practices to support remote urine C-peptide monitoring in clinical trial settings. Methods:Randomly-voided urine was collected from 18 non-diabetic participants (mean age: 46.6 years; 94.4% female). Samples were treated with no preservative (NP), boric acid (BA), or sodium carbonate (SC) and incubated at 4°C or room temperature (RT, 22°C) for up to 72 h. Use of cold packs after initial refrigeration was also tested. UCP was quantified using the TOSOH immunoenzymatic assay and normalized to urine creatinine (UCP:Cr). Stability was expressed as percent change from baseline (%UCP:Cr). Results:NP samples lost %UCP:Cr more rapidly at RT, with decreases at 48 h (-16%, P < 0.05) and 72 h (-21%, P = 0.02) compared to 4°C. BA-preserved samples had declined %UCP:Cr at 72 h (-16%; P = 0.04) compared to 4°C. SC maintained UCP:Cr stability, showing no significant change in %UCP:Cr between 4°C and RT. Samples kept on cold packs following initial refrigeration showed no significant loss in %UCP:Cr compared to samples continuously refrigerated for 72 h. Conclusions:Cold storage of urine slows UCP:Cr degradation, and SC stabilizes UCP:Cr at room temperature. Our findings suggest that UCP:Cr offers a practical option for at-home urine collection in clinical studies.

INTRODUCTION:We report the feasibility and cognitive outcomes of a stage 1b randomized trial testing 3 months of home-delivered high polyphenol snacks (e.g., nuts, berries) and online speed of processing training among older adults with 12 or fewer years of education. METHODS:One hundred eighty participants were randomized to polyphenol-rich snacks and online cognitive training, polyphenol snacks and online control games, control snacks and cognitive training, or control snacks and control games. The outcomes were feasibility of recruitment, retention, and adherence (RRA) and change in a cognitive composite score. RESULTS:Feasibility goals for RRA were met. Improvements in the cognitive score were evident in all groups (effect sizes ranged from 0.15-0.35) but improvements did not differ significantly between arms. DISCUSSION:Dementia prevention trials with longer intervention and follow-up focused on adults with limited formal education should be considered given the observed cognitive gains in those with elevated risk. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov (NCT03419052). HIGHLIGHTS:The study focused on adults with low education; a group with a high risk for cognitive decline. Two interventions were tested in a randomized trial design that included two controls. Nutrition intervention was designed with input from adults with limited education. PRIMARY OUTCOME:A cognitive composite score was formed from five established cognitive tests. The study establishes the feasibility of dementia prevention targeting adults with low education.

Pancreatic ductal adenocarcinoma-related diabetes mellitus (PDAC-DM) is a paraneoplastic syndrome with a poorly understood pathophysiology. PDAC-DM is often clinically confused with type 2 diabetes, resulting in delayed cancer detection and poorly individualised hyperglycaemia treatment. We investigated whether these forms of diabetes can be distinguished at the metabolic level. Adults with either cancer treatment-naive PDAC-DM (n=28) or type 2 diabetes (n=97), and with diabetes onset within 3 years, underwent mixed-meal tolerance tests to investigate glucose metabolism. Outcomes included insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), beta cell function (oral disposition index), insulin clearance, and postprandial glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) responses. Compared with type 2 diabetes, individuals with PDAC-DM showed 2.5-fold greater insulin sensitivity, 81

Tirzepatide induces weight reduction but the underlying mechanisms are unknown. This 6-week phase 1 study investigated early effects of tirzepatide on energy intake. Male and female adults without diabetes (n = 114) and a body mass index from 27 to 50 kg per m2 were randomized 1:1:1 to blinded once-weekly tirzepatide or placebo, or open-label once-daily liraglutide. The primary outcome was change from baseline to week 3 in energy intake during an ad libitum lunch with tirzepatide versus placebo. Secondary outcomes assessed self-reported ingestive behavior and blood-oxygenation-level-dependent functional magnetic resonance imaging with food photos. Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference -524.6 kcal (95% confidence interval -648.1 to -401.0), P < 0.0001). With regard to secondary outcomes versus placebo, tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment but did not impact volitional restriction of dietary intake. At week 3 versus placebo, tirzepatide did not statistically significantly impact blood-oxygenation-level-dependent activation to highly palatable food photos (aggregated category of high-fat, high-sugar foods and high-fat, high-carbohydrate foods) but decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus. Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior. ClinicalTrials.gov registration: NCT04311411 .

Introduction and Objective: Type 1 diabetes (T1D) is characterized by decreased endogenous insulin production and reduced levels of C-peptide, which is secreted alongside mature insulin from pancreatic β cells. Measurement of serum C-peptide after a mixed meal challenge is the gold standard for testing endogenous insulin production in T1D; however, urine C-peptide (UCP) has emerged as an alternative that avoids venipuncture and has the potential for home collection. Our objective was to establish best practices for handling urine samples to facilitate remote monitoring of C-peptide in clinical cohorts. Methods: Randomly voided urine was collected from 18 non-diabetic individuals (mean age = 46.6 years, range 22-63 years, 94.4% female). Samples were treated immediately with 66.5 mg boric acid (BA), 42.5 mg sodium carbonate (SC), or no preservative (NP). Following incubation for 12, 24, 48, or 72 hours at either 4°C or 22°C, samples were frozen at -80°C. UCP was quantitated with the TOSOH immunoenzymatic assay normalized to urine creatinine measured by the Jaffe method on a Roche Integra 400. UCP degradation was expressed as the percent change in the UCP/creatinine ratio (%UCPCR) relative to 0-hour baseline. Data was analyzed using two-way repeated measures ANOVA and Tukey post-hoc test. Results: In NP groups, incubation at 22°C decreased %UCPCR at 48 hours (-16%, p=0.0309) and at 72 hours (-21%, p =0.0068) compared to 4°C. In BA groups, incubation at 22°C reduced the %UCPCR at 72 hours (-16%; p=0.0053) compared to 4°C. SC samples showed no significant change in %UCPCR between 4°C and 22°C incubation. Comparing the difference between 22°C and 4°C samples, SC groups showed a trend of improved %UCPCR over BA groups at 24 hours (p=0.0559), 48 hours (p=0.0640), and 72 hours (p=0.0658). Conclusion: C-peptide is stable in randomly voided urine and the UCP/creatinine ratio may be a valuable alternative for long-term follow-up of clinical cohorts. UCP stability is improved with refrigeration and sodium carbonate as a preservative. E.H. Hagedorn: None. C. Rostron: None. R.V. Considine: Research Support; Lilly USA LLC, Adipo Therapeutics. A.J. Acton: None. M.A. Oswalt: None. C. Evans-Molina: Advisory Panel; DiogenX. Research Support; Bristol-Myers Squibb Company, Lilly Diabetes. Advisory Panel; Isla Technologies, Neurodon. Research Support; Neurodon. R01 DK127236-01A1, R01 DK127308-01, R01 DK133881P30, DK097512VA, 5I01BX001733-11 VA, 3T32DK064466-22S1

Introduction and Objective: Brown fat in humans has been associated with a lower risk of obesity and type 2 diabetes. This study investigated the regulation of browning marker UCP1 by a novel γ-secretase inhibitor ADPO-002 in mice in vivo, and in adipose tissue excised from humans with obesity. Methods: Lyophilized PLGA nanoparticles (NP; ~4.5% ADPO-002 w/w, 0.2 and 1 mg) and blank NPs were injected into inguinal white adipose tissue (iWAT) of C57BL/6J mice (N=3/group). After 7 days, iWAT was collected for histology, RNA isolation, and UCP1 mRNA quantification by RT-qPCR (statistics: ANOVA). For the human explant study, adipose tissue was collected from 10 bariatric surgery patients (3 men and 7 women, BMI 41.4±11.5 kg/m2). These tissue samples were cultured and treated with DMSO or 30 µM ADPO-002. The tissue was homogenized after 7 days, and UCP1 expression was quantified via ELISA (ng UCP1/mg total protein, statistics: Wilcoxon paired t test). Results: In mice, 0.2 and 1 mg ADPO-002 NP up-regulated UCP1 mRNA expression by 23-fold (p=0.4387) and 109-fold (p=0.0043), respectively compared to the control group. The browning phenotype was further confirmed by H&E staining. In human omental adipose tissue samples treated with 30 µM ADPO-002 (N=10 subjects) UCP1 protein expression significantly increased compared to the DMSO control (5.8±1.1 vs 3.1±0.7 ng/mg, p=0.0098). In human subcutaneous adipose tissue samples treated with 30 µM ADPO-002 (N=8 subjects) there was a trend for UCP1 protein expression to increase compared to the DMSO control (6.3±1.5 vs 3.8±0.8 ng/mg; p= 0.1094). Conclusion: The results suggest that ADPO-002 has a promising browning effect on mice iWAT and human subcutaneous and omental adipose tissue. M. Abedin: Employee; Adipo Therapeutics. K. Benkato: None. M.A. Oswalt: None. C.B. Crawford: None. R.V. Considine: Research Support; Lilly USA LLC, Adipo Therapeutics. M. Deng: Other Relationship; Adipo Therapeutics. Indiana Voucher Program and Adipo Therapeutics

The marked individual variability in response to common dietary exposures necessitates tailoring of dietary guidance to individuals, or small groups of individuals with similar needs, to optimize health. This is a complex task requiring integration of environmental, cultural, psychological, and biological contributions. Work in the area of precision nutrition is an effort to translate science into practice. A research roadmap developed through a National Institutes of Health conference identified many of the inputs that require quantification. Better characterization of ingestive behaviors is one key area. The aim of this narrative review is to summarize current understanding of the influences of age, sex, body mass index, ethnicity, and genetics on ingestive behaviors, including culture, sensory function, appetite, dietary intake, the gut-brain axis, and microbiome. To do so, the extant literature was accessed through search engines relevant to the various topics covered. Outcomes assessed varied topically. In addition to compiling evidence on the nature and magnitude of these relationships, this review highlights the degree of individual variability in attributes or responses to an intervention. More broadly, it documents: 1) that cause-and-effect relationships are difficult to establish as most are dynamic and interactive; 2) there are inherent and learned contributions to both behavior and biology that will require different considerations and offer different opportunities for manipulation; 3) a focus on intuitive approaches may not be as successful as desired; 4) that external influences can, and often do, override internal influences of biology; and 5) there are multiple ways to construct healthful diets. At the same time, it is vital that improved methods to characterize the multiple relevant inputs to ingestive behavior be developed. It is hoped that the evidence compiled here will inform efforts to develop precision nutrition guidance.

Introduction and Objective: Tirzepatide is a GIP/GLP-1 receptor agonist approved in the US for T2D and obesity treatment. Both GIP and GLP-1 receptors are found in brain areas involved in appetite regulation. We investigated tirzepatide’s effects on brain activation in response to food images using blood oxygenation level dependent (BOLD) functional MRI (fMRI). Methods: In this 6-week, phase 1 study, 114 participants with obesity were randomized to QW tirzepatide 5 mg or QW placebo (blinded), or QD liraglutide 1.8 mg (open label). Participants had fMRI scans when fasting at baseline and the primary endpoint, week 3, while viewing images of high-fat and high-sugar (HFHS) foods or high-fat and high-carbohydrate (HFHC) foods and non-food items. Changes in positive brain activation from baseline to week 3 to HFHS and HFHC images were assessed relative to non-food images within brain regions of interest shown in the Figure. Results: At week 3, only tirzepatide-treated participants showed statistically significant decreases in HFHS activation vs. placebo in four brain regions: medial frontal and cingulate gyri, hippocampus, and orbitofrontal cortex, see Figure. Changes in HFHC activation for tirzepatide or liraglutide were non-significant vs. placebo in all brain regions of interest. Conclusion: Tirzepatide reduced brain activation to images of high-fat high-sugar foods in multiple brain regions implicated in appetite regulation. O. Carmichael: Research Support; Eli Lilly and Company. Advisory Panel; Novo Nordisk. C.K. Martin: Advisory Panel; EHE Health, Wondr Health. Other Relationship; Academy of Nutrition and Dietetics, ABGIL. Research Support; Foundation for Food and Agriculture Research; Kroger Co. Zero Hunger / Zero Waste Foundation, Weight Watchers International, Eli Lilly and Company, Evidation Health. Other Relationship; Obesity Action Coalition, The Bray Course. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. D.A. Kareken: Other Relationship; Eli Lilly and Company. S. Carnell: Research Support; Eli Lilly and Company. U. Dydak: Consultant; American Regent, Inc. R.D. Mattes: Research Support; Lilly Diabetes, Almond Board of California, Grain Food Foundation. Advisory Panel; Mars Foods, General Mills, Grain Food Foundation. Consultant; Bright Seed, Calorie Control Council, Medifast, Inc. D. Scott: None. D.O. Svaldi: Employee; Eli Lilly and Company. H. Nishiyama: None. L. Biernat: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly Diabetes. Stock/Shareholder; Lilly Diabetes. Z. Milicevic: Employee; Eli Lilly and Company. S. Shcherbinin: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Eli Lilly and Company

Journal Article Accepted manuscript Anamorelin: Ghrelin Receptor Agonism as a Potential Intervention for Osteosarcopenia Get access Palak Patadia, MD, Palak Patadia, MD Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Search for other works by this author on: Oxford Academic Google Scholar Robert V Considine, PhD Robert V Considine, PhD Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Corresponding author: Robert V Considine, PhD, Indiana University School of Medicine, 639 Barnhill Dr., Rm MS224B, Indianapolis, Indiana 46202, 317-278-2389, rconsidi@iu.edu https://orcid.org/0000-0002-5033-3642 Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, dgae043, https://doi.org/10.1210/clinem/dgae043 Published: 23 January 2024 Article history Received: 09 January 2024 Editorial decision: 13 January 2024 Accepted: 19 January 2024 Published: 23 January 2024

Background and Aims: Identifying simple markers of risk for worsening glucose can allow care providers to target therapeutic interventions according to risk of worsening glycemic control. We aimed to determine which routine clinical measures herald near-term glycemic worsening in early type 2 diabetes(T2D). Methods: The Early Diabetes Intervention Program (EDIP) was a clinical trial in individuals with screen-detected T2D [HbA1C 6.3+0.63%(45+5mmol/mol)]. During the trial some participants experienced worsening fasting blood glucose (FBG). We investigated the time course of FBG, HbA1c, weight, and other clinical factors to determine which might herald glycemic worsening over the next year. Results: Progressors (62/219, 28.5%) had higher FBG than non-progressors at baseline [118 vs 130mg/dL (6.6 vs 7.2 mmol/L), p=<0.001]. FBG was stable except in the year of progression, when progressors exhibited a large 1-year rise [mean change 14.2mg/dL(0.79 mmol/L)]. Current FBG and antecedent year change in FBG were associated with progression(p<0.01), although the magnitude of change was too small to be of clinical utility (0.19 mg/dL; 0.01 mmol/L). Current or antecedent year change in HbA1c, weight, TG or HDL were not associated with progression. In the year of glycemic worsening, rising glucose was strongly associated with a concurrent increase in weight (p<0.001). Conclusions: Elevated FBG but not HbA1c identified individuals at risk for imminent glycemic worsening; the subsequent large rise in glucose was associated with a short-term increase in weight. Glucose and weight surveillance provide actionable information for those caring for patients with early diabetes.

Does tirzepatide (TZP) influence energy intake and eating attitudes in chronic weight management (CWM)?

Objectives: Chronic pancreatitis (CP) is associated with a high lifetime prevalence of diabetes mellitus (CPDM). However, our understanding of the pathophysiology of CP-DM in contrast to type 2 DM (T2DM) remains incomplete. Method: We used a mixed meal tolerance test (MMTT 120 min) to assess metabolic alterations in 170 participants with CPDM or with T2DM < 3 years. The DM duration in CP was dichotomized as ≥ or < 3 years. We compared estimates of insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and beta cell function (oral disposition index or ODI) between subgroups using Wilcoxon rank-rum tests. Results: Area under the curve (AUC) for glucose was increased, while measures of insulin secretion were reduced in CPDM vs T2DM (Table 1). Glucagon and GIP did not differ. Insulin sensitivity was increased in CPDM <3 yrs but this cohort differs from T2DM with BMI being lower. Interestingly, CPDM ≤ 3 yrs and CPDM >3 yrs did not show any significant differences in insulinogenic index, Matsuda index and ODI. Conclusion: The most important difference seen in both CPDM cohorts was a significant reduction in insulin secretion. Future studies are needed to understand how these differences can be used to develop personalized anti-hyperglycemic therapy for this patient population. Disclosure Y.C. Kudva: Research Support; Dexcom, Inc. Other Relationship; Tandem Diabetes Care, Inc., Medtronic. Y. Li: Stock/Shareholder; Agenus, Inc., Mink Therapeutics, Inc. F. Wang: None. D. Yadav: Consultant; Pfizer Inc. Research Support; AbbVie Inc. D.K. Andersen: None. Z.I. Saeed: None. M. Bellin: Research Support; ViaCyte, Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated, Insulet Corporation. Research Support; Dexcom, Inc. W.E. Fisher: Other Relationship; Intuitive Surgical. K. Cusi: Research Support; Echosens, Boehringer-Ingelheim, Quest Diagnostics, Inventiva Pharma, LabCorp, Nordic Bioscience A/S. Consultant; Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer-Ingelheim, Lilly Diabetes, 89bio, Inc., GlaxoSmithKline plc, Novo Nordisk, Siemens Healthcare Diagnostics, Sagimet Biosciences, Terns Pharmaceuticals. W. Park: Research Support; AbbVie Inc. Advisory Panel; Pfizer Inc. Consultant; Arctx Medical. Advisory Panel; Ariel Medicine. Consultant; Capsovision, Olympus. Advisory Panel; Horizon Therapeutics plc, Nestlé Health Science. S. Rizvi: None. F.G. Toledo: Advisory Panel; Sanofi. Research Support; Dompé. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. J. Serrano: None. M.O. Goodarzi: Advisory Panel; Nestlé Health Science, Organon. P. Hart: None. Funding NIDDK (U01DK108327)

Background Depression is an independent risk factor for cardiovascular disease (CVD), but it is unknown if successful depression treatment reduces CVD risk. Methods Using eIMPACT trial data, we examined the effect of modernized collaborative care for depression on indicators of CVD risk. A total of 216 primary care patients with depression and elevated CVD risk were randomized to 12 months of the eIMPACT intervention (internet cognitive-behavioral therapy [CBT], telephonic CBT, and select antidepressant medications) or usual primary care. CVD-relevant health behaviors (self-reported CVD prevention medication adherence, sedentary behavior, and sleep quality) and traditional CVD risk factors (blood pressure and lipid fractions) were assessed over 12 months. Incident CVD events were tracked over four years using a statewide health information exchange. Results The intervention group exhibited greater improvement in depressive symptoms ( p < 0.01) and sleep quality ( p < 0.01) than the usual care group, but there was no intervention effect on systolic blood pressure ( p = 0.36), low-density lipoprotein cholesterol ( p = 0.38), high-density lipoprotein cholesterol ( p = 0.79), triglycerides ( p = 0.76), CVD prevention medication adherence ( p = 0.64), or sedentary behavior ( p = 0.57). There was an intervention effect on diastolic blood pressure that favored the usual care group ( p = 0.02). The likelihood of an incident CVD event did not differ between the intervention (13/107, 12.1%) and usual care (9/109, 8.3%) groups ( p = 0.39). Conclusions Successful depression treatment alone is not sufficient to lower the heightened CVD risk of people with depression. Alternative approaches are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02458690

Introduction: Transformation of white adipocytes into beige adipocytes, known as adipocyte browning, holds great promise for development of new therapeutics. Our previous studies have demonstrated nanoparticle-based delivery of dibenzazepine (ADPO-002), a γ-secretase inhibitor, induces browning of white adipose tissue in obese mice and in pigs. The current study aims to investigate the browning efficacy of ADPO-002 in human adipose tissue organ culture. Methods: Abdominal subcutaneous and omental adipose tissue samples were collected from 24 subjects undergoing bariatric surgery (BMI 47.5±3.2 kg/m2, age 44.8±3.0 yr). The study was approved by the Ascension St. Vincent hospital IRB and all subjects provided informed consent. Tissues were cut into small pieces (~5-10 mg) using surgical scissors and cultured in medium M199 supplemented with 0.7 nM insulin and 10 nM dexamethasone. The treatment groups were DMSO (negative control), 50 µM forskolin (positive control), and 3, 10 and 30 µM ADPO-002. After 7-days treatment, total RNA was isolated, and RT-qPCR performed for the browning marker genes PRDM16 and PGC1A. Statistical significance was determined using Wilcoxon non-parametric paired t-test. Results: In omental adipose tissue, 30 µM ADPO-002 significantly increased PRDM16 (429.1±149.3 vs 10.6±4.9 relative units, p=0.0020) and PGC1A (117.4±58.7 vs 58.5±30.2 relative units, p=0.0273) expression compared to the control group. In subcutaneous adipose tissue, 30 µM ADPO-002 significantly upregulated PRDM16 expression compared to control group (398.9±198.6 vs 22.06±6.28 relative units, p=0.0039). Conclusion: These findings suggest that ADPO-002 treatment increases the expression of genes associated with increased mitochondrial expression. This finding supports the hypothesis that inhibition of γ-secretase can increase browning in human adipose tissue. Disclosure M. Abedin: Employee; Adipo Therapeutics LLC. W. Freije: None. M.A. Oswalt: None. A.J. Acton: None. C.B. Crawford: None. M.M. Inman: None. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. M. Deng: Other Relationship; Adipo Therapeutics. Funding Indiana Innovation Voucher

ObjectiveBariatric surgery reduces sweet-liking, but mechanisms remain unclear. We examined related brain responses.MethodsA total of 24 nondiabetic bariatric surgery and 21 control participants with normal weight to overweight were recruited for an observational controlled cohort study. They underwent sucrose taste testing outside the scanner followed by stimulation with 0.40M and 0.10M sucrose compared with water during functional magnetic resonance imaging. A total of 21 bariatric participants repeated these procedures after surgery.ResultsPerceived sweet intensity was not different among the control, presurgery, or postsurgery groups. Bariatric participants' preferred sweet concentration decreased after surgery (0.52M to 0.29M; p = 0.008). Brain reward system (ventral tegmental area, ventral striatum, and orbitofrontal cortex) region of interest analysis showed that 0.40M sucrose activation (but not 0.10M) decreased after surgery. Sensory region (primary somatosensory and primary taste cortex) 0.40M sucrose activation was unchanged by surgery and did not differ between control and bariatric participants. Primary taste cortex activation to 0.10M sucrose solution was greater in postsurgical bariatric participants compared with control participants.ConclusionsBariatric surgery reduces the reward system response to sweet taste in women with obesity without affecting activity in sensory regions, which is consistent with reduced drive to consume sweet foods.

Diabetes due to pancreatic ductal adenocarcinoma (PDAC-D) is often difficult to clinically distinguish from type 2 diabetes (T2D) and both insulin resistance and reduced insulin secretion have been implicated in its pathophysiology. Although these metabolic defects are similar to those seen in T2D, the degree to which they relatively contribute to hyperglycemia in PDAC-D has not been established. Additionally, there is a lack of understanding of alpha cell function in PDAC-D. We sought to address these gaps in the DETECT study (NCT03460769). Adults with PDAC-D (n=28) or T2D (n=99) (diabetes diagnosis <3 years) underwent a standardized liquid mixed-meal tolerance test with serum glucose, insulin, and glucagon measurements. Insulin sensitivity was assessed by the Matsuda index, insulin secretion by the insulinogenic index, and beta cell function by the oral disposition index. The mean duration of diabetes was 10.8 months in PDAC-D and 12.5 months in T2D (P=0.51). HbA1c was higher in PDAC-D (7.27% vs 6.58%, P=0.03). The area under the curve (AUC) of the glucose response was similar in PDAC-D vs T2D (232 vs. 238 mg.min/ml, P=0.08). Insulin sensitivity was 2.5x higher in PDAC-D than in T2D (3.65 vs 1.45, P<0.001). In contrast, insulin secretion was 81% lower in PDAC-D (18 vs 95 μU/mg, P<0.001), and the oral disposition index was 40% lower (0.80 vs. 1.32, P<0.001). Fasting glucagon was similar in PDAC-D and T2D (21.1 vs 17.7 pM, P=0.09). In both groups, glucagon rose after the meal, but the incremental AUC was 57% higher in PDAC-D (581 vs. 370 pM.min, P=0.01). These results suggest that impaired insulin secretion is considerably more important than insulin resistance in the etiology of hyperglycemia of PDAC-D and that post-prandial alpha-cell dysregulation is likely to play a greater role than previously recognized. Collectively, these data also suggest that targeting insulin and glucagon levels, rather than insulin resistance, may be a more effective strategy to treat PDAC-D. Disclosure F.G.S.Toledo: Research Support; Dompé. R.V.Considine: Research Support; Lilly Diabetes. S.T.Chari: Advisory Panel; Nestlé Health Science, Guardant, Bluestar genomics. S.C.Graham: None. D.K.Andersen: None. J.Rinaudo: None. J.Serrano: None. M.O.Goodarzi: Advisory Panel; Nestlé Health Science, Other Relationship; Nestlé Health Science. P.Hart: Consultant; Sagent Pharmaceuticals. On behalf of the cpdpc: n/a. Y.Li: Stock/Shareholder; Agenus, Inc. F.Wang: None. D.Yadav: None. M.Bellin: Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Research Support; Dexcom, Inc., ViaCyte, Inc. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. W.E.Fisher: None. Y.C.Kudva: Advisory Panel; Novo Nordisk, Research Support; Dexcom, Inc. W.Park: Advisory Panel; AbbVie Inc., Ariel Medicine, Nestlé Health Science, Consultant; Arctx Medical, Craif, Research Support; AbbVie Inc., Stock/Shareholder; Arctx Medical. Funding National Institutes of Health (U01DK108306, U01DK108288, U01DK108320, U01DK108323, U01DK108326, U01DK108327, U01DK108328, U01DK108300, U01DK108314, U01DK126300)

PURPOSE:Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM).METHODS:Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index.RESULTS:The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments.CONCLUSIONS:Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769).