bluuebunny/crossref_metadata_2025 huggingface dataset:
1564-P: Impaired Insulin Secretion Increases Glucagon Action on the Liver
Authors: TONELLO ALESSIO , LAURENTI MARCELLO C. , COBELLI CLAUDIO , VELLA ADRIAN , DALLA MAN CHIARA
Published: June 2023

The transition from prediabetes to diabetes is characterized by defects in insulin secretion and glucagon suppression in response to glucose. However, simultaneous estimation of both hormones actions on endogenous glucose production (EGP) remains a challenge. To address this, we studied 36 nondiabetic subjects on 2 occasions when endogenous hormone secretion was inhibited by somatostatin. Glucagon was infused at 0.65 ng/kg/min, at 0 min to prevent a fall in its concentration (non-suppressed - NS) or at 120 min to create a transient fall (suppressed - S). [3-3H]-glucose was infused to mimic an oral glucose challenge together with a prandial insulin infusion - one group received the full dose (100%), another 80% and another 60%. We tested models describing EGP as a function of glucose, insulin and glucagon concentrations. The optimal model assumes that EGP is suppressed by the actions of glucose, its rate of change and insulin in a remote compartment, while plasma glucagon stimulated EGP (through parameter SGn), with an effect that is evanescent. With 60% replacement (corresponding to severely impaired insulin secretion), SGn was significantly higher than with 80% (moderately impaired) and 100% replacement (p=0.02, Fig.1). This demonstrates that glucagon action on EGP is modulated by insulin concentrations, emphasizing the need to quantify secretion and action of both hormones when measuring postprandial islet function.

Disclosure

A. Tonello: None. M.C. Laurenti: None. C. Cobelli: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company.

Funding

Italian Minister for Education; National Institutes of Health (DK116723)
157-LB: A Randomized Trial of Continuous Glucose Monitoring upon Emergency Department Discharge
Authors: O'CONNOR MARK J. , DING XINYI , HERNANDEZ CAMILA , HUBACZ LISA M. , CHURCH RICHARD J. , O'CONNOR LAUREL
Published: June 2023

Background: People with type 2 diabetes (T2D), particularly those with limited access to longitudinal care, frequently present to the emergency department (ED), leading to increased hospital utilization and disjointed care. Continuous glucose monitoring (CGM) has been shown to improve patient engagement and glycemic outcomes in outpatients, so we hypothesized that it would be beneficial if initiated upon ED discharge.

Methods: We randomized adults with T2D who were seen in the ED for hypo- or hyperglycemia to either flash CGM or care coordination alone. All participants were scheduled to follow up in our diabetes specialty clinic within two or three weeks. Outcomes included clinic attendance, patient-reported diabetes-related distress, satisfaction with CGM, and follow-up hemoglobin A1c.

Results: We recruited 30 participants, including 13 with newly diagnosed T2D. We found no significant difference between the CGM (n=16) and control (n=14) groups in terms of clinic attendance (75 versus 64%, P=0.69) or the change in diabetes-related distress as measured via the Diabetes Distress Scale. Among participants in the CGM group who returned for follow up, 83% found CGM helpful, as did 90% of their providers. The mean A1c reduction after approximately 3 months was greater in the CGM group (5.2 versus 1.9%, P=0.051), although the groups were not balanced in terms of diabetes duration. Among participants with newly diagnosed T2D, excluding those missing data, five out of five in the CGM group had a follow-up A1c under 7% (from a mean baseline of 12.9%) compared to zero out of two in the control group (P=0.048).

Discussion: Our study demonstrates the feasibility of starting CGM in the ED, an important setting for engaging difficult-to-reach patients. We did not see an effect of CGM on follow-up clinic attendance or diabetes-related distress, but there was a trend towards improved A1c at 3 months in the CGM group. Our study was limited by its small sample size, however, as recruitment in the ED can be challenging.

Disclosure

M. J. O'connor: None. X. Ding: None. C. Hernandez: None. L. M. Hubacz: None. R. J. Church: None. L. O'connor: None.

Funding

Herman G. Berkman Diabetes Clinical Innovation Fund
1581-P: Systemic Alteration of Amino Acids Metabolism in Glutamate Dehydrogenase Gain-of-Function Mutation Knockin Mice
Authors: SU CHANG , HAN DONGNA , MENG SHI , ZHU QIUSHA , ZHOU XUE , JIANG HAOWEN , LI JIA , GONG CHUNXIU , LI CHANGHONG
Published: June 2023

Patients with gain-of-function (GoF) mutations of glutamate dehydrogenase (GDH) have protein-sensitive hypoglycemia, hyperammonemia, epilepsy, and intellectual disability (HI/HA syndrome). Studies of mouse models with a beta-cell specific expression of H454Y hGDH suggest that the mechanisms of HI are caused by increased glutaminolysis induced by GDH GoF in islets. However, the mechanism of hyperammonemia is still unknown. In order to study the systemic effects of GDH GoF, H454Y GDH knockin mice (H454Y-GDH-KI) were created. Enzyme kinetic of GDH in the brain, kidney and liver confirmed that H454Y was successfully expressed with impaired GTP inhibition. H454Y-GDH-KI mice have a ~2.5-fold elevation of plasma ammonia and fasting hypoglycemia, similar to HI/HA patients. Tissues (brain, liver and kidney) and plasma amino acids profiles were determined by LC-MS. Compared to wildtype, the amino acids profile in the kidney was unaltered in KI mice. In contrast, KI liver had 60% lower glutamine, unchanged glutamate and aspartate, increased branch chain amino acids, etc. The glutamine of KI brain was 40% lower than the wildtype, glutamate and GABA was unchanged. Interestingly, plasma glutamine in KI mice was 30% higher compared to controls. A similar phenomenon has also been observed in HI/HA patients. We hypothesize that hyperammonemia is mainly caused by the increased glutaminolysis in KI liver. Higher plasma glutamine can be explained by the increased activity of tissue glutamine synthetase (GS). GS and glutamine serve as an ammonia sink, which is the main mechanism for the removal of increased ammonia in KI mice. We therefore applied the GS inhibitor, methionine sulfoximine (MSO) to KI mice. MSO significantly increased ammonia levels in KI mice after a single dose of injection. These studies in H454Y-GDH-KI mice suggest that GDH GoF in the liver is the main cause of hyperammonemia. GS plays an important role in ammonia removal.

Disclosure

C.Su: None. D.Han: Employee; Nanjing AscendRare Pharmaceutical Technology. S.Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. Q.Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. X.Zhou: Employee; Nanjing AscendRare Pharmaceutical Technology. H.Jiang: None. J.Li: None. C.Gong: None. C.Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology.

Funding

Beijing Natural Science Foundation (L212037)
1586-P: Post-OGTT Low Blood Glucose in Individuals with Metabolic Syndrome, Metabolic Phenotypes, and Metabolic-Associated Fatty Liver Disease
Authors: GIGNAC THEO , MORISSETTE ARIANNE , AGRINIER ANNE-LAURE , GAGNON CLAUDIA , VOHL MARIE-CLAUDE , MARETTE ANDRE , CARREAU ANNE-MARIE
Published: June 2023

Introduction: Post-prandial low blood glucose (LBG) is usually associated with late postprandial hyperinsulinemia in metabolic syndrome (MetS), but have not been well studied.

Objectives: We aimed to 1) characterize insulin/glucose metabolism associated with LBG post 75g OGTT in a sample of individuals with MetS; and 2) assess the association between MAFLD (≥ 5% liver fat at MRI) and LBG.

Methods: Plasma glucose, insulin and c-peptide concentrations were measured on OGTT over 180 mins. Insulin sensitivity and secretion were assessed with the Oral Minimal Model. During OGTT, we defined glucose ≤ 50 mg/dl as LBG, glucose > 70 mg/dl as no LBG and glucose 51-70 mg/dl as undefined status and were excluded from this analysis.

Results: Of 82 participants, 50 were included and 15 (18 %) experienced LBG. Of the 33 participants who underwent MRI, 48% had MAFLD. Median age and BMI were 59 [IQR: 49-74] years and 28 [IQR: 26-31] kg/m2 respectively. Women represented 70% (n=35) of participants and experienced less LBG (p=0.0002) than men. Individuals experiencing LBG had higher insulin sensitivity (p=0.02), higher ß cell function (p=0.03), earlier glucose peaks (p<0.0001) and lower c-peptide peaks (p=0.007) than those without LBG. MAFLD was not associated with more LBG (p=0.7), but was associated with a different insulin curve. LBG+MAFLD status was associated with higher and later c-peptide and insulin levels compared to LBG without MAFLD status.

Conclusion: In contrary to our hypothesis, individuals with MetS without MAFLD experiencing glucose ≤ 50 mg/dl during OGTT displayed a healthier metabolic profile. However, individuals with MAFLD experiencing a LBG during OGTT had a glucose phenotype similar to the late post-prandial hyperinsulinemic hypoglycemia often found in prediabetes state and associated with worst metabolic parameters. This suggests that MAFLD may be an important feature of MetS associated with a different post-OGTT glucose metabolism.

Disclosure

T.Gignac: None. A.Morissette: None. A.Agrinier: None. C.Gagnon: Advisory Panel; Novo Nordisk, Other Relationship; Ascendis Pharma A/S, Research Support; Novo Nordisk. M.Vohl: None. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti. A.Carreau: Advisory Panel; Novartis, Consultant; Valbiotis, Speaker's Bureau; Novo Nordisk Canada Inc.
1587-P: The NADPH Oxidase 4 Regulates Anti-inflammatory Signals to Modulate Lipid Depot Distribution between Adipose Tissue and Liver
Authors: SZANTO ILDIKO
Published: June 2023

Excessive white adipose tissue (WAT) expansion and lipid load is associated with the onset of insulin resistance and Type 2 diabetes. In addition, lipid storage may “overflow” into the liver triggering the apparition of nonalcoholic fatty liver disease (NAFLD). Two major components linking white adipose tissue (WAT) dysfunction and NAFLD to insulin resistance are the deregulation of cellular redox homeostasis and the onset of chronic, low-grade inflammation. NADPH oxidases (NOX-es) produce oxidant molecules that control redox homeostasis and cytokine signaling in inflammatory cells. In particular, NOX4 is essential for the signal transduction of the transcription factor, Stat6 that mediates anti-inflammatory actions of IL-4 and IL-13. In order to elucidate the in vivo interaction between NOX4 and Stat6 and to assess their relevance in the onset of “obese” WAT and NAFLD, we created mice with double knock-out for NOX4 and Stat6 (DKO) and compared their metabolic phenotype to littermates with single NOX4 deletion (NOX4KO) upon a 13-week high-fat diet feeding (60 % of calorie from fat). DKO and NOX4KO mice displayed similar food intake. By contrast, DKO mice displayed less body weight gain than NOX4KO mice due to lower energy efficiency leading to reduced WAT accumulation. DKO mice shifted lipid deposition away from the WAT and enhanced lipid storage in the liver. DKO mice displayed similar fed and starved glucose levels with no alterations in glucose tolerance assessed by intra-peritoneal glucose tolerance tests. Gene expression analysis confirmed a less inflammatory state of both WAT and liver of DKO mice. Our results demonstrate that anti-inflammatory signaling is modulated by NOX4-derived signals in vivo in mice, and that NOX4 and IL-4/IL-13 interaction is a critical component in the regulation surplus lipid storage distribution between WAT and the liver.

Disclosure

I. Szanto: None.

Funding

Insuleman Foundation (ISZ-1); Foundation for the Innovation in Research in Cancer and Biological Sciences
16-OR: Cost-Effectiveness of the 2017 Hypertension Guidelines among U.S. Adults with Diabetes—Results from a Simulation Study
Authors: TANG SHICHAO , SHAO HUI , HOERGER THOMAS J. , ZHANG PING
Published: June 2023

In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) changed their guideline for defining hypertension by lowering the blood pressure level threshold from ≥140/90 mmHg to ≥130/80 mmHg. For adults with diabetes and hypertension, initiation of antihypertensive drug treatment was recommended. We used the 2017-March 2020 National Health and Nutrition Examination Survey to create a nationally representative sample of people with diabetes. We used a new diabetes microsimulation model developed by CDC and RTI international to project the lifetime health and cost consequences of implementing this guideline. Hypertension treatments specified in the study follow the guideline. The cost-effectiveness (CE) from a health care system perspective was measured by the incremental CE ratio in terms of cost per quality-adjusted life year (QALY). Under the new guideline, the number of persons with diabetes eligible for treatment would increase from 11.3 million to 20.1 million. Treating these additional patients would increase QALYs by 189,000 and reduce health care cost by $50.7 billion in lifetime. Cost-saving results holds for all subgroups examined (Table). The 2017ACC/AHA guideline yields an additional nearly 9 million people with diabetes recommended for hypertension treatment. Treating this newly eligible population would be cost-saving.

Disclosure

S.Tang: None. H.Shao: Consultant; Lilly Diabetes. T.J.Hoerger: Research Support; Gilead Sciences, Inc. P.Zhang: None.
1605-P: Hepatic Glycogen Directly Regulates Gluconeogenesis in Energy Shortage through AMPK
Authors: ZHANG BICHEN , JOHNSON MORGAN M. , YUAN TIMOTHY , NGUYEN TAMMY-NHU , SALTIEL ALAN
Published: June 2023

Hierarchical synthesis and breakdown of nutrients in the liver maintain metabolic homeostasis in feeding and fasting cycles. Liver glycogen is the first choice for glucose storage and utilization. Patients with obesity and type 2 diabetes show aberrant hepatic glycogen metabolism, contributing to their increased glucose levels. However, whether and how liver glycogen per se regulates glucose metabolism is unknown. Protein targeting to glycogen (PTG) is the scaffolding protein that controls glycogen metabolism. Here, using a mouse model with liver-specific PTG knockout (LKO), we report that rather than a mere passive reservoir of energy, hepatic glycogen itself senses nutritional and hormonal cues to regulate gluconeogenesis, maintaining sufficient glucose output in energy shortage. Glycogen levels are decreased by 75% in the whole liver and 55% in isolated primary hepatocytes from LKO mice. LKO mice show 40% lower glucose levels in response to short-term fasting because of blunted glycogenolysis. Interestingly, the glucose level is similar in WT and LKO mice after overnight fasting, indicating enhanced gluconeogenesis in LKO mice. In agreement with this, LKO mice show significantly increased glucose production in a pyruvate tolerance test. LKO hepatocytes show increased gene expression of key regulators of gluconeogenesis (Nr4a3, Pgc1a, Pck1) when treated with glucagon or cell-permeable cAMP. Glucose production is also enhanced in LKO hepatocytes with fasting or cAMP treatment. Mechanistically, decreased glycogen levels in LKO hepatocytes increases the activity of AMPK. Pre-treatment of LKO hepatocytes with an AMPK inhibitor abolishes the increase in both gluconeogenic gene expression levels and cellular glucose production. Together, these results reveal a new regulatory role for hepatic glycogen in glucose metabolism, indicating that glycogen is an active molecule that signals the gluconeogenesis pathway through AMPK, to fine tune glucose production during energy shortage.

Disclosure

B.Zhang: None. M.M.Johnson: None. T.Yuan: None. T.Nguyen: None. A.Saltiel: Board Member; Elgia Therapeutics.
1606-P: Tg/HDL Ratio and Liver Fibrosis in Diabetic Patients at an Indian Tertiary Care Center
Authors: CHANDRA ABHISHEK , DINKAR JYOTI , RANJAN RAJEEV
Published: June 2023

Introduction: According to the most recent International Diabetes Federation (IDF) atlas, there are 537 million persons worldwide who have diabetes. Indians had increased central adiposity and insulin resistance. Diabetes patients are more likely to develop Nonalcoholic Fatty Liver Disease (NAFLD) due to high insulin resistance. An increasingly sensitive indicator of insulin resistance is the TG/HDL ratio. Measuring liver stiffness helps diabetics predict progressive fibrosis. The current investigation uses fibro scans to evaluate the TG/HDL ratio and liver stiffness in diabetic patients.

Methods: After receiving consent, 181 newly diagnosed diabetics underwent fibro scans to measure their liver stiffness. Participants who had already had thiazolidinedione treatment or lipid-lowering therapy were disqualified from the study.

Results: The median stiffness ranged from 2.3 kpa to 34.8 kpa (8.0 kpa), and the median TG/HDL ratio ranged from 0.5 to 29.3 (4.5). The connection between the median stiffness and the TG/HDL ratio was 0.2. Further, 26.5% of participants (Liver stiffness measurement (LSM) > 9.1), 23.7% of subjects who were men, and 30% of subjects who were women, showed advanced fibrosis. Both men and women with LSM > 9.1 had high TG/HDL ratios, with a mean of 4.9 in the former group and 4.9 in the latter. These numbers were significantly higher than the TG/HDL cut-offs for predicting insulin resistance, which were 0.9 and 1.2 for females and males, respectively.

Conclusion: TG/HDL ratio and NAFLD have previously been linked utilising ultrasonography in nondiabetic persons. The more precise and sensitive method for NAFLD screening is the fibro scan. Liver fibrosis is predicted by median stiffness. In the index research, there is a high incidence of advanced fibrosis, which is associated with the TG/HDL

ratio. The TG/HDL ratio was high in all of the male and female individuals with advanced fibrosis.

Disclosure

A. Chandra: None. J. Dinkar: None. R. Ranjan: None.
161-OR: Validation of the Short Type 1 Diabetes Stigma Assessment Scale (DSAS-1) and Its Association with Affective States, Diabetes Distress, Diabetes Self-Management, and Glycemic Control
Authors: CRESPO-RAMOS GLADYS , HOOGENDOORN CLAIRE J. , SCHNEIDER STEFAN , HERNANDEZ RAYMOND , PHAM LOREE T. , PETERS ANNE L. , RUELAS VALERIE F. , CRANDALL JILL P. , LEE PEY-JIUAN , JIN HAOMIAO , PYATAK ELIZABETH , SPRUIJT-METZ DONNA , GONZALEZ JEFFREY S.
Published: June 2023

Introduction: We validated an 8-item version of the DSAS-1 and examined its relationship with momentary ratings of affective states, diabetes distress, diabetes self-care, and glycemic control over time.

Methods: We recruited 184 adults with T1D from Los Angeles, California, and the Bronx, New York. Participants completed a short version of the DSAS-1, other validated questionnaires, and 10-14 days of intensive longitudinal data collection using blinded continuous glucose monitoring and Ecological Momentary Assessment (EMA) via smartphone. Psychometric validation included exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and internal consistency reliability assessment. We used Spearman's rho correlations to explore the convergent validity using EMA data.

Results: EFA indicated an acceptable fit of a 3-factor model (Bartlett's = 0.000; KMO = 0.774). This was corroborated with CFA, which demonstrated a reasonable three-factor fit (chi-squared = 36.44; RMSEA = 0.079; SRMR = 0.036; TLI = 0.985; CFI = 0.991); less so for a single-factor model. Satisfactory convergent and discriminant validity was demonstrated. The DSAS-1 was significantly correlated with momentary ratings of negative emotions (0.30, p = <0.001), diabetes distress (0.32, p = <0.001), insulin regimen adherence (-0.20, p = 0.007), diabetes self-care (-0.24, p = 0.002), mean blood glucose (0.20, p = 0.008) and time in range (-0.21, p = 0.006), but was not significantly associated with positive emotions.

Conclusions: The 8-item DSAS-1 is a valid and reliable measure of T1D stigma. Convergent validity confirms the importance of diabetes-related stigma in relation to psychosocial and blood glucose outcomes, and underscores the need for further examination of stigma in diabetes, which may be facilitated by this shorter scale.

Disclosure

G.Crespo-ramos: None. H.Jin: None. E.Pyatak: Research Support; Abbott Diabetes. D.Spruijt-metz: None. J.S.Gonzalez: Consultant; Virta Health Corp. C.J.Hoogendoorn: None. S.Schneider: None. R.Hernandez: None. L.T.Pham: None. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. V.F.Ruelas: None. J.P.Crandall: Research Support; Abbott. P.Lee: None.

Funding

National Institutes of Health (R01DK121298)
1614-P: Metabolomic Profiling Reveals Thiamine-Mediated Regulation of Triglyceride Synthesis and Lipid Turnover in Brown Fat
Authors: WANG CHUNQING , ZHANG XING , LIU MEILIAN
Published: June 2023

Brown adipose tissue (BAT) functions as a metabolic sink to dispose glucose as well as fatty acids (FAs) and exerts profound effects on energy and glucose homeostasis. Intermittent fasting (IF) has become an attractive option for combating obesity and treating diabetes, yet how IF regimen impacts BAT metabolism and thermogenic capacity remains poorly understood. Using metabolomics and lipidomic assays, we show that alternate day fasting (ADF) elicited robust activation of upper glycolysis and increased production of glycerol-3-phosphate (G3P) and lactate accompanied with stimulation of glycolytic shunts, pentose phosphate pathway (PPP) and glycogenesis, in BAT but not in gonadal white adipose tissue (gWAT) in feeding state. As a result, feast BAT exhibited a notable increase in triglyceride (TG) synthesis, tissue volume, and thermogenic capacity compared to ad libitum group. Mechanistically, repeated fasting and refeeding suppressed the expression of thiamine transporter ThTr2 and decreased the levels of free thiamine, thiamine pyrophosphate (TPP) and thiamine monophosphate (TMP), in part through periodic activation of mTORC1. Genetic inhibition of mTORC1 in BAT restored expression of ThTr2 and diminished ADF-preserved lipid storage in vivo, and inactivating thiamine metabolism with specific inhibitors induced G3P production and TG synthesis in vitro. Taken together, our study reveals a new mechanism involving thiamine that reprograms BAT carbohydrate metabolism to preserve lipids and improves metabolic health.

Disclosure

C.Wang: None. X.Zhang: None. M.Liu: None.
1617-P: Small Intestinal Protein Sensing Mechanism in Feeding and Glucose Regulation
Authors: BARROS DANIEL , LI ROSA J.W. , LIM YUMI , ZHANG SONG-YANG , KUAH RACHEL , GAO ANNA , LAM TONY K.
Published: June 2023

Protein activates small intestinal calcium sensing receptor (CaSR) and/or peptide transporter 1 (PepT1) to increase GLP-1, but the role in glucose and feeding regulation remains elusive. We performed intravenous glucose tolerance test and refeeding studies and infused 8% (w/v) casein hydrolysate into the upper small intestine (USI) or ileum of male rats. We found that USI casein vs. saline infusion increased glucose tolerance in chow (p<0.01) and HF-fed rats (p<0.05) and suppressed feeding in chow (p<0.01) but not HF rats. We inhibited CaSR via injecting lentivirus expressing shRNA of CaSR into the USI (reduced expression by ~40%) and CaSR knockdown negated casein to increase glucose tolerance but not to lower feeding (p<0.01). Instead, viral-mediated PepT1 knockdown by ~50% negated casein to lower feeding as similar to previously reported for glucose control. Thus, CaSR and PepT1 are required for casein in the USI to increase glucose tolerance, while PepT1 but not CaSR mediates casein to lower feeding, in chow rats. The differential role of PepT1 vs CaSR may explain why HF disrupts casein to regulate feeding but not glucose tolerance as HF inhibited PepT1 expression (p<0.05) but increased CaSR expression (p<0.05) in the USI. Ileal casein vs saline infusion increased glucose tolerance (p<0.01) and lowered feeding (p<0.01). Ileal CaSR inhibition negated casein vs saline to increase glucose tolerance and lower feeding, whereas ileal PepT1 inhibition failed to do so, indicating that ileal casein regulates glucose tolerance and food intake via PepT1-independent but CaSR-dependent pathways in chow rats. HF feeding inhibited ileal CaSR expression by ~60% (p<0.05) in association with a disruption in ileal casein action on feeding but surprisingly not on glucose control (p<0.01), suggesting that ileal casein could even regulate glucose tolerance independent of CaSR. In sum, we discover differential role of CaSR vs. PepT1 in the USI and ileum that alter feeding and glucose regulatory abilities of protein sensing.

Disclosure

D.Barros: None. R.J.W.Li: None. Y.Lim: None. S.Zhang: None. R.Kuah: None. A.Gao: None. T.K.Lam: None.

Funding

Canadian Institutes of Health Research (PJT183901)
1618-P: Fasting Decreases Pyruvate Carboxylase Flux in the Perfused Exocrine Pancreas
Authors: RUSHIN ANNA , MCLEOD MARC , GLANZ MAX , GRAHAM DALTON S. , MERRITT MATTHEW
Published: June 2023

The exocrine pancreas displays structural and functional abnormalities in type 1 diabetes, such as acinar atrophy and fibrosis. Metabolic dysfunction may occur alongside these changes. We established a method to investigate exocrine metabolism using nuclear magnetic resonance (NMR) and hyperpolarized (HP) substrates. This approach conserves the native environment while permitting analysis of metabolic flux in the living pancreas. Here, we compared exocrine pancreas metabolism in fed (n=4) and fasted (n=5) male C57BL/6J mice. Each pancreas was perfused for 30 minutes with oxygenated Krebs-Heinsleit buffer in a 14 T NMR instrument. NMR spectra were collected after injection of 4 mM HP [1-13C] pyruvate into the common bile duct. 13C signals from several central carbon metabolites were detected, such as alanine, malate, and fumarate. Pancreata from fasted mice produced less (p<0.05) fumarate and aspartate compared to those from the fed mice. After perfusion, all pancreata were analyzed by gas chromatography - mass spectrometry for metabolite quantification. Malate was significantly enriched (p<0.05) by 13C in the fed pancreas with similar total malate between groups. Overall, these results suggest that the exocrine pancreas displays higher pyruvate carboxylase (PC) flux in the fed state compared to the fasted state. The methodology presented here provides a unique avenue to assess pancreatic metabolism in real-time.

Disclosure

A.Rushin: None. M.Mcleod: None. M.Glanz: None. D.S.Graham: None. M.Merritt: None.

Funding

National Institutes of Health (T32DK10876); National Science Foundation (DMR-1644779)
1619-P: Creation of a Mouse Model That Phenocopies Human MODY8—A Valuable Tool to Interrogate Exocrine–Endocrine Cross Talk
Authors: EL JELLAS KHADIJA , KAHRAMAN SEVIM , LOWE MARK E. , MOLVEN ANDERS , KULKARNI ROHIT
Published: June 2023

Despite the intimate anatomical relationship between the two compartments of the pancreas, little is known about the biological components mediating the exocrine-endocrine communication in regulating glucose homeostasis. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited autosomal form of monogenic diabetes, caused by heterozygous mutations in the carboxy ester lipase (CEL) gene expressed in acinar cells. MODY8 is characterized by chronic pancreatitis (CP) and exocrine dysfunction from childhood, followed by diabetes in adulthood. Heterozygous MODY8 mice develop CP but are normoglycemic. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. This mouse model (MODY8/16R) acts as a unique tool to directly interrogate the dynamic communication between the exocrine and endocrine compartments by phenotyping longitudinally from weaning to age 2 yrs. Preliminary histopathological analyses of the pancreata reveal features of CP in some lobes, including inflammation, fibrosis and fat infiltration, mirroring the disease in humans. Moreover, confocal microscopy showed the presence of zymogen granules containing mutant CEL within beta cells. These data argue that the mutant CEL protein is transferred from acinar cells to beta cells in pathological conditions, with implications of directly impacting beta cell viability. Examination of glucose homeostasis revealed that inducing stress (e.g. a high-fat diet) leads to glucose intolerance in MODY8/16R mice compared to their control littermates. In conclusion, the availability of a MODY8/16R mouse model provides a unique opportunity to carefully characterize the endocrine-exocrine communication in the pancreas in a longitudinal manner that is otherwise not possible in humans.

Disclosure

K.El jellas: None. S.Kahraman: Employee; Boehringer Ingelheim Pharmaceuticals Inc. M.E.Lowe: Other Relationship; MilliporeSigma, Wolters Kluwer Health. A.Molven: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago.

Funding

National Institutes of Health (U01135095)
1621-P: Commercially Available Stevia-Based Sweetener, Antidiabetic or Toxic—An Ad Libitum Feeding Study in a Type 2 Diabetes Model of Rat
Authors: ISLAM SHAHIDUL , DLAMINI SIPHIWE N.
Published: June 2023

The use of non-nutritive sweeteners as sugar substitutes by overweight, obese and diabetic individuals has been increased rapidly in recent years, when Stevia is the most popular one not only due to its natural source of origin but also for it antidiabetic potential. However, the effects commercially available stevia-based NNS are not investigated at all. The present study was conducted to investigate the effects of ad libitum consumption of commercially available stevia-based non-nutritive sweetener (NNS) in an experimentally-induced rat model of type 2 diabetes (T2D). Seven-week-old male Sprague-Dawley rats were randomly divided into three groups, namely: Normal Control (NC), Diabetic Control (DBC) and Diabetic Stevia (DSTV). T2D was induced in the DBC and DSTV groups only. The control groups were received normal drinking water, whilst rats in the DSTV group were administered with stevia-containing NNS solution, at a concentration equivalent to the sweetness of 10% sucrose. After 13 week intervention, although food and fluid intake, body weight, weekly blood glucose, glucose tolerance, serum insulin, fructosamine, ALT, ALP, creatinine and brain, liver and pancreatic histopathology were not significantly affected; serum AST, LDH and CK-MB as well as heart and kidney histopathology were significantly deteriorated in stevia-based NNS consuming group compared to the DBC group. The data of this study suggest that uncontrolled consumption of stevia-based NNS has no significant antidiabetic effect but have some toxicological effects in an animal model of T2D. Hence, diabetic patients consuming stevia-based NNS should limit their daily intake.

Disclosure

S. Islam: None. S.N. Dlamini: None.

Funding

South African Sugar Association (Project 233)
1624-P: Hudev-PRE, a Combination of Plant Extracts, Improves Glucose Homeostasis in Both High-Fat Diet C57Bl/6J and Ob/Ob Mice
Authors: LE MAY CEDRIC , BLUA JEAN-LOUIS , CARIOU BERTRAND
Published: June 2023

Despite advances in the understanding of the pathogenesis of type 2 diabetes (T2D), new therapeutic & nutritional solutions are needed to delay its emergence and prevent the development of its associated complications. Here, we tested the effect of HUDEV-PRE, an original mixture of plant extracts, on glucose homeostasis in in two different mouse models of T2D. In a first experiment, 8 weeks old C57Bl/6J males were fed with high-fat diet during 8 weeks to induce insulin resistance. In a second set-up, we used 6 weeks old Ob/Ob males. In both experiments, mice received a double daily oral administration of vehicle, metformin (150mg/kg) or HUDEV-PRE for 30 days. Food intake, body weight change, random fed plasma glucose, cholesterol and triglyceride levels were measured once weekly. Finally, oral glucose tolerance tests (GTT) were performed after 7 and 21 days of treatment. In both models, HUDEV-PRE did not alter food intake and body weight. Interestingly, a rapid, sustainable and significant reduction of random fed blood glucose levels was observed in HFD fed C57Bl/6J and Ob/Ob mice receiving metformin or HUDEV-PRE administration. In HFD fed C57Bl/6J mice, GTT revealed no significant effects at day 7 but a strong improvement of glucose tolerance in mice treated for 21 days with metformin or HUDEV-PRE compared to control vehicle treated mice. In Ob/Ob mice, we observed similar results and the glucose tolerance was even improved after only 7 days of treatment. Finally, at day 21, we also measured a significant reduction of fasting plasma insulin levels and HOMA-IR in both mouse models treated with HUDEV-PRE. Together, our data demonstrate that HUDEV-PRE rapidly improve glucose homeostasis in two mouse models of T2D. Although additional studies are warranted to decipher the mechanisms of action, these findings indicate that HUDEV-PRE could represent a nutritional supplement of interest to delay the onset of insulin resistance and T2D in patients at metabolic risk.

Disclosure

C.Le may: None. J.Blua: None. B.Cariou: Board Member; Eli Lilly and Company, Novartis, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca, Novo Nordisk, Sanofi.
1625-P: Osteoprotection by FNIP1 Signaling in Skeletal Muscle
Authors: YAN MAO , XU ZHISHENG , YIN YUJING , FU TINGTING , ZHOU ZHENG , YANG LIKUN , GAN ZHENJI
Published: June 2023

Obesity is increasingly recognized to exert negative impact on bone mass. Skeletal muscle and bone are closely related throughout life, and muscle dysfunction can cause osteoporosis. Understanding of the crosstalk between muscle and bone could have implications for maintaining bone fitness in various disease states such as obesity. FNIP1 is emerging as key regulator of muscle metabolism acting via AMPK. However, the role of muscle FNIP1 in bone mass control is unknown. Using both gain- and loss-of function muscle-specific genetic models, we show that in addition to the known role in the regulation of mitochondrial function muscle fiber type, FNIP1 participates in muscle programs that govern bone homeostasis. FNIP1 KO mice showed a decrease in trabecular bone volume and bone mineral density, whereas muscle specific restoration of FNIP1 expression in KO mice (FNIP1Tg/KO) reversed the bone loss phenotypes. Femoral bending tests revealed a marked decrease in elastic modulus and maximum force in FNIP1 KO mice but increase in FNIP1 TgKO mice. Consistent with these findings, muscle cell-specific deletion of FNIP1 resulted in a pronounced bone structural and mechanical dysfunction. Using AMPKα1/α2 KO lines, we show that muscle FNIP1 exerts control actions upon bone homeostasis independently of AMPK. Through comprehensive RNA-seq and genomic analyses, we reveal that muscle FNIP1 deficiency induces IGF2 secretion, thereby driving an IGF2-depenent osteoclast program. Importantly, we also found that the muscle FNIP1-IGF2 regulatory circuit is associated with osteoporosis in humans. Thus, muscle FNIP1 is a critical safeguard of bone mass. These findings provide new therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and musculoskeletal diseases.

Disclosure

M.Yan: None. Z.Xu: None. Y.Yin: None. T.Fu: None. Z.Zhou: None. L.Yang: None. Z.Gan: None.
163-LB: Youth with Delayed Sleep Phase Have Reduced Insulin Sensitivity
Authors: HITT TALIA A. , STEFANOVSKI DARKO , KELLY ANDREA , MALINA SARA , WANG CYNTHIA X.D. , SGAMBATI FRANCIS P. , ZEMEL BABETTE S. , JUN JONATHAN , MAGGE SHEELA N.
Published: June 2023

Background: U.S. adolescents have short and delayed sleep, which may have metabolic consequences. We hypothesized that shorter sleep duration and later sleep phase are associated with decreased insulin sensitivity (SI) and worse glucose tolerance in overweight youth.

Methods: We enrolled healthy youth aged 12-21y with BMI ≥80%ile (or ≥23kg/m2 if ≥18y). We obtained 14 days of wrist actigraphy (ActiGraph GT3XP-BTLE), a frequently-sampled 180 min OGTT (fsOGTT) with 10 samples, and administered validated questionnaires to estimate obstructive sleep apnea (OSA) risk. From actigraphy, we derived average sleep duration (SLD), mid-sleep time (MST), and sleep onset (SO). From the fsOGTT, we estimated SI using the OGTT Minimal Model and the disposition index (DI = SI x incremental insulin AUC 180min). We used multivariable linear regression to examine associations between sleep patterns and glycemic outcomes adjusting for confounders.

Results: To date, we enrolled 24 youth (13F) with a median (IQR) age of 20.6y (19.2, 21.5), BMI of 25.2kg/m2 (24.3, 28.9), and fsOGTT glucoses of: fasting 91mg/dL (86, 95), 1h 141mg/dL (113, 179), and 2h 117mg/dL (78, 144). Participants had a median SLD of 7.3h (6.8, 8.1) per night, with SO of 1:13am (12:27am, 2:09am) and MST of 4:48am (4:23am, 6:01am). Age, race, and sex were not associated with sleep outcomes and not included in regressions. We found that (1) later MST [β=10.3, p=0.01] and SO [β=11.4, p=0.01] were each associated with higher fsOGTT 2h glucose, (2) later SO was associated with lower log-transformed SI [β= -0.27, p=0.04], and (3) later MST trended towards lower log-transformed DI [β= -0.1, p=0.055] adjusting for BMI and OSA risk. SLD was not related to any fsOGTT variables.

Conclusions: To our knowledge, this is the first study in overweight youth to show that delayed sleep phase (SO and MST), but not short SLD, was associated with lower SI using the rigorous OGTT minimal model. Further studies are needed to examine if delayed sleep is a modifiable risk factor for diabetes prevention in youth.

Disclosure

T. A. Hitt: None. D. Stefanovski: None. A. Kelly: None. S. Malina: None. C. X. D. Wang: None. F. P. Sgambati: None. B. S. Zemel: None. J. Jun: None. S. N. Magge: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115648); National Institutes of Health (UL1TR001878, UL1TR001079)
163-OR: Association between Diabetes Distress and Suicide Risk in Emerging Adults with Type 1 Diabetes
Authors: MOSS ASHLEY , LOWRY SARAH J. , ROBERTS ALISSA J. , HUANG ALYSSA , PIHOKER CATHERINE , WEAVER KATHRYN , HIRSCH IRL B. , EHRHARDT NICOLE M. , ZENNO ANNA , MALIK FAISAL
Published: June 2023

Aim: Emerging adults (EA) with type 1 diabetes (T1D) have higher rates of suicide risk compared to their peers without T1D. This is the first known study to examine the association between diabetes distress (DD) and suicide risk in EA with T1D.

Methods: EA completed measures of DD (Problem Areas in Diabetes-Teen; PAID-T), depressive symptoms (Patient Health Questionnaire-9; PHQ-9) and anxiety (General Anxiety Disorder-7) as part of routine clinical care. Suicide risk was assessed as a binary variable using PHQ-9 item 9, which queries about thoughts of suicide or self-harm. Mixed effects logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess the relationship between DD and suicide risk. Analyses were adjusted for depression as measured by the PHQ-8 (first 8 PHQ-9 items), anxiety, sex, and BMI.

Results: Sample included 450 EA. Approximately 9% of participants reported suicide risk; endorsement of suicide risk was associated with elevated A1C and female sex (Table 1). Adjusted regression analyses show an additional 10 points on the PAID-T was associated with over doubled odds of endorsing suicide risk (OR 2.07, 95% CI 1.12-3.83).

Conclusion: DD may be a unique risk factor for suicide risk in EA with T1D. Routine screening of DD is critical for early identification and offers a potential intervention point for patients who may be at increased risk for suicide.

Disclosure

A.Moss: Other Relationship; American Diabetes Association. F.Malik: None. S.J.Lowry: None. A.J.Roberts: None. A.Huang: None. C.Pihoker: None. K.Weaver: None. I.B.Hirsch: Consultant; Abbott Diabetes, Lifecare, Inc., Hagar, Research Support; Beta Bionics, Inc., Insulet Corporation, Dexcom, Inc. N.M.Ehrhardt: Advisory Panel; Novo Nordisk, Dexcom, Inc., Consultant; Nestlé Health Science. A.Zenno: None.
1630-P: Reduced Fatty Acid Oxidation Does Not Prevent Intralipid-Induced Peripheral Insulin Resistance in Humans
Authors: GILLINGHAM MELANIE B. , GREGOR ASHLEY N. , VARLAMOV OLEG , ROBINO JACOB J. , MCCURDY CARRIE E. , GREYSLAK KEENAN T. , CHOI DONGSEOK , BAETSCHER ERIC , ROONEY WILLIAM , PURNELL JONATHAN Q.
Published: June 2023

Mitochondrial handling of excess lipid substrate is thought to be an important determinant of insulin resistance. Evidence from animal models support insulin signaling defects resulting from either intra-cellular lipid accumulation or by mitochondrial dysfunction and altered fatty acid oxidation (FAO) flux. To explore the relationship between FAO and insulin sensitivity, we measured the change in peripheral glucose disposal (Rd) during a 5-hour hyperinsulinemic euglycemic clamp with co-infusion of a control glycerol solution versus a 20% intralipid solution in 18 subjects with an inherited defect in FAO (FAOD; including Carnitine Palmitoyltransferase 2, Very long-chain, medium-chain or long-chain 3-hydroxy AcylcoA Dehydrogenase Deficiencies) and 18 age, sex, and weight-matched normal healthy controls. Rd was similar between groups during the glycerol control clamp. Intramyocellular lipid (IMCL) content as measured by MRS increased after the 5 hour intralipid infusion in controls but not in participants with FAOD. Plasma free fatty acids during intralipid infusion were higher in FAOD compared to controls suggesting infused lipid remained in circulation. Muscle fiber type and expression of lipid transporters CD36 and FATP1 were similar in biopsy samples between groups and cannot explain decreased lipid uptake into muscle among FAOD subjects. However, intralipid suppressed Rd equally in subjects with FAOD and controls inducing peripheral insulin resistance in both groups. Impaired FAO decreased lipid accumulation in the muscle during intralipid infusion, but despite lower IMCL, subjects with FAOD developed peripheral insulin resistance similar to controls. Increased IMCL is not essential for, nor is reduced FAO flux protective against, the development of peripheral insulin resistance during intralipid infusion.

Disclosure

M.B.Gillingham: None. J.Q.Purnell: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk. A.N.Gregor: None. O.Varlamov: None. J.J.Robino: None. C.E.Mccurdy: None. K.T.Greyslak: None. D.Choi: None. E.Baetscher: Consultant; Biogen. W.Rooney: Consultant; Ultragenix, Research Support; Revalesio.

Funding

National Institutes of Health (DK102813)
1631-P: scEMC10 Suppresses Glucose Uptake in Skeletal Muscle via the Inhibition of AMPK Signaling
Authors: JIN SHUOSHUO , WANG YAHAO , CHEN KUANGYANG , DAI JIARONG , CHEN LIJIAO , LIU SHAN , WANG XUANCHUN
Published: June 2023

Skeletal muscle is one of the most important organs involved in the glucose metabolism, and is mainly responsible for postprandial glucose uptake. We have previously shown that overexpression of the secreted isoform of endoplasmic reticulum protein complex subunit 10 (scEMC10) impairs, while Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice. In this study, we presented evidence the regulation of glucose metabolism is achieved through the impacts of scEMC10 on skeletal muscle. PET-CT analyses showed Emc10 KO increased, whereas overexpression of scEMC10 decreased glucose uptake of skeletal muscle in mice, which can be accounted for by the corresponding changes in GLUT4 expression in their skeletal muscle tissues. Recombinant scEMC10 protein reduced both expression and membrane translocation of GLUT4, thus inhibiting glucose uptake in L6-GLUT4myc skeletal muscle cells. Mechanistically, scEMC10 decreased phosphorylations of both AMPK and its downstream target TBC1D1 in both skeletal muscle cells and tissues. Intraperitoneal administration of a scEMC10 neutralizing antibody increased both expression and membrane translocation of GLUT4 accompanied by increased uptake of glucose in gastrocnemius in mice. These data support scEMC10 as an inhibitor of glucose uptake in skeletal muscle and suggest the inhibition of scEMC10 will be a promising way to lower blood glucose in diabetes.

Disclosure

S.Jin: None. Y.Wang: None. K.Chen: None. J.Dai: None. L.Chen: None. S.Liu: None. X.Wang: None.

Funding

National Natural Science Foundation of China (81873645); Science and Technology Commission of Shanghai Municipality (22140902700)
1633-P: Type 1 Diabetes Induced Alterations in Motor Unit Discharge Rate
Authors: MINNOCK DEAN , VALLI GIACOMO , WU RUI
Published: June 2023

Type 1 diabetes (T1D) is a contributing factor in alterations in skeletal muscle health. It has been attributed to accelerated muscle ageing (Monaco et al., 2019), and the molecular alterations in the muscle are also associated with impaired adaptations to physical exercise (Minnock et al., 2022). However, there is no evidence about the consequences of this condition on the behaviour of individual motor units (MUs), despite them being the effectors of the contractile stimulus coming from the nervous system via modulation of their recruitment and discharge activity. This study aimed to investigate whether MUs discharge rate (DR) differs between people living with T1D compared with a control (CON) group of people living without diabetes. Eight people with T1D (4M/4F, 30.50 ± 3.66 years, HbA1c of 8.31 ± 2.40%) without comorbidities and 8 age and sex-matched CON participants undertook the study. MUs DR was evaluated from the vastus lateralis muscle during trapezoidal submaximal isometric contractions with High-Density Electromyography at 20, and 40% of the maximum voluntary contraction (MVC) and DR modulation was defined as the difference between DR at recruitment (i.e., first 3 MUs firings) and DR during the steady-state phase of the contraction. Groups were compared for maximum torque (182.06 ± 47.65 Nm T1D and 171.99 ± 101.97 Nm Non-D). MUs DR was lower for those with T1D at recruitment and during the steady-state phase, both during contractions at 20 and 40% MVC (p<0.05). MUs DR modulation was comparable between the two groups. In conclusion, reductions in MUs DR indicate initial alterations of MUs properties in people living with uncomplicated T1D when compared to CON counterparts. The reduced DR, however, was not accompanied by a reduced range of DR modulation (gain) and was not reflected in reduced force production. These findings suggest that initial alterations of MUs properties are present in people living with uncomplicated T1D and that these alterations are detectable before they become functionally manifest.

Disclosure

D.Minnock: Employee; Innovation Zed. G.Valli: None. R.Wu: None.