bluuebunny/crossref_metadata_2025 huggingface dataset:
152-LB: Implementing a Pilot Clinic for Steroid-Induced Hyperglycemia in Graft vs. Host Disease
Authors: PHAM DANIEL , GRDINOVAC KRISTINE , LEAL JORDAN , RODRIGUEZ LIZA , SALVA ALEXIS , WESSON WILLIAM , MCGUIRK JOSEPH
Published: June 2023

Introduction: Malignant hematologic disorders are often treated with hematopoietic stem cell transplantation. This can be complicated by graft versus host disease (GVHD). Treatment is high dose corticosteroids, which often leads to steroid induced hyperglycemia (SIH). Uncontrolled hyperglycemia is associated with increased morbidity and mortality. Despite evidence favoring glycemic control in this population, there are no formal protocols or clinics in place to achieve this.

Methods: The University of Kansas Blood and Marrow Transplant Program collaborated with the Department of Endocrinology to establish a pilot clinic for patients with GVHD who have SIH. Over 12 months, patients were referred to a physician assistant specializing in diabetes. They were seen at 1-4 week intervals based on acuity and glycemic control. Data was collected on blood glucose, hemoglobin A1c, fructosamine, steroid doses, insulin doses, hospitalizations, infections, and death.

Results: 64 patients were referred to this clinic. 24 were excluded due to lack of hyperglycemia or declined being seen. Median time to index visit from referral was 20.5 days (IQR 8.25-29). Median A1c at index visit was 5.9 (IQR 5.4-7.2) and at 3 months was 5.3 (IQR 4.6-6.3). Median highest glucose within the first 3 months was 230 mg/dL (IQR 183-362) and at 3-6 months was 161 mg/dL (IQR 119.8-247, p-value = 0.0025). Median lowest glucose at 3 months was 86 mg/dL (IQR 78.5-103) and at 6 months was 87 mg/dL (IQR 75-115.8). There were 20 patients who were hospitalized and 9 patient deaths.

Conclusions: Managing SIH is complex and requires a multidisciplinary approach. Patients who were seen had reduced episodes of hyperglycemia without increased episodes of hypoglycemia. A1c is an unreliable measurement in this patient population due to high cell turnover and frequent transfusions. Future studies using continuous glucose monitors could be investigated to assess the efficacy and feasibility of this pilot clinic.

Disclosure

D. Pham: None. K. Grdinovac: None. J. Leal: None. L. Rodriguez: None. A. Salva: None. W. Wesson: None. J. McGuirk: None.
1521-P: Healthy, Nonobese South Asian Men Have Both Greater Peripheral and Hepatic Insulin Resistance than Chinese Men
Authors: LIM AMANDA Y.L. , CHANG TAN HONG , MENG KHOO CHIN
Published: June 2023

Introduction: South Asian individuals, despite a healthy weight, are at a greater risk of type 2 diabetes mellitus than Chinese individuals. This may be secondary to higher peripheral and/or hepatic insulin resistance (IR). Using the 2-stepped hyperinsulinemic-euglycemic clamp, we examined the differences in peripheral and hepatic insulin resistance between healthy and non-obese South Asian and Chinese men. Bioimpedance analysis was performed to assess body composition.

Methods: A 2-stepped hyperinsulinemic-euglycemic clamp was performed together with a “pancreatic” clamp by infusing somatostatin. A low-dose insulin (10 mU/m2/min) was infused for 2 hours, followed by high-dose insulin infusion (40 mU/m2/min) for 2 hours. Intravenous 20% glucose was infused to maintain euglycemia (blood glucose = 95-100 mg/dl) for the clamp duration. A higher M value (mg glucose per kg bodyweight per minute) during low-dose insulin infusion reflects lower hepatic IR while a higher M value during high-dose insulin infusion reflects lower peripheral IR.

Results: The 2 groups (26 South Asian and 26 Chinese men) had similar age (27.3 vs 26.2 years, p = 0.338), but the South Asian group had slightly higher BMI (24.6 vs 22.9 kg/m2, p = 0.027) and body fat % (23.9 vs. 20.6%, p < 0.05). During low-dose step, the M-value was lower among South Asians compared to Chinese (0.8 ± 0.58 vs. 1.1 ± 0.55 mg/kg/min, p = 0.027). During high-dose step, the M-value was also lower among South Asians compared to Chinese (3.2 ± 2.6 vs. 5.2 ± 3.3 mg/kg/min, p = 0.015). The differences in the M-values between South Asian and Chinese individuals remained significant after correcting for body weight and fat-free mass.

Conclusion: Despite a healthy weight, young South Asians have both greater hepatic and peripheral muscle IR than Chinese.

Disclosure

A.Y.L.Lim: None. H.Tan: None. C.Khoo: None.

Funding

National Medical Research Council of Singapore (MOH-CNIG19NOV-0002)
1522-P: Identification of AgRP Cells in the Murine Hindbrain That Drive Feeding
Authors: BACHOR TOMAS P. , ATTAL KUSH , VAGENA EIRINI , MIFSUD FRANCOIS , PHAM VIANA , VALDEARCOS-CONTRERAS MARTIN , VAISSE CHRISTIAN , XU ALLISON
Published: June 2023

The central melanocortin system is essential for the regulation of food intake and body weight in humans and rodents. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to express exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding regulation. Here we describe a previously unknown population of AgRP cells in the area postrema (AP) and the adjacent commissural nucleus of the solitary tract (cNTS) of the causal brainstem. AgRP was expressed in the embryonic AP, and hindbrain AgRP expression in adult mice was low under ad libitum fed condition but increased with food deprivation. AgRP cells in the AP and cNTS consisted of locally projecting neurons as well as tanycyte-like cells. In mice that lack hypothalamic AgRP neurons, diphtheria-toxin mediated ablation of AgRP cells led to anorexia and weight loss, whereas chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. Moreover, focal transcranial photo-stimulation of AgRP cells in the AP and cNTS with a step-function opsin with ultra-high light sensitivity (SOUL) stimulated feeding in mice with or without hypothalamic AgRP neurons, suggesting that the hyperphagic effects of hindbrain AgRP neurons are independent of hypothalamic AgRP neurons. Collectively, our study indicates that the hindbrain has a balanced melanocortin system, complete with both orexigenic and anorexigenic components, and that AgRP neurons in the hindbrain drive feeding in adult animals.

Disclosure

T.P.Bachor: None. K.Attal: None. E.Vagena: None. F.Mifsud: None. V.Pham: None. M.Valdearcos-contreras: None. C.Vaisse: None. A.Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK098722-01A1, P30DK63720-06A1)
1524-P: Selective Deletion of Nav1.7 in Cerebellar Purkinje Neurons Prevents Diet-Induced Obesity by Promoting Voluntary Locomotion
Authors: FENG BING , GAO PEIYU , HARMS JERNEY , LUO PEI , XU PINGWEN , HE YANLIN
Published: June 2023

The pacemaker activity of cerebellum Purkinje neurons is well-known to be essential in multiple physiological functions, including voluntary locomotion, balance, aggressive behavior, and cognitive behavior. However, the specific ionic mechanism of Purkinje neurons in regulating voluntary locomotion is still unclear. To this end, we ex vivo electrophysiologically recorded the activity changes of Purkinje neurons after wheel running by using Pcp2-Cre/Rosa26-LTL-tdTOMATO reporter mice with tdTOMATO selectively expressed in Purkinje neurons. We found that the Purkinje neural activity was reduced by wheel running, associated with decreases in voltage-gated sodium current and expression of the voltage-gated sodium ion channel Nav1.7 (Scn9a), suggesting a potential role of Nav1.7-mediated sodium current. To test whether Nav1.7 is required for the activity dynamics of Purkinje neurons induced by voluntary wheel running and subsequent beneficial metabolic effects, we crossed Scn9a flox/flox mice with Pcp2-Cre mice to generate a mouse model with Nav1.7 selectively deleted from Purkinje neurons (Pcp2-Cre/Scn9a flox/flox, Nav1.7-KOPcp2). Nav1.7-KOPcp2 significantly decreased Purkinje neural dynamics, mimicking wheel running-induced neural activity reduction. Nav1.7-KOPcp2 mice also significantly increased voluntary locomotion compared to the control littermates. Further, Nav1.7-KOPcp2 mice showed decreased body weight gain, reduced blood glucose, and improved insulin sensitivity when fed a high-fat diet (HFD). These beneficial metabolic effects were associated with increased running activity but not food intake.

In summary, these findings provide evidence to support the vital role of the Nav1.7 ion channel expressed by Purkinje neurons in the beneficial metabolic effects of voluntary locomotion activity.

Disclosure

B. Feng: None. P. Gao: None. J. Harms: None. P. Luo: None. P. Xu: None. Y. He: None.

Funding

National Institutes of Health (R01DK123098, R01DK129548)
1526-P: Cephalic Phase Insulin Release Requires Alpha Cells
Authors: TRIMIGLIOZZI KELLY A. , WIEDEMANN SOPHIA J. , MEIER DANIEL T. , RACHID LEILA , MEREAU HELENE , BÖNI-SCHNETZLER MARIANNE , DONATH MARC Y.
Published: June 2023

The glucose-independent rise of insulin levels immediately at the start of a meal is known as the cephalic phase of insulin release and is a neurally mediated physiological reflex. We recently found that IL-1β mediates cephalic phase insulin secretion by modulating parasympathetic neuronal transmission. It has been established that pancreatic islets are richly innervated by the parasympathetic nervous system, yet the mechanism underlying neuronally mediated insulin release at basal glucose, as seen in cephalic phase, remain to be studied.

Methods: We assessed the role of glucagon in cephalic phase insulin secretion using a transgenic mouse model in which alpha cells are selectively ablated. Further, we isolated pancreatic islets of wild-type mice, as well as alpha cell-ablated mice, and assessed insulin and glucagon secretion at low glucose after stimulation with IL-1β, a muscarinic agonist (carbachol) and both combined.

Results: We observed that mice lacking glucagon-producing alpha cells fail to exhibit a cephalic phase insulin response. In vitro, we found that muscarinic activation stimulated glucagon secretion at basal glucose, but not insulin secretion. Co-stimulating islets with the muscarinic agonist and IL-1β stimulated insulin secretion at basal glucose, and strikingly this was not the case in alpha cell-ablated islets.

Conclusion: Cephalic phase of insulin release mediated by IL-1β stimulation of parasympathetic nerves requires pancreatic alpha cells. This beta-cell response may be mediated by glucagon.

Disclosure

K.A.Trimigliozzi: None. S.J.Wiedemann: None. D.T.Meier: None. L.Rachid: None. H.Mereau: None. M.Böni-schnetzler: None. M.Y.Donath: Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk.
1529-P: Hypothalamic FGF1 Regulates Systemic Glucose and Energy Homeostasis
Authors: SHIN HY EMI , MYOUNG SUH JAE
Published: June 2023

Systemic glucose and energy homeostasis is maintained by interorgan communication networks and the hypothalamus plays a key part in this process. Many research are being conducted to investigate the hypothalamus as a therapeutic target for metabolic diseases such as diabetes and obesity. Recent studies demonstrate that a single intracerebroventricular (icv) injection of FGF1 causes sustained glucose remission in diabetic rodent models (Scarlett et al.), and further study is being conducted. However, there are limited findings about how metabolic status affects endogenous brain FGF1 expression and how brain FGF1 plays in energy homeostasis. A study published in 2012 (Jonker et al.) found severe insulin resistance and a defect in adipose tissue remodeling in HFD-fed FGF1 null-mice. However, these investigations have a limitation in that it is not obvious which tissue/organ mediates insulin resistance due to FGF1 depletion. We found that CNS-deletion of FGF1 (BKO) shows impaired glucose sensing and decreased ERK/STAT3 signaling in ventromedial hypothalamus (VMH) and arcuate nucleus (ARC). This decreased leptin sensitivity leads to decreased muscle glucose uptake following glucose intolerance. We evaluated FGF1 expression in hypothalamus in several metabolic states such as fasting-feeding or other postprandial stimuli to discover which hypothalamic area mediates endogenous FGF1 activity. Interestingly, FGF1 expression in the VMH, but not other brain regions, are increased upon feeding or glucose administration and this induction of FGF1 does not require leptin or insulin. Acute FGF1 deletion in adult VMH causes glucose intolerance as well as increased body weight gain due to reduced leptin sensitivity and brown fat dysfunction, which leads to decreased energy expenditure. In keeping with this finding, germ-line ablation of FGF1 in VMH neurons results in increased adiposity. We propose that endogenous brain FGF1 regulates glucose and energy homeostasis through modulating VMH leptin sensitivity.

Disclosure

H.Shin: None. J.Suh: None.
1532-P: A Novel Light-Responsive Adipose–Hypothalamus Axis in Metabolic Regulation
Authors: TSUJI TADATAKA , LIAN HUANG TIAN , ZHANG YANG , LYNES MATTHEW , PROFETA GERSON , NARAIN NIVEN , KIEBISH MICHAEL , TSENG YU-HUA
Published: June 2023

Light plays an essential role in life. Animals and humans possess light-sensing photoreceptors in visual and non-visual organs. We and others recently showed a non-visual role for Opsin3 (Opn3) in regulating adipose function. In this study, we discovered that direct blue light exposure to subcutaneous white adipose tissue (WAT) could reduce lipids accumulation in WAT and improve high-fat diet-induced metabolic abnormalities in an Opn3-dependent manner. Adipose tissue is an orchestrated matrix comprising high innervation that can engage in crosstalk with other organs. Particularly, it communicates with the brain via the sympathetic nervous system (SNS). Using the metabolomic approach, we found that blue light increased circulating levels of histidine, which then triggered the activation of histaminergic neurons in the hypothalamus and turned on brown adipose tissue via SNS. The administration of histidine decarboxylase antagonist blunted the effects of blue light. Taken together, these data demonstrate a novel light-responsive adipose-hypothalamus axis in metabolic regulation and provide a potential light-based therapeutic approach for obesity.

Disclosure

T.Tsuji: None. T.Huang: None. Y.Zhang: None. M.Lynes: None. G.Profeta: None. N.Narain: None. M.Kiebish: None. Y.Tseng: Consultant; Cellarity, LyGenesis.

Funding

American Heart Association (903968)
1533-P: Mind over Metabolism—A Molecular Subtype of Vagal Neurons That Can Improve Glucose Tolerance
Authors: CONLEY NICHOLAS J. , KAUFFMAN LILY S. , CAMPBELL JOHN
Published: June 2023

Parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV) control glucose metabolism through the vagus nerve and so are potential targets for diabetes treatment. Currently, little is known about the molecular identity or organization of the glucose-regulating DMV neurons. To identify these neurons for further study, we optogenetically activated them in awake mice during a glucose tolerance test (GTT). We transgenically targeted a blue light-sensitive ion channel, CaTCh, selectively to all DMV neurons based on co-expression of Chat - and Phox2b- driven recombinases (Chat-Cre::Phox2b-Flp::CaTCh mice). We implanted optical fibers over the DMV in these adult mice (2 females, 1 male), acclimated them to the test environment and procedure, and then fasted them overnight. After recording baseline glucose levels, we administered intraperitoneal glucose (20% glucose, 10uL/g) and concurrently began photostimulation (time=0-30min; 5Hz, 1ms pulse, 2.5s off, 1s on) or sham stimulation. We performed tail blood glucometry at 5-min increments from -20-120min and compared average readings between stimulation and sham trials. Results: sham 0-30min 472.6 ± 74mg/dL, stim 0-30min 352 ± 48mg/dL (p=0.0005, paired t-test); other timepoints, p>0.05 between conditions. Our results indicate that activating DMV neurons can significantly improve glucose tolerance. To identify specific DMV neurons controlling glucose tolerance, we optogenetically activated a molecular subtype of DMV neurons defined by co-expression of Calb2 and Chat (2 female Calb2-Cre::Chat-Flp::CaTCh adult mice). We photostimulated Calb2+ DMV neurons while performing GTT as described above. Results: sham 0-30min 493 ± 90mg/dL, stim 0-30min 407 ± 69mg/dL (p=0.0390, paired t-test); other timepoints, p>0.05 between conditions. Together our data indicates that activating DMV neurons generally or Calb2+ DMV neurons specifically improves glucose tolerance.

Disclosure

N.J.Conley: None. L.S.Kauffman: None. J.Campbell: None.

Funding

American Diabetes Association (1-18-INI-14 to J.C.)
1535-P: Physiological Role of Stress-Activated Neurons in the Paraventricular Hypothalamus
Authors: ESPINOZA DIEGO G. , ALVARSSON ALEXANDRA , JIMENEZ GONZALEZ MARIA , HAMPTON ROLLIE F. , LI ROSEMARY Y. , DEVARAKONDA KAVYA , CHOUDHURY JESLYN , WAXMAN TALIA S. , STANLEY SARAH
Published: June 2023

Psychological stimuli that disrupt homeostasis - stressors - lead to acute and chronic metabolic disturbance but the underlying neural circuits are incompletely understood. The paraventricular nucleus of the hypothalamus (PVH) plays a significant role in behavioral, autonomic and hormonal responses to stress. The PVH contains multiple cell types including neurons expressing tyrosine hydroxylase (TH). However, the contributions of PVHTH neurons to the acute stress response are largely unknown. We aim to determine the roles of PVHTH neurons in the metabolic and behavioral responses to acute stress.

We first generated mice with tdTtomato expression in TH+ neurons (TH-tdTomato) by crossing validated TH-cre mice to mice with cre-dependent expression of tdTomato. Using immunohistochemistry for PVH neuropeptides linked to energy metabolism and stress in TH-Tdtomato mice, we quantified overlap of PVHTH neurons with CRH, oxytocin and vasopressin. We found small fractions of PVHTH neurons co-express CRH, oxytocin and vasopressin suggesting PVHTH neurons are a distinct population. Next, we assessed activation of PVHTH in response to acute stress by examining Fos expression in TH-tdTomato mice. Acute stress significantly increased the number of FOS+ PVHTH neurons. Finally, we examined whether chemogenetic activation of PVHTH neurons mimicked behavioral, hormonal and metabolic adaptations to stress using PVH injection of AAV with cre-dependent hM3DGq-mCherry or mCherry (control) in TH-cre mice. Chemogenetic activation of PVHTH neurons acutely suppressed dark-phase food intake and impaired glucose tolerance without effects on plasma corticosterone or anxiety-like behavior.

These findings suggest acute stress may recruit PVHTH neurons to elicit hypophagia and impair glucose tolerance, independent of HPA axis activation and anxiety-like behavior. Future studies using chemogenetic inhibition will determine if PVHTH neurons are required for the full metabolic response to acute stress.

Disclosure

D.G.Espinoza: None. A.Alvarsson: None. M.Jimenez gonzalez: None. R.F.Hampton: None. R.Y.Li: None. K.Devarakonda: None. J.Choudhury: None. T.S.Waxman: None. S.Stanley: Consultant; Redpin Therapeutics.
1536-P: Effects of Sucralose vs. Sucrose on Hypothalamic Blood Flow, Glucose Signaling, and Appetite
Authors: CHAKRAVARTTI SANDHYA P. , KULLMANN STEPHANIE , VEIT RALF , YUNKER ALEXANDRA G. , ANGELO BRENDAN C. , JANN KAY , LUO SHAN H. , XIANG ANNY , MONTEROSSO JOHN R. , PAGE KATHLEEN A.
Published: June 2023

Sucralose is a non-nutritive sweetener (NNS) commonly consumed to provide sweet taste without calories. Yet, some studies suggest NNS stimulate appetite, potentially by altering post-ingestive metabolic signals that communicate with the hypothalamus to reduce hunger. We tested the hypothesis that sucralose vs sucrose would elicit different metabolic, hypothalamic blood flow (BF) and appetite responses, and that post-ingestive increases in metabolic signals would be associated with reductions in hypothalamic BF and hunger. In a randomized cross-over trial, hypothalamic BF (measured by perfusion MRI), appetite ratings, and glucose/hormone responses were obtained before, 15 and 30 min after ingestion of drinks containing sucrose (75g) or sucralose (sweetness matched). Paired t-tests were used to compare sucralose vs sucrose on metabolic responses, hypothalamic BF, and appetite. Linear regression was used to examine associations between peripheral glucose, insulin, GLP-1 and hypothalamic BF and hunger. 76 adults (43F; 23.3±3.9 yrs; BMI 27.2±5) completed the study. Subjects reported increased hunger at 15 (p<.04) and 30min (p<.003) after sucralose vs sucrose. Peripheral glucose, insulin, and GLP-1 were lower after sucralose vs sucrose (all p<.0001). Glycemic response (whole hypothalamus (β=-.002, p=.05), medial subfield (β=−.005, p<.006)), but not insulin or GLP-1, was associated with the hypothalamic response to sucrose at 30 min, controlling for age, sex, BMI. These associations were not observed after sucralose (β=.008 p=.2). The medial hypothalamic response predicted hunger response after both drinks (β=1.79, p<.02). Sucralose vs sucrose elicited disparate metabolic, hypothalamic, and hunger responses. Sucrose-induced increases in glycemia were associated with reductions in medial hypothalamic BF, which was linked to reduced hunger. Compared to sucrose, post-ingestive signaling responses were altered after sucralose, which may affect appetite.

Disclosure

S.P.Chakravartti: None. K.A.Page: None. S.Kullmann: None. R.Veit: None. A.G.Yunker: None. B.C.Angelo: None. K.Jann: None. S.H.Luo: None. A.Xiang: None. J.R.Monterosso: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102794)
1538-P: Brain TGFß Regulates Glucose Tolerance in Male Mice with Metabolic Syndrome
Authors: ELGAZZAZ MONA , MIAO KEVIN , NUZZO ANNA R. , RESTIVO LUKE , MOLES KARL , LAZARTIGUES ERIC D.
Published: June 2023

Hypothalamic inflammation contributes to insulin resistance and obesity. Transforming growth factor beta (TGFβ) is among the inflammatory mediators inducing hypothalamic inflammation. In this study, we investigated the role of brain TGFβ on metabolic function. We hypothesized that TGFβ in the brain promotes insulin resistance and reduces glucose tolerance in diabetic and obese mice. C57BL/J male mice were fed either hypercaloric diet (HCD, 52% fat) or regular diet (RD) from weaning. At 3 months age, intraperitoneal glucose tolerance test (GTT), insulin tolerance test (ITT) and weight confirmed the acquisition of metabolic syndrome. Hypothalamic protein expression was assessed for TGFβ receptor 2, phosphorylated SMAD3, SMAD6 and SMAD7, as downstream signal transducer proteins for TGFβ. Compared to RD male mice (n=6), mice on HCD (n=6) showed glucose intolerance (AUC; 60587 ±2460 vs. 30802±1923, p<0.0001), insulin intolerance (AUC; Mean±SEM; 19025836.0 vs.11436±1087, p=0.02) and weight gain (33.67±2.028 vs. 26.89±0.4231 g). HCD mice also exhibited increased protein levels of TGFβR2 (normalized to total protein, Fold Change (FC)±SEM to RD group; 3.54±0.3, p<0.0001), pSMAD3 (FC 2±0.5, p=0.04) while inhibitors for TGFβ signaling such as SMAD6 and SMAD7, were downregulated (FC 0.7±0.1, p=0.03 and 0.8±0.04, p=0.03, respectively). To understand the role of brain TGFβ on metabolic regulation, 3 months HCD mice were subjected to intracerebroventricular (ICV) infusion with either TGFβ neutralizing antibody (nAb, n=4) or IgG control antibody (n=4) using subcutaneous osmotic pumps connected to ICV cannula for 2 weeks. GTT was measured after 2-week infusion. Treatment with TGFβ nAb resulted in lower fasting blood glucose compared to before treatment (166.1 ±6.878 vs. 229.9 ±3.923 mg/dL) and at 120 min time point (229.9 ±28.69 vs. 382.2 ±24.33 mg/dL). In conclusion, brain TGFβ plays a key role in regulating glucose metabolism probably through inflammation-induced insulin resistance.

Disclosure

M.Elgazzaz: None. K.Miao: None. A.R.Nuzzo: None. L.Restivo: None. K.Moles: None. E.D.Lazartigues: None.

Funding

American Diabetes Association (1-19-IBS-291 to E.D.L.)
1539-P: Effects of Free Fatty Acids (FFA) on Central Regulation of Glucose Metabolism
Authors: FABIOLA NOGUEIRA CORDEIRO MONICA , ROUTH VANESSA H. , MANAVALAN ANJALI , MATHIAS PRIYANKA M. , BOYLE CAROLINE E. , RIOS CHEN ANA C. , JIANG NANCY , FRIEDMAN NAOMI , EMRE DEMIRHAN YUNUS , HAWKINS MEREDITH , ZHANG KEHAO
Published: June 2023

Activation of hypothalamic KATP channels reduces endogenous glucose production (EGP) in nondiabetic rodents and humans, but this response is lost in T2D. Lowering FFA with nicotinic acid (NA) restored central regulation of EGP in T2D subjects (Diabetes 2019; 1799P). High FFA levels, typical of T2D, may increase endoplasmic reticulum (ER) stress and thereby impair hypothalamic control of EGP.

To explore how increased FFA might impact central regulation of EGP, we harvested hypothalamic wedges from n=10 Zucker Diabetic Fatty (ZDF) rats (glucose ~ 370 mg/dL) following infusion of NA or saline (Alzet minipump) for 18 h. Nondiabetic rats (n=5) were studied as controls.

Gene expression of KATP channel subunit Kir6.2 was decreased in ZDF rats. Upon lowering FFA with NA, hypothalamic expression of this major subunit was restored (Fig 1a). Conversely, increased expression of genes regulating ER stress was reversed by NA (Fig 1b). Directly treating ZDF rat brain slices with NA did not alter the expression of these genes, suggesting that NA's effects were mediated by lowering FFA (Fig 1c).

In conclusion, hypothalamic effects of elevated FFA include reduced KATPchannel expression and increased expression of ER stress genes, both of which may contribute reversibly to the loss of central regulation of EGP in T2D. These findings are consistent with our observations in humans noted above, suggesting that FFA could be a therapeutic target in T2D.

Disclosure

M. Nogueira Cordeiro: None. V.H. Routh: None. A. Manavalan: None. P.M. Mathias: None. C.E. Boyle: None. A.C. Rios Chen: None. N. Jiang: None. N. Friedman: None. Y. Demirhan: None. M. Hawkins: None. K. Zhang: None.

Funding

American Diabetes Association (7-08-CR-28 to M.H.); National Institutes of Health (R01DK069861); Diabetes Action Research and Education Foundation
1540-P: Diazoxide (DZ) May Lower Endogenous Glucose Production (EGP) via Mitochondrial ATP-Sensitive K+ (mt KATP) Channels
Authors: VAIL GWYNDOLIN , PATEL VISHWENDRA , SARKAR PALLABI , ZHANG KEHAO , HAWKINS MEREDITH , ROUTH VANESSA H.
Published: June 2023

Rodent and human studies suggest that ventromedial hypothalamus (VMH) KATP channels suppress EGP. The VMH possesses glucose-sensing neurons that are either excited (GE) or inhibited (GI) by glucose. Since administration of the KATP channel activator DZ reduces EGP in rodents and humans, we examined the impact of DZ on VMH glucose sensing neurons. DZ opens both plasma membrane and mt KATP channels; the former inhibits neurons while the latter maintains mitochondrial metabolic function. We hypothesize that the concentration of brain DZ that lowers EGP affects the mt and not the plasma membrane KATP channel of VMH glucose sensing neurons. VMH glucose-excited (GE) neurons were exposed to 0.1 µM DZ in 2.5 mM glucose for 20 minutes prior to lowering glucose to 0.1 mM in the presence of DZ. DZ did not alter membrane potential (MP; 2.5 glucose: −63 ± 4 mV; DZ: −64 ± 5 mV, P = 0.3807, N = 7) or cell resistance (R; 2.5 glucose: 658 ± 136 MΩ; DZ 656 ± 146 MΩ, P = 0.9526, N = 7) in 2.5 mM glucose. There was also no difference in the MP or R response to lowering glucose from 2.5 to 0.1 mM in the presence or absence of DZ (% change MP control: −20.8 ± 3, diazoxide: −19.9 ± 3, P = 0.9044, N = 5; R control: −59.0 ± 5, diazoxide: −55.3 ± 6, P = 0.7134, N = 5). Similar results were seen with VMH glucose-inhibited neurons (N=4; Fig. 1). Our results are consistent with an action of DZ on mt but not plasma membrane KATP channels of VMH glucose sensing neurons.

Disclosure

G.Vail: None. V.Patel: None. P.Sarkar: None. K.Zhang: None. M.Hawkins: None. V.H.Routh: None.

Funding

National Institutes of Health (2R01DK069681-11)
1541-P: Sympathetic Nervous System Activity in Response to Food Ingestion Is Impacted by Obesity
Authors: CHUNG TAMMY J. , DEAJON-JACKSON JELANI , BINI JASON , SONG HUIJIA , SANCHEZ RANGEL ELIZABETH , YECKEL CATHERINE W. , HWANG JANICE J. , STACHENFELD NINA , BELFORT-DEAGUIAR RENATA
Published: June 2023

Studies have shown that sympathetic nervous system activity (SNSA) may differ in obese (OB) compared to lean individuals. In addition, increased (SNSA) has been observed after ingestion of food. However, it remains unclear whether obesity alters post-meal (SNSA). We tested the hypothesis that (SNSA) is increased post-meal in OB individuals. We used a dual strategy to assess SNSA: i) a whole-body PET radiotracer ([11C]MRB) in combination with CT imaging (PET-CT). [11C]MRB binds to norepinephrine (NE) transporter allowing measurement of NE release from SNS. ii) Skeletal muscle microneurography to measure muscle sympathetic nerve activity (MSNA). Participants underwent two PET-CT and MSNA visits: fasting and mixed meal test (MMT). We ​​examined 5 subjects, 3F/2M, age 41±7 years (2 OB) and 3 normal weight (NW). During the MSNA fasting visit, RR intervals were longer at 15 minutes (P=0.03), while opposite findings were observed with MMT, which diminished between 15 until 60 minutes indicating increased heart rate (HR). We also observed increased total MSNA area/burst at 60 min after MMT (P<0.02). No statistically significant differences in MSNA were observed between OB and NW. PET-CT of deltoid muscle (n=4, 2 OB and 2 NW) showed changes in distribution volume ratio (DVR) between days (MMT - fasting) were correlated with BMI (R2=0.71, P=0.16). DVR changes in both NW were reduced, while both OB were increased (P=0.01), suggesting that OB had less endogenous NE competing with [11C]MRB to bind at the NE transporter compared to NW. These preliminary data suggest that MSNA increases following MMT in both NW and OB subjects which may be further impacted by obesity.

Disclosure

T.J.Chung: None. J.Deajon-jackson: None. J.Bini: None. H.Song: None. E.Sanchez rangel: None. C.W.Yeckel: None. J.J.Hwang: None. N.Stachenfeld: None. R.Belfort-deaguiar: Research Support; Fractyl Health, Inc., Silver Palate Kitchens.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK129344)
1542-P: Commercially Available Aspartame-Based Sweetener Damages Morphology of Major Organs Both in Normal and Type 2 Diabetic Rats
Authors: DLAMINI SIPHIWE N. , ISLAM SHAHIDUL
Published: June 2023

Non-nutritive sweeteners (NNS) such as aspartame have become highly popular as sugar substitutes for diabetics. Majority of studies have reported controversial results and used aspartame in its pure form, which is not consumed by people practically. Hence, the present study was aimed at investigating the effects of commercially available aspartame-based sweetener on diabetes related parameters and its associated complications in both normal and type 2 diabetic rats. Seven-week-old male Sprague-Dawley rats were randomly divided into four groups, namely: Normal Control (NC), Toxicological Aspartame (TASP), Diabetic Control (DBC) and Diabetic Aspartame (DASP). Type 2 diabetes was induced experimentally in the DBC and DASP groups only and animals with non-fasting blood glucose levels >300 mg/dL were considered as diabetic. During 13 weeks experimental period, the control groups received normal drinking water, whilst TASP and DASP groups were given aspartame-containing NNS solutions, ad libitum, at concentrations equivalent to the sweetness of 20% and 10% sucrose solution, respectively. Treatment with toxicological aspartame resulted in significantly reduced serum fructosamine and creatinine levels in normal rats, when brain, heart, liver, kidney and pancreatic tissue morphologies were significantly damaged in both normal and diabetic rats. The data of this study suggest that although aspartame-based NNS may not have higher degree of detrimental effects on diabetes associated parameters, the significantly damaged morphology of the major organ tissues as well as deterioration of related serum biomarkers both in normal and diabetic conditions raises a concern of its use as a NNS in various food and food products.

Disclosure

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

Funding

South African Sugar Association (Project 233)
1546-P: Gut-Specific Neprilysin Deletion Increases Insulin Secretion in High-Fat–Fed Mice
Authors: ESSER NATHALIE , MONGOVIN STEVE M. , BARROW BREANNE , ZRAIKA SAKENEH
Published: June 2023

Global deletion of the ubiquitous peptidase neprilysin (NEP) protects against high fat diet (HFD)-induced insulin secretory dysfunction. Since NEP is expressed in the gut, it can cleave locally produced insulinotropic peptides. We previously found that under physiological conditions, acute inhibition of gut NEP enhances glucose-stimulated insulin secretion (GSIS) in mice. Thus, we determined whether this beneficial effect on GSIS also occurs in mice with gut-specific NEP deletion that are fed HFD. Mice with conditional deletion of NEP in enterocytes (NEPGut-/-) were generated by crossing Vil1-cre and floxed NEP mice. NEP activity was almost abolished throughout the gut in NEPGut-/- vs control mice (5±2 vs 164±20 vs 120±20 pmol MNA/h/μg, NEP Gut-/- vs Vil1-cre vs NEPfl/fl mice; n=5-6/group; p<0.0001), and was similar in plasma, pancreas and kidney among all mice. At 11 weeks of age, mice were fed HFD for 14 weeks, after which an OGTT was performed and GSIS assessed as ∆insulin/∆glucose from 0 to 10 min. Despite similar body weights in NEP Gut-/- and control mice, fasting plasma glucose was lower and GSIS higher in NEP Gut-/- vs controls (Table). In sum, gut-specific NEP deletion decreases fasting plasma glucose and increases GSIS in HFD-fed mice, suggesting gut NEP impairs ß-cell function under conditions of HFD. Thus, strategies to inhibit NEP specifically in the gut may protect against fat-induced ß-cell dysfunction.

Disclosure

N.Esser: None. S.M.Mongovin: None. B.Barrow: None. S.Zraika: None.

Funding

National Institutes of Health (DK098506, (P30DK017047)
1549-P: scEMC10 Promotes Glucose Intolerance via the Inhibition of PKA-Mediated Insulin Secretion
Authors: DAI JIARONG , LIU SHAN , CHEN KUANGYANG , JIN SHUOSHUO , WANG YAHAO , CHEN LIJIAO , WANG XUANCHUN
Published: June 2023

It has been shown recently that overexpression of the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) impairs, whereas Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice fed with high fat diet. In humans, serum scEMC10 levels correlate positively with fasting plasma glucose and HbA1c. The mechanism underlying the regulation of glucose metabolism by scEMC10 remains largely unknown. In this study, alation of EMC10 significantly improved glucose tolerance in chow diet-fed mice, which was attributed to increased glucose-stimulated insulin secretion (GSIS), but not improved insulin sensitivity evaluated by euglycemic-hyperinsulinemic clamp. Using an adeno-associated virus, either reconstitution of scEMC10 in Emc10 KO mice or overexpression of scEMC10 in wildtype mice significantly decreased glucose tolerance accompanied by blunted GSIS. Recombinant scEMC10 inhibited GSIS in both INS-1 cells and isolated primary islets in vitro. Mechanistically, we presented evidence that extracellular scEMC10 can be transported into beta cells where it binds to the catalytic subunit of PKA and inhibits phosphorylations of PKA substrates including phosphorylated CREB, along with reduced PDX-1 expression. Furthermore, antibody neutralization of circulating scEMC10 alleviated hyperglycemia in both STZ-treated mice and ob/ob mice. This work identifies scEMC10 as a suppressor of insulin secretion via the inhibition of PKA signaling in islet beta cells and suggests scEMC10 neutralizing antibody as a promising pharmaceutical agent to treat diabetes.

Disclosure

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

Funding

National Natural Science Foundation of China (81873645); Science and Technology Commission of Shanghai Municipality (22140902700)
1556-P: Hepatic AMP-Activated Protein Kinase Governs Adaptations in Liver Glucose Fluxes and Lipid Homeostasis in Response to Exercise Training in Mice
Authors: HUGHEY CURTIS C. , BRACY DEANNA , LANTIER LOUISE , FORETZ MARC , VIOLLET BENOIT , WASSERMAN DAVID
Published: June 2023

During acute exercise the liver increases glycogenolysis and the energetically costly process of gluconeogenesis to supply glucose to the working muscle. In response to exercise training, the liver undergoes adaptations in glucose and lipid metabolic pathways to more effectively meet the ATP demand of the next exercise bout. We tested the hypothesis that the energy sensor and master regulator of ATP provision, AMP-activated protein kinase (AMPK), is necessary for liver glucose and lipid adaptations to exercise training. This was accomplished by studying mice with liver-specific deletion of AMPK α1 and α2 subunits (KO) and wild type (WT) littermates undergoing sedentary and exercise training protocols. In vivo isotope infusions combined with 2H/13C metabolic flux analysis quantified liver nutrient fluxes at rest and during treadmill running. Liver metabolite concentrations and the expression of molecular regulators of liver nutrient metabolism were evaluated. The results of this study showed that liver glycogen deposition in response to exercise training was impaired in KO compared to WT mice and that this lower glycogen availability resulted in diminished glycogenolysis, glucose production, and circulating glucose during acute exercise. Exercise training decreased liver diacylglycerides (DAGs) in both genotypes, however, the response was less pronounced in KO mice. Moreover, exercise training led to higher liver triacylglycerides (TAGs) in KO mice. A lack of AMPK action prevented exercise training from promoting the desaturation of DAG fatty acyl chains as evidenced by higher 16:1/16:0 and 18:1/18:0 ratios in KO mice. Unexpectedly, the differences in DAG fatty acyl chain composition between genotypes were not observed in TAGs. Together, these results suggest that AMPK is a critical regulator of the liver glycogen and lipid availability and selectively remodels DAG fatty acyl chain composition in response to exercise training.

Disclosure

C.C.Hughey: None. D.Bracy: None. L.Lantier: None. M.Foretz: None. B.Viollet: None. D.Wasserman: None.

Funding

National Institutes of Health (DK050277, DK054902, DK059637, DK020593)
1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA , YANG BIN , DIMARCHI RICHARD , HABEGGER KIRK M.
Published: June 2023

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity.

Disclosure

S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc.

Funding

National Institutes of Health
156-LB: Nursing Burden Administering/Monitoring Complex Insulin Regimens vs. Basal Insulin/GLP-1 RA Fixed-Ratio Combinations (FRCs) for People with Type 2 Diabetes (PWT2D) in Long-Term Care (LTC)
Authors: DAVIDSON HARLEY E. , NELSON ASHLEY , HAN LISA F. , LAMANTIA MELISSA , DESAI KERRY , LI XUAN , DEX TERRY A. , VANCE JACQUELINE F. , OVERBECK KEVIN
Published: June 2023

Aim: Management of older PWT2D in LTC is challenging due to comorbidity, functional dependence, and hypoglycemia risk, and is further complicated by nurse shortages. This cross-sectional survey emailed to LTC nurses assessed perceived nursing burden associated with complex insulin regimens (basal-bolus [BB], sliding scale insulin [SSI]) vs FRCs.

Methods: The survey comprised 3 hypothetical cases of PWT2D receiving BB, SSI, or FRC. Perceived burden was assessed using the unweighted NASA-Task Load Index (TLX). Responses for the 6 TLX subscales (mental, physical, and temporal demand; effort, frustration, performance) and perceived frequency of fingerstick use were summarized descriptively.

Results: 10,982 nurses received the survey. Of the 250 who qualified (administered BB/SSI/FRC in past 90 days), 87% were female, 51% were ≥45 y, 49% had ≥11 y experience in LTC. TLX scores (max 20 higher = worse) were lower for FRCs vs BB or SSI (Table). Nurses perceived FRCs to require fewer fingersticks vs BB or SSI (Table).

Conclusions: FRCs were perceived to reduce nursing burden and fingerstick use compared with complex insulin regimens. These findings, coupled with the lower hypoglycemia risk for FRCs vs complex insulin regimens reported in clinical trials suggest that use of FRCs in LTC has potential to reduce nursing workload.

Disclosure

H. E. Davidson: Research Support; Sanofi-Aventis U. S. A. Nelson: Research Support; Sanofi-Aventis U. S. L. F. Han: Research Support; Sanofi-Aventis U. S. M. Lamantia: Research Support; Sanofi-Aventis U. S. K. Desai: Employee; Sanofi. X. Li: Employee; Sanofi-Aventis U. S. T. A. Dex: Employee; Sanofi-Aventis U. S., Stock/Shareholder; Pfizer Inc., Viatris Inc., Teva Pharmaceutical Industries Ltd. J. F. Vance: None. K. Overbeck: None.

Funding

Sanofi
1560-P: Combining Glucagon with Insulin Can Lessen the Hypoglycemic Potential of Insulin
Authors: KRAFT GUILLAUME , SCOTT MELANIE , SMITH MARTA S. , FARMER BEN , EDGERTON DALE S. , CHERRINGTON ALAN D.
Published: June 2023

We showed previously in people with T1D that by infusing glucagon along with insulin can buffer insulin’s hypoglycemic effect without worsening its ability to limit hyperglycemia. Our aim was to determine in the conscious dog the mechanisms by which glucagon limits the insulin driven fall in glucose. Somatostatin was infused to disable the endocrine pancreas and insulin and glucagon were infused into a leg vein at basal rates. After a 140 min control period, the insulin infusion rate was increased 4-7-fold for 3h to induce hypoglycemia. Glucagon was also infused into a leg vein, then was either increased proportionately to insulin (constant I/G molar ratio, HiGGN), or in a second study on the same dog, it was kept at its basal rate (Ba GGN). Hepatic sinusoidal insulin levels rose from 11±2 to 65±17 μU/ml regardless of the glucagon level, which remained basal in BaGGN (50±10pg/mL) but rose from 52±8 pg/ml to 238±50pg/ml in HiGGN. Plasma glucose fell over the first hour, reaching a nadir of 45±2 mg/dl when glucagon was basal, and fell more slowly when glucagon was elevated (nadir of 50±2 mg/dl). This difference was due to a greater increase in net hepatic glucose output in the HiGGN group (1.4 ± 0.2 vs 2.4 ± 0.2 mg/kg/min in BaGGN and HiGGN respectively). Interestingly the rise in plasma cortisol and epinephrine were reduced by 33 and 39%, respectively, in the group with elevated glucagon. Further, this lessening in the counterregulatory response was associated with reductions in lipolysis and lactate production by muscle. Thus, by maintaining a fixed I/G molar ratio the hypoglycemic potential of insulin is buffered. This could allow more aggressive insulin treatment which would in turn increase time in range for glucose.

Disclosure

G.Kraft: None. M.Scott: None. M.S.Smith: None. B.Farmer: None. D.S.Edgerton: None. A.D.Cherrington: Advisory Panel; Metavention, vTv Therapeutics, Diakard, Sekkei Bio, Sensulin Labs, LLC, Other Relationship; Fractyl Health, Inc., Novo Nordisk, Abvance Therapeutics, Research Support; Cellular Longevity, Inc, dba Loyal, Senda Biosciences.
1562-P: Hepatic ChREBP-ß Overexpression Enhances Peripheral Glucose and Lipid Homeostasis Independently of FGF21
Authors: HANNOU SARAH , SARGSYAN ASHOT , TONG WENXIN , AN JIE , NEWGARD CHRISTOPHER B. , ASTAPOVA INNA , HERMAN MARK A.
Published: June 2023

Carbohydrate Response Element-Binding Protein (ChREBP) is a key transcription factor activated by carbohydrate metabolites which transactivates metabolic gene programs involved in the glycolytic and lipogenic response to dietary and circulating sugars. Genetic variants in the ChREBP locus associate with multiple aspects of cardiometabolic disease including dyslipidemia and risk of type 2 diabetes (T2D). Studies overexpressing ChREBP in the liver suggest that ChREBP can play a protective role in preserving glucose and lipid homeostasis. We hypothesized that this protective effect may be mediated through ChREBP’s effect to increase hepatic expression and circulating levels of the beneficial hepatokine, FGF21. To test this hypothesis, we transduced male mice with liver-specific knockout of FGF21 (L-FGF21KO) and lox/lox controls with adenovirus (ADV) containing the constitutively active isoform of murine ChREBP, ChREBP-β, versus ADV-GFP control (N = 4-7 / group). ADV-ChREBP-β transduction induced a 5-fold increase in hepatic (p<0.001) and circulating FGF21 (p<0.0001) in control mice and this was fully abrogated in L-FGF21KO mice. While no significant changes in body weight were detected, ADV-ChREBP-β transduction reduced fasting glycemia and enhanced glucose tolerance in both controls and L-FGF21KO mice. ADV-ChREBP-β transduction induced glycolytic and lipogenic genes similarly in L-FGF21KO and control mice, increased hepatic triglyceride content (3-fold, p<0.005) and induced steatosis, while reducing circulating triglycerides and increasing browning of white adipose tissue. In conclusion, hepatic FGF21 does not mediate the beneficial effect of hepatic ChREBP-β overexpression on peripheral glucose and lipid homeostasis.

Disclosure

S.Hannou: None. A.Sargsyan: Employee; AstraZeneca. W.Tong: None. J.An: None. C.B.Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk, AstraZeneca. I.Astapova: None. M.A.Herman: Research Support; Eli Lilly and Company.

Funding

National Institutes of Health (R01DK100425)