bluuebunny/crossref_metadata_2025 huggingface dataset:
296-OR: Submicron Ultrasound Contrast Agents as Therapeutic Delivery Vehicles in Type 1 Diabetes
Authors: CICCAGLIONE MARK , MCDANIEL KRISTEN , MICHELS AARON W. , EXNER AGATA A. , BENNINGER RICHARD K.
Published: June 2023

Type 1 diabetes (T1D) is characterized by immune-mediated destruction of insulin-producing beta cells resulting in severe hyperglycemia if untreated. Prior work has shown that islet microvasculature becomes hyperpermeable during presymptomatic T1D, allowing for ‘nanobubble (NB)’ submicron ultrasound contrast agents to accumulate in immune-infiltrated islets, which can be quantified using ultrasound contrast. We investigated the utility of these lipid-shelled NBs as peptide delivery vehicles to provide islet-targeted delivery, for acoustically driven therapeutic release and where therapeutic delivery can be visualized in real-time with ultrasound. We developed this platform to enhance efficacy of insulin peptide mimotopes, which can promote the expansion of anti-inflammatory regulatory T cells (Tregs) and prevent T1D in mice. We modified insulin B:9-23 peptides with a palmitoyl fatty acid tail to incorporate in the NB lipid shell. NBs accumulated specifically in NOD islets and not in other abdominal organs or NOD-SCID (control) islets (p < 0.0001). We found that palmitoylation enhanced peptide retention in NBs (p < 0.001) and is essential for delivery to NOD islets (p < 0.0001), where the extent of peptide delivery correlates with extent of insulitis (p < 0.05). Peptide incorporation did not affect NB echogenicity (in vitro and in vivo), ability to burst, and size distribution. Palmitoylation and incorporation in NBs does not affect the ability for peptide-pulsed antigen presenting cells to stimulate insulin-reactive T cells in vitro (p < 0.0001). Finally, NOD mice treated with peptide-NBs had a higher proportion of Tregs amongst insulin-reactive CD4+ T cells in islets, as compared to mice treated with NBs or peptide alone (p < 0.05). This serves as an important proof-of-principle for the usage of NBs for targeted peptide delivery and has the potential to improve therapeutic intervention in T1D.

Disclosure

M.Ciccaglione: None. K.Mcdaniel: None. A.W.Michels: Stock/Shareholder; Immnomolecular Therapeutics. A.A.Exner: None. R.K.Benninger: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102950, R01DK106412, P30DK116073, T32DK120520); National Center for Advancing Translational Sciences (TL1TR002533); JDRF (1-INO-2017-435-A-N); University of Colorado
299-OR: A Combinatorial Approach with Monoclonal Antibodies to SerpinB13 and CD3 Is Therapeutically Superior to Single Antibody Use in Autoimmune Diabetes
Authors: SZEPIETOWSKA BARBARA , AVDULOV SVETLANA V. , KRYVALAP YURY , CZYZYK JAN
Published: June 2023

A successful approach to autoimmune diabetes therapy may require simultaneous insulin-producing cell regeneration and T-cell mediated autoimmunity resolution in pancreatic islets. While CD3 antibody has been proved to reduce islet inflammation, the monoclonal antibody (mAb) to serpinB13 protease inhibitor, developed in our laboratory, was shown to cause regenerative changes in beta cells. Whether a combination of both antibodies is superior to single antibody use in the treatment of autoimmune diabetes is unclear. To address this non-obese diabetic (NOD) female mice at late pre-diabetic stage were injected with serpinB13 mAb (clone B29, 10, 40 or 200 micrograms/animal) and CD3 mAb (clone 145-2C11; at a suboptimal dose of 10 micrograms). All experimental injections were controlled with nonspecific hamster IgG and mouse IgG (clone HB-158). After the last antibody injection, random blood glucose levels were assessed for 20 weeks, and mice were declared diabetic after two measurements of glucose exceeding 300 mg/dL. We found that the combination of 40 micrograms of serpinB13 mAb with CD3 mAb offered a significant level of protection from diabetes (p=0.0027, Kaplan-Meyer with log rank test), while the combination with 10 micrograms of serpinB13 mAb had no effect. The higher dose of 200 micrograms of serpinB13 mAb showed a trend in favor of diabetes inhibition. Interestingly, at 6 to 7 weeks after completing the treatment with 40 micrograms of serpinB13 mAb alone, NOD mice showed a strong tendency to remain healthy, and separated from the double-negative control, which continued to progress to diabetes. Our results indicate that a combinatorial approach with mAbs to serpinB13 and CD3 is beneficial in autoimmune diabetes. The observations also suggest that an intermediate dose of serpinB13 mAb, and a sufficient time following administration of this mAb, is critical for its positive impact on diabetes prevention.

Disclosure

B.Szepietowska: None. S.V.Avdulov: None. Y.Kryvalap: None. J.Czyzyk: None.

Funding

JDRF (2-SRA-2022-1215-S-B)
3-LB: Effects of Sustained Somatostatin Receptor 2 Antagonism (SSTR2a) on Glycemia in Type 2 Diabetic (T2D) Male Rats—A Pilot Study
Authors: ALEALI NADIA , D'SOUZA NINOSCHKA C. , SHAKERI DORSA , SIMONSON ERIC , LIGGINS RICHARD , CHAN OWEN , RIDDELL MICHAEL C.
Published: June 2023

Introduction: Somatostatin may be elevated in diabetes, which can reduce glucagon secretion at mealtimes and during hypoglycemia. In this pilot study, we investigated the effect of a sustained low-dose delivery of a novel SSTR2a (ZT-01), using a mini-osmotic pump, on oral glucose tolerance (OGT) and response to an insulin-induced hypoglycemia challenge in a T2D rat model.

Methods: Male Sprague Dawley rats (n=4/5 per group) were placed on a high-fat diet (3 weeks) then injected with low-dose streptozotocin (35 mg/kg), inducing T2D. Basal bolus insulin was administered for 7 days (2-3 units/day) to maintain fed-state glycemia targeting 12-25 mmol/L, after which the rats were treated with ZT-01 (0.18 mg/day) or vehicle using implanted mini-osmotic pumps (Alzet). An OGT test on day 3 was followed by a hypoglycemic challenge (12U regular insulin) on day 5.

Results: Drug and vehicle groups displayed similar glycemic levels in the fasted state and post oral glucose ingestion. Glycemia was also similar prior to insulin challenge and there was no difference in basal glucagon between groups, but SSTR2a treatment attenuated the drop in blood glucose after bolus insulin.

Conclusion: Sustained exposure to low-dose SSTR2a does not appear to affect basal glucose or glucagon levels, nor affect the response to OGT but may improve the glucose response to insulin-induced hypoglycemia in this T2D model.

Disclosure

N. Aleali: None. N. C. D'souza: None. D. Shakeri: None. E. Simonson: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics.

Funding

GlycoNet (CD-85); Zucara Therapeutics Inc.
301-OR: Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
Authors: TORRES IRIZARRY VALERIA C. , YE HUI , LUO PEI , CARRILLO-SÁENZ LESLIE , YANG XIAOHUA , MUNOZ MARCOS D. , ANTONY NIMISHA , JIANG YUWEI , HE YANLIN , XU PINGWEN
Published: June 2023

Brain estrogen receptor α (ERα) signaling plays a vital role in the regulation of energy homeostasis and adipose tissue metabolism. It has been demonstrated that ERα is abundantly expressed in the ventrolateral region of the ventromedial hypothalamus (vlVMH), a sex-dimorphic structure that directly modulates brown adipose tissue (BAT) thermogenesis. We previously showed that an ERαvlVMH-originated neural circuit responds to changes in ambient temperature and nutritional states, suggesting a potential role of this neural circuit in metabolic adaptation. Here, we found that chronic activation of ERαvlVMH neurons in male mice reduces body weight, decreases adiposity, and prevents diet-induced obesity (DIO), which is associated with increases in BAT thermogenesis and core temperature. Conversely, chronic inhibition of ERαvlVMH neurons increases body weight, promotes adiposity, and decreases baseline BAT temperature. Notably, ERαvlVMH neural inhibition also impairs cold-induced food consumption and BAT thermogenesis, resulting in lethal phenotypes during chronic cold exposure. Post hoc histology analysis further revealed that ERαvlVMH neural inhibition induces adipose tissue whitening. Finally, we explored the anatomical distribution of ERαvlVMH downstream neural circuitries. Anterograde tracing revealed ERαvlVMH-originated projections to the medial preoptic area (MPA), paraventricular nucleus (PVN), substantia nigra (SNR) and dorsal raphe nucleus (DRN). Interestingly, transsynaptic retrograde tracing further demonstrated that these brain regions send projections to inguinal white adipose tissue (iWAT), suggesting potential ERαvlVMH-originated circuits involved in adipose tissue adaptation. Together, these findings support a model that estrogens act through ERαvlVMH neurons to modulate fat-specific outputs and subsequently regulate adipose tissue adaptation to cold challenges.

Disclosure

V.C.Torres irizarry: None. P.Xu: None. H.Ye: None. P.Luo: None. L.Carrillo-sáenz: None. X.Yang: None. M.D.Munoz: None. N.Antony: None. Y.Jiang: None. Y.He: None.

Funding

National Institutes of Health (R01DK123098, T32AA026577); U.S. Department of Defense (W81XWH-19-PRMRP-DA); National Institute of Diabetes and Digestive and Kidney Diseases (DK020595); American Heart Association (915789)
304-OR: Reduced VDAC1 Limits ROS Release to Restrain Oxidative Damage in Muscle of 3-Year-Old Nonhuman Primates with Early-Life Exposure to Maternal Western Diet or Obesity
Authors: GREYSLAK KEENAN T. , MCCURDY CARRIE E.
Published: June 2023

Offspring from obese pregnancies have an elevated risk for childhood obesity and chronic metabolic diseases. Using a Japanese macaque model of early-life maternal Western-style diet (mWD) exposure, we previously observed decreased oxidative capacity and elevated markers of mitophagy in skeletal muscle of 3-yr-old offspring. We also found substantial reductions in VDAC1 content, the loss of which significantly correlated with decreased whole-muscle lipid peroxidation in mWD offspring. For this study, we isolated the impact of mWD from mWD-induced obesity by studying offspring from both lean (Ln, body fat <25%) or obese (Ob, body fat >30%) dams fed a WD or lean dams fed a control diet (CD) prior to and throughout pregnancy and lactation. All offspring were weaned to CD and offspring gastrocnemius was collected at 40 months of age. This design created three offspring groups: LnCD, LnWD and ObWD. In offspring muscle, VDAC1, but not VDAC2, was significantly decreased in LnWD, and was further reduced in ObWD. In contrast to whole-tissue, lipid peroxidation in a mitochondrial-enriched fraction was increased in offspring muscle from LnWD and ObWD groups. Markers of mtDNA damage were also elevated in ObWD muscle. Lastly, Sirt3 abundance, a master regulator of mitochondrial antioxidant defense, was reduced in muscle from both LnWD and ObWD. These data suggest that ROS are retained within the mitochondrial compartment due, in part, to VDAC1 suppression, resulting in an overall reduction in cellular oxidant burden. These findings elucidate a long-term adaptation to early life stress caused by mWD and obesity which limits cellular damage at the expense of mitochondrial function.

Disclosure

K.T.Greyslak: None. C.E.Mccurdy: None.

Funding

National Institutes of Health (R24DK090964); Eugene Evonuk Memorial Graduate Fellowship
306-OR: PEA15 Regulates Metabolism and Adiposity in a Sex-Dependent Manner through Alterations in Metabolic Flexibility
Authors: J. TOWNS T. , BRINKER EMILY , WATANABE RIE , ODENIYI IFEOLUWA A. , MCCAFFERTY KAYLEEN J. , GRABAU NATASHA , KROEGER DANIEL , GREENE MICHAEL W. , JUDD ROBERT L. , GRAFF EMILY
Published: June 2023

Phosphoprotein enriched in astrocytes 15kDa (PEA15) is a ubiquitously expressed cytosolic protein with high expression in the brain, and enhanced expression in the hypothalamus. Humans with type 2 diabetes mellitus have increased expression of PEA15 in adipose tissue and skeletal muscle, and overexpression of PEA15 in transgenic mice and pigs results in peripheral insulin resistance. Despite these findings, studies of PEA15 in high fat diet (HF)-mediated obesity are limited. Male and female Pea15-/- mice (KO) and littermate controls (WT) were fed a control diet (CD) or HF for 20 weeks, with a GTT at 19 weeks and metabolic cage data at 20 weeks, just prior to serum and tissue collection. The effects of PEA15 on metabolic parameters varied based on sex. Female KO mice fed HF had a significant increase in body weight due to increased inguinal adipose and liver weight, and impaired insulin sensitivity compared to HF-fed WT females. The KO mice had similar food intake but decreased activity during the light cycle compared to HF-fed WT female mice. In contrast, a genotypic effect in male mice was noted in CD-fed mice with KO mice having an increased body weight and corresponding increases in inguinal and gonadal adipose compared to WT with no significant change in insulin sensitivity, food intake or energy expenditure. KO males on CD were significantly more active during the light phase than WT controls despite increased body weight. Substrate utilization and its associated diurnal switch were altered in both sexes of KO mice compared to WT, with KO male mice having increased preference towards carbohydrate utilization while female KO mice had increased lipid utilization. These findings suggest that PEA15 regulates metabolism in a sex-dependent manner through alterations in metabolic flexibility, energy substrate utilization, and diurnal rhythms. Further work will investigate the sex-dependent role of PEA15 on central and peripheral regulators of diurnal rhythm and metabolism.

Disclosure

T.J.Towns: None. E.Graff: None. E.Brinker: None. R.Watanabe: None. I.A.Odeniyi: None. K.J.Mccafferty: None. N.Grabau: None. D.Kroeger: None. M.W.Greene: None. R.L.Judd: None.

Funding

Auburn University
307-OR: Delineating the Origin of Supraclavicular Brown Adipocytes
Authors: RAN YALI , WANG ZIYI , WATERSTRAAT MARK G. , CABALLERO-JUAREZ ROMMEL , CHEN MIAO-HSUEH
Published: June 2023

Brown adipose tissue (BAT) can use nutrients through non-shivering thermogenesis to generate heat. Thus, activation of BAT can be utilized to maintain body temperature and regulate metabolism. Healthy adult humans possess small amounts of BAT, with the most visible depot, the supraclavicular BAT (scBAT), located in the supraclavicular region of the neck. To understand how human scBAT functions, we previously identified BAT depots in the supraclavicular region of the mouse neck that anatomically resemble human scBAT. Similar to human scBAT, mouse scBAT contains a high density of mitochondria and expresses high levels of uncoupling protein 1. Mouse scBAT first appears in the late fetal stage in the ventral neck and continues to expand toward the lateral neck after birth. To identify the stem/progenitor cells that give rise to supraclavicular brown adipocytes, we performed a series of lineage tracing analyses. Unlike the well-studied mouse interscapular BAT depot, scBAT did not originate from the Myf5, Pax3, or Pax7-labeled progenitor cells that also give rise to skeletal muscle. Rather, a large portion of the supraclavicular brown adipocytes were labeled by Cre recombinase driven by the Mef2c anterior heart field promoter (AHF), which marks cells that give rise to the outflow tract and right ventricle of the heart. Mef2c-AHF+ cells isolated from the scBAT can spontaneously differentiate into highly thermogenic brown adipocytes in vitro, and the differentiation efficiency is further enhanced by addition of Bmp7 and PPARγ agonist, rosiglitazone. Together, our lineage tracing studies revealed that the scBAT is composed of heterogeneous brown adipocyte progenitor cells and that Mef2c-AHF-marked cardiac progenitor cells are one of the ancestors of these brown adipocytes. Understanding the trajectories of and molecular mechanisms by which these progenitor cells give rise to scBAT will provide new insights for developing a novel cell-based therapeutic tool for treating obesity and related metabolic complications.

Disclosure

Y.Ran: None. Z.Wang: None. M.G.Waterstraat: None. R.Caballero-juarez: None. M.Chen: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116899)
308-OR: Hippo-YAP/TAZ Signaling Coordinates Adipose Plasticity and Energy Balance by Uncoupling Leptin Expression from Fat Mass
Authors: CHOI SUNGWOO , PARK KUN-YOUNG , SHIN HYEMI , MYOUNG SUH JAE
Published: June 2023

Adipose tissue regulates systemic energy homeostasis by acting as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the underlying mechanisms are unknown. Here we show that the transcriptional coregulators YAP and TAZ mediate the crosstalk between adipose tissue mass and leptin levels to maintain systemic energy balance. The activation of adipocyte-specific YAP/TAZ via genetic ablation of the upstream regulators LATS1 and LATS2 resulted in a profound reduction in fat mass due to the conversion of mature adipocytes into delipidated cells with progenitor-like features. Rosiglitazone treatment normalized fat mass, indicating that PPARG inhibition is a major contributor to YAP/TAZ-induced lipoatrophy. Surprisingly, LATS1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction. This phenotype was attributed to a paradoxical increase in circulating leptin levels, which was found to offset the energy storage deficit by increasing fat oxidation and energy expenditure. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by direct binding to an upstream enhancer site of the leptin gene. Finally, we show that YAP/TAZ activity is associated with leptin regulation during fasting and refeeding, indicating that YAP/TAZ links nutrient status in adipose tissue to systemic energy homeostasis. Taken together, we reveal that adipocyte Hippo-YAP/TAZ functions as a nexus for coordinating nutrient storage capacity and systemic energy balance by regulating adipocyte plasticity and leptin gene transcription.

Disclosure

S.Choi: None. K.Park: None. H.Shin: None. J.Suh: None.
309-OR: Adipose RNA N6-Methyladenosine (m6A) Modification Promotes Obesity and Insulin Resistance through Suppressing Lipolysis
Authors: KANG QIANQIAN , RUI LIANGYOU , REN DECHENG
Published: June 2023

Excessive white adipose tissue (WAT) promotes insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obesity; however, the WAT expansion mechanism remains poorly understood. We reported that WAT lipolysis is suppressed in obesity, likely contributing to WAT growth. Adipose triglyceride lipase (Atgl) catalyzes the lipolysis reaction, and its lipolytic activity is increased by phosphorylation and binding to cofactor Cgi58. The sympathetic nervous system activates adipocyte β adrenergic receptor (Adrb)/cAMP/PKA pathway to stimulate lipolysis via Atgl and Cgi58. In this study, we have identified a novel m6A modification of Adrb, Atgl, and Cgi58 transcripts that promotes obesity and metabolic disorders. We found that obesity was associated with increased expression of adipose Mettl3 and Mettl14 and elevated m6A levels in WAT. Mettl14 directly binds to Mettl3 to form a methyltransferase complex that catalyzes m6A on RNA. Insulin also increased Mettl14 expression and m6A levels in adipocytes. We generated adipocyte-specific Mettl14 knockout mice (Mettl14 Δfat) and placed mice on a high fat diet (HFD). Remarkably, Mettl14 Δfat mice, both males and females, were resistant to HFD-induced obesity, insulin resistance, and NAFLD. Adipose Adrb2/3, Atgl, and Cgi58 protein levels were significantly upregulated in Mettl14 Δfat mice and consequently, adipose β adrenergic signaling and lipolysis were significantly higher in Mettl14 Δfat than in Mettl14f/f mice. Mettl14 deficiency dramatically decreased the m6A content of Adrb2/3, Atgl, and Cgi58 transcripts in WAT; strikingly, m6A inhibition markedly increased translational rates of these transcripts in adipocytes. Collectively, these results unravel a previously unrecognized adipose Mettl14/m6A/translation axis that promotes obesity, insulin resistance, and NAFLD by suppressing adipose β adrenergic signaling, lipolysis, and fatty acid oxidation.

Disclosure

Q.Kang: None. L.Rui: None. D.Ren: None.

Funding

National Institutes of Health (R01DK130111)
31-LB: The Relationship between Improvements in Glycemic Control following a Digital Health Intervention and the Food Environment in a Medicare Advantage Population
Authors: EDWARDS CAITLYN , VOELKER LOUISE , ZIMMERMANN GRETCHEN , RAWLINGS KELLY , VENKATESAN AARATHI
Published: June 2023

Diabetes is a complex disease that is influenced by social determinants of health (SDOH). An inadequate food environment, as a function of socioeconomic status and proximity to food retailers, has been associated with both increased prevalence of diabetes and barriers to diabetes self-management. This work examined the relationship between improvements in glycemic control as a result of a digital health intervention and the food environment in Medicare Advantage members at risk for diabetes-related complications (hemoglobin A1c [A1c] ≥ 8%). Participants enrolled in the Vida Health Diabetes Management program as part of their medical insurance benefit and utilized remote sessions with Registered Dietitians and Certified Diabetes Care and Education Specialists as well as content related to goal-setting to account for SDOH factors. The 2010 USDA Food Access Research Atlas was used to identify areas of low income and the absence of a food retailer within 0.5 or 1 urban and 10 rural miles (LILA). Participants were included if they had a laboratory A1c between -365 to -1 and 60 to 365-days of enrollment. Participants with baseline A1c ≥ 8.0 (n=430, 229 F, 68.9 y) demonstrated a decrease of -0.90 points (SD 1.71, p<0.001). Thirty-five percent resided in LILA areas at the 0.5, and twenty percent at 1 mile distance. Participants who resided in LILA areas had higher baseline A1c (0.5 difference: 0.37 (p=0.02), 1 difference: 0.51 (p=0.005)). Those with baseline A1c ≥ 9.0 (n=216, 120 F, 67.8 y) demonstrated a decrease of -1.38 points (SD 1.96, p<0.001). Thirty-nine percent resided in LILA areas at the 0.5, and twenty-three percent at 1 mile distance. Baseline A1c differences were not observed. Differences in improvements in A1c based on LILA were not observed (p’s > 0.05). Irrespective of LILA residence, the Vida Health program demonstrated significant improvements in glycemic control within 1 year in a high-risk Medicare Advantage population.

Disclosure

C. Edwards: Employee; Vida Health. L. Voelker: Employee; Vida Health. G. Zimmermann: Employee; Vida Health. K. Rawlings: Employee; Vida Health. A. Venkatesan: Employee; Vida Health.

Funding

Vida Health
31-OR: Sex-Specific Differences in Subcutaneous Adipose Tissue in Persons with HIV May Contribute to Diabetes Risk
Authors: BAILIN SAMUEL , MASHAYEKHI MONA , GABRIEL CURTIS L. , HANNAH LATOYA , KALAMS SPYROS , MALLAL SIMON A. , KROPSKI JONATHAN A. , WANJALLA CELESTINE N. , KOETHE JOHN
Published: June 2023

Background: Men with HIV have greater visceral adipose tissue (VAT) accumulation compared to women, which contributes to insulin resistance and derives, in part, from a failure to sequester lipids in subcutaneous adipose tissue (SAT). We assessed whether sex-specific differences in SAT composition are associated with measures of VAT volume and insulin resistance.

Methods: Adults with HIV and consistent viral suppression on antiretroviral therapy had SAT and VAT measured by CT imaging, HOMA2-IR using fasting plasma glucose and insulin, and a subset had abdominal SAT lipoaspirates for single-cell RNA-sequencing to define proportions of CD4 and CD8 T effector memory cells (TEM), perivascular (PVM) and intermediate (IM) macrophages, and fibroblasts. Adjusted ordinal regression models and partial Spearman’s assessed the interaction between sex and cell proportions.

Results: We enrolled 111 participants (24% female) with a median age of 48 years, BMI of 31.5 kg/m2, and HOMA2-IR of 3.0. VAT volume was significantly associated with HOMA2-IR. Women had lower VAT volumes and higher proportions of SAT PVMs and lower IMs, as well as fewer cytotoxic CD4 and CD8 T cells compared with men (p ≤ 0.05 for all). The proportions of SAT CD4 TEM, CD8 TEM, myofibroblasts, MYOC fibroblasts, and IMs were associated with VAT volume (p ≤ 0.05 for all), but an interaction by sex was not observed. The proportions of CD4 and CD8 TEM cells were significantly associated with HOMA2-IR and there was evidence of an interaction by sex status (interaction term p = 0.09 & p = 0.06, respectively).

Conclusions: Women with HIV have a greater adjusted proportion of PVMs and lower cytotoxic CD4 and CD8 T cells in SAT. While the relationship between immune cell proportions and HOMA-IR only appeared to differ for CD4 and CD8 TEM cells, lower ectopic fat deposition in the context of reduced SAT inflammatory cells in women suggests the sex difference in diabetes risk among persons with HIV may relate to adipose tissue cellular composition.

Disclosure

S.Bailin: None. M.Mashayekhi: None. C.L.Gabriel: None. L.Hannah: None. S.Kalams: None. S.A.Mallal: None. J.A.Kropski: Advisory Panel; APIE Therapeutics, Research Support; Boehringer Ingelheim Inc., Bristol-Myers Squibb Company, Genentech, Inc. C.N.Wanjalla: None. J.Koethe: Advisory Panel; Merck Sharp & Dohme Corp., Janssen Pharmaceuticals, Inc., Gilead Sciences, Inc., Theratechnologies, Research Support; Merck Sharp & Dohme Corp.

Funding

National Institutes of Health (R01DK112262, UL1RR024975, T32AI007474, P30AI110527)
312-OR: Effect of Nutritional Ketosis Trajectory on Change in Glycemia, Weight, and Atherogenic Dyslipidemia over Two Years in People with Type 2 Diabetes
Authors: MCKENZIE AMY L. , ATHINARAYANAN SHAMINIE J. , ROBERTS CAROLINE G.P. , ADAMS REBECCA N. , VOLK BRITTANIE M. , PHINNEY STEPHEN D. , VOLEK JEFF
Published: June 2023

A very low carbohydrate diet with nutritional ketosis (NK) improves HbA1c, weight, and atherogenic dyslipidemia in people with type 2 diabetes (T2D), but effects of degree and duration of NK sustained on outcomes are unknown. Hemoglobin A1c, weight, triglycerides, and HDL-C among people with T2D who received a NK intervention via continuous telemedicine care (CC; n=262) or usual care without carbohydrate restriction (UC; n=87) over two years were assessed. Latent class trajectory modeling identified four ketosis trajectory groups within the CC. Annual change in these markers were compared among the CC groups and UC as reference using a linear mixed effects model. A dose-response relationship between the concentration of blood ketones (proxy for degree of carbohydrate restriction) and duration of NK maintenance was observed (Table 1), where the group with sustained NK of ~1mM maintained the greatest improvements. Changes in weight and HbA1c were observed with low NK (0.3-0.4mM), though continued improvements in atherogenic dyslipidemia required greater degrees of sustained NK (~0.7 followed by 0.5mM). These results inform clinical practice, showing that improvement in HbA1c and weight can occur with modest NK, though greater and broader improvements occur with moderate NK of ~0.7-0.5mM, and optimal outcomes occur with consistently sustained NK of ~1mM.

Disclosure

A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.D.Phinney: Board Member; Virta Health Corp., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. J.Volek: Stock/Shareholder; Virta Health Corp.

Funding

Virta Health
326-OR: Rod Photoreceptor Contribution to Inflammation and Angiogenesis in Diabetic Retinopathy
Authors: DE LA HUERTA IRINA , POLOWAY JACOB M. , REDDY VARUN , PENN JOHN S.
Published: June 2023

Purpose: Rod photoreceptors (rods) are the most numerous and metabolically active retinal cells, and are susceptible to metabolic stress in response to hyperglycemia. Yet the role of rods in diabetic retinopathy (DR) is controversial. This study aims to investigate if rods exposed to high glucose can trigger inflammatory and angiogenic responses in Müller glia (MG) and retinal microvascular endothelial cells (RMEC).

Methods: The streptozocin-induced (STZ) model was used at 10 weeks of diabetes. Transcriptomic shifts in rods were analyzed by RNAseq. The mediators produced by rods were analyzed by multiplex ELISA. The effect of rod-produced mediators on RMEC permeability was assessed. Angiogenic responses of RMECs treated with rod-produced mediators were evaluated by proliferation, migration, and tube formation assays. The effect of rods on proangiogenic mediator production by RMECs and MG was evaluated by western blot.

Results: Diabetes induced upregulation of transcripts for tnf (3-fold, P=0.006) and il1a (2.2-fold, P=0.001) in rods. Primary rod cultures treated with 25 mM D-glucose (high glucose) produced increased levels of VEGF (2.5-fold, p<0.05), TNF-α (2.4-fold, p<0.05), and IL-6 (2-fold, p<0.05) compared to rods treated with 5 mM D-glucose (normal glucose), or with 25 mM L-glucose (osmotic control). The mediators produced by rods treated with high glucose elicited increased RMEC proliferation (2.5 fold, p<0.001), RMEC migration (2-fold, p<0.001), and RMEC tube lengths (1.9-fold, p<0.001). The rod-produced mediators induced RMEC secretion of matrix metalloproteinase 2 (MMP-2) (8-fold increase, p<0.001) and of MMP-9 (5-fold increase, p<0.001). MG treated with rod-produced mediators increased their production of VEGF (4-fold, p<0.001) and of MMP-9 (5-fold, p<0.001).

Conclusion: Rods in hyperglycemic conditions produce mediators that increase RMEC permeability, proliferation, migration, and branching and induce a proangiogenic secretory shift in RMEC and MG.

Disclosure

I.De la huerta: None. J.M.Poloway: None. V.Reddy: None. J.S.Penn: None.

Funding

National Institutes of Health (K08EY032620); International Retinal Research Foundation; Knights Templar Eye Foundation
331-OR: Fasting Metabolic Flexibility in Prediabetes
Authors: FOPPIANI ANDREA , DE AMICIS RAMONA , LEONE ALESSANDRO , BERTOLI SIMONA , BATTEZZATI ALBERTO
Published: June 2023

Metabolic flexibility cannot be easily clinically assessed, but the respiratory exchange ratio (RER) measured via indirect calorimetry can indicate substrate utilization. When indirect calorimetry is performed to measure resting metabolic rate, a normal RER should reflect a lipolytic metabolism (close to 0.7). We aimed to describe fasting glucose metabolism in relation to RER in patients seeking a nutritional intervention. In 10175 patients (7,222 (71%) females, median (quartiles) age of 46 (36, 55) years, and BMI of 28.3 (25.0, 32.3) kg/m2) a greater RER was associated with higher fasting values of glucose, insulin and higher insulin resistance (HOMA-IR), controlling for sex, age, and BMI (differences going from a RER of 0.7 to 1 RER for glucose 1.7 (95% CI 0.66, 2.8; p=0.002), for insulin 1.9 (95% CI 1.3, 2.6; p=<0.001), and for HOMA-IR 0.49 (95% CI 0.32, 0.66; p=<0.001)). As an higher RER relates to an altered glucose metabolism, within the whole sample we selected patients with prediabetes with 1 year follow-up. We matched 86 patients having either a RER indicating a lipolytic metabolism (<0.775) or glycolytic metabolism (>0.925). Patients were matched for sex, age, BMI, waist circumference, and arm muscle area. The high RER group had a lower probability of normalizing fasting glucose level within 1 year (log(OR) -0.89 (95% CI -1.8, -0.03; p=0.046)), with higher fasting glucose levels at followup (5.4 (95% CI 0.98, 9.9; p=0.017)). Moreover, while losing similar weight than the low RER group (-0.55 (95% CI -3.7, 2.6; p=0.7)), they lost a lower amount of fat mass (1.2 (95% CI 0.02, 2.4; p=0.047)). Our results suggest than an higher RER relates to a dysfunctional glycolytic metabolism at rest. We also show that prediabetic patients with higher RER are more likely to not respond to a lifestyle intervention, warranting a more intensive treatment for this subgroup. This lower probability of success doesn’t seem related to a lower adherence to the proscription, as weight loss was similar across RER categories, but to a lower weight loss quality.

Disclosure

A.Foppiani: None. R.De amicis: None. A.Leone: None. S.Bertoli: None. A.Battezzati: None.

Funding

Italian National Recovery and Resilience Plan Mission 4 Component 2 Investment 1.3 - Call for Proposals (341) of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU (PE00000003) Concession Decree (1550) of 11 October 2022 adopted by the Italian Ministry of University and Research (CUP D93C22000890001)
334-OR: Implementation of a Modified Diabetes Prevention Program in WIC Clinics—A Pilot Study
Authors: DORANS KIRSTEN S. , SCHULTHEIS MARY E. , BRIDGEFORTH CELIA , ALVARADO FLOR , DANDRIDGE ERIN , DOBSON TARA , HE JIANG , MARTIN COURTNEY , MILLS KATHERINE T. , SALLES MARTINA M. , SCHOONENBERG BROOKE , UWAIFO GABRIEL I. , BAZZANO ALESSANDRA N. , HARVILLE EMILY
Published: June 2023

Background: The aim of this study was to pilot implementation of a postpartum 8-week Diabetes Prevention Program (DPP)-like intervention in Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinics.

Methods: Participants had gestational diabetes mellitus in their most recent pregnancy, delivered 6 weeks-12 months prior to recruitment, and used WIC services in the New Orleans region. The following implementation strategies were tested: partnership with and buy-in from WIC, intervention tailoring, variety of health coaches, and combining in-person and online delivery with tracking tools.

Results: We enrolled 20 women; 18 completed the study. Health coaches delivering the intervention included a community dietitian, a WIC nutritionist, and a WIC health educator. Average participant age was 31.5 years, 55% of participants were Black and 30% were Hispanic/Latina. Session attendance was high and most participants liked the idea of joining a 1-year DPP program and thought it would be feasible (Table). Average 2-month changes in clinical outcomes were -1.5 kg (95% CI: -3.9, 0.8 kg) for weight, 0.02% (95% CI: -0.10, 0.14%) for hemoglobin A1c, and -4.9 mg/dL (95% CI: -11.3, 1.4 mg/dL) for fasting glucose.

Conclusion: Based on these findings, we are conducting a cluster randomized trial to test different implementation strategies for delivering a 1-year postpartum DPP intervention in WIC clinics.

Disclosure

K.S.Dorans: None. M.M.Salles: None. B.Schoonenberg: None. G.I.Uwaifo: None. A.N.Bazzano: None. E.Harville: None. M.E.Schultheis: None. C.Bridgeforth: None. F.Alvarado: None. E.Dandridge: None. T.Dobson: None. J.He: None. C.Martin: None. K.T.Mills: None.

Funding

National Heart, Lung, and Blood Institute (OT2HL158287); National Institute of General Medical Sciences (P20GM109036)
341-OR: Association between Age at Diagnosis of Type 2 Diabetes and Subsequent Risk of Dementia and Its Major Subtypes
Authors: KIM YOUNGJOON , HEA SEO DA , KIM MINA , CHO YONGIN , HEE AHN SEONG , HONG SEONGBIN , HUN KIM SO
Published: June 2023

Objectives: Type 2 diabetes mellitus (T2DM) is recognized as a major contributor to cognitive decline and dementia in older adults but its importance for its contribution according to age at diagnosis of T2DM remains uncertain. We aimed to investigate the association between dementia and its subtypes in relation to the age at diagnosis of T2DM.

Research design and methods: In a population cohort study with the Korean National Health Insurance Service data (2012-2014), a total of 612,201 patients with newly diagnosed T2DM were included. Controls were randomly selected from the general population and matched with a 1:2 ratio based on the propensity score. Participants were followed for until December, 2019. Outcomes of interest were all-cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD). The association of T2DM with dementia was stratified by baseline fasting glucose concentration in patients with T2DM. Cox regression was used to study the excess risk of outcomes.

Results: During 6.25 years follow-up, dementia developed in 66,186 patients with T2DM compared with 85,358 control subjects. Patients with T2DM diagnosed at ≤50 years had the highest excess risk for most outcomes relative to control with hazard ratio (HR) (95% CI) of 3.30 (3.11-3.50) for all-cause dementia, 4.08 (3.17-5.23) for AD, and 5.86 (3.87-8.88) for VD. All risks attenuated progressively with each increasing decade at diagnostic age but remained significant; for T2DM diagnosed at ≥80 years, the HR (95% CI) was 1.38 (1.34-1.41) for all-cause dementia, 1.36 (1.32-1.40) for AD, and 1.99 (1.71-2.31) for VD. When the analyses were stratified by fasting glucose concentration, a dose-response association was observed.

Conclusion: In this population-based cohort study, younger age at diagnosis of T2DM was associated with a higher risk of risk of both AD and VD. Physicians should closely monitor cognitive function in diabetic patients especially in those with young onset T2DM.

Disclosure

Y.Kim: None. D.Seo: None. M.Kim: None. Y.Cho: None. S.Ahn: None. S.Hong: None. S.Kim: None.
343-OR: Health Care Utilization in Older Adults with Diabetes and Dementia—Medical Expenditure Panel Survey (2000–2020)
Authors: DAWSON APRILL Z. , THORGERSON ABIGAIL , LINDE SEBASTIAN , WALKER REBEKAH J. , BHANDARI SANJAY , EGEDE LEONARD E.
Published: June 2023

Adults with diabetes have two times the risk of developing dementia compared to adults without diabetes. The aim of this analysis was to determine the rates of healthcare utilization in older adults with diabetes and dementia.

Data representing 102,176,914 adults aged 50 and older from the Medical Expenditure Panel Survey (2000-2020) were used. Inpatient, outpatient, emergency, dental, pharmacy, home-health, and total medical visits were dependent variables. The primary independent variable had 4 categories: no diabetes or dementia, diabetes only, dementia only, comorbid diabetes and dementia (DD). Covariates included age, race/ethnicity, sex, marital status, education, region, poverty, comorbidities, and survey year. Unadjusted and fully adjusted negative binomial regression models were run. Analyses were conducted using Stata v17.0, and statistical significance was p-value<0.05.

In fully adjusted models, those with diabetes only (IRR:1.48; 95%CI:1.45, 1.51), dementia only (IRR:1.58; 95%CI:1.48, 1.69), and DD (IRR:1.59; 95%CI:1.43, 1.78) had significantly greater rate of pharmacy visits compared to individuals without diabetes or dementia. In addition, those with dementia only and DD had significantly higher rate of inpatient [dementia: (IRR:2.02; 95%CI: 1.60, 2.54); DD (IRR:1.56; 95%CI:1.02, 2.38)], ED [dementia: (IRR:1.63; 95%CI:1.44, 1.84)], and home health visits [dementia: (IRR:14.90; 95%CI:7.74, 28.69); DD (IRR:7.38; 95%CI:3.55, 15.34)] compared to individuals without diabetes or dementia.

Adults aged 50 and older with comorbid diabetes and dementia have significantly higher rates of inpatient, pharmacy, and home health utilization compared to older adults with neither condition. In addition, having dementia is a key driver of healthcare utilization among adults aged 50 and older in the US.

Disclosure

A.Z.Dawson: None. A.Thorgerson: None. S.Linde: None. R.J.Walker: None. S.Bhandari: None. L.E.Egede: None.

Funding

American Diabetes Association (11-22-JDFHD-01 to A.Z.D.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118038, R01DK120861); National Institute on Minority Health and Health Disparities (R01MD013826)
345-OR: Exercise and Liraglutide Synergistically Attenuate Vascular Inflammation and Enhance Metabolic Insulin Action in Diet-Induced Obesity
Authors: LIU JIA , AYLOR KEVIN W. , LIU ZHENQI
Published: June 2023

Endothelial oxidative stress and vascular inflammation induce microvascular insulin resistance which is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise and glucagon-like peptide 1 (GLP-1) receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development, we performed an euglycemic insulin clamp, in conjunction with contrast enhanced ultrasound, in adult male rats after 2 weeks of high-fat diet feeding with either access to running wheel (exercise), liraglutide (200 mg/kg subcutaneously twice daily), or the combination of both. Rats exhibited increased visceral adiposity and blunted microvascular responses (microvascular blood volume, flow velocity, and total flow) and metabolic insulin actions (glucose infusion rates). Exercise and liraglutide alone each improved muscle insulin sensitivity but their combination fully restored insulin-mediated glucose infusion rates. The combined exercise and liraglutide intervention enhanced insulin-mediated muscle microvascular perfusion, reduced perivascular macrophage accumulation and oxidative stress in the muscle, attenuated blood vessel inflammation and improved endothelial function, along with increased nucleus translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and phosphorylation of AMP-activated protein kinase (AMPK) and nitric oxide synthase (eNOS) in endothelial cells. We conclude that exercise and liraglutide synergistically enhance the metabolic actions of insulin and reduce vascular oxidative stress and inflammation in the early stage of obesity development. Our data suggest that early combination use of exercise and GLP-1 receptor agonism might be an effective strategy in preventing microvascular and metabolic insulin resistance and associated complications during the development of obesity.

Disclosure

J.Liu: None. K.W.Aylor: None. Z.Liu: None.

Funding

National Institutes of Health (R01DK125330), (R01DK1124344 to Z.L.)
35-OR: Incretin Production Is Impaired in Atypical Low BMI Diabetes Mellitus
Authors: JEBASINGH FELIX , ANOOP SHAJITH , KURIAN MATHEWS E. , SANDEEP VENKATA N. , CHRISTINA FLORY , JENNIFER SHIRLY , JOSE ARUN , CHRISTUDOSS PAMELA , REBEKAH GRACE , JIANG NANCY , HAWKINS MEREDITH , THOMAS NIHAL
Published: June 2023

Introduction: Atypical Low BMI Diabetes Mellitus (ALBDM) constitutes an unclassified form of diabetes that is likely to be prevalent in low- and middle-income countries. Recently, we reported in Diabetes Care that such individuals demonstrate striking defects in insulin secretion, despite absence of visible pancreatic pathology (PMID: 35522035). This study aims to determine whether defects in the incretin axis might contribute to impaired insulin secretion in ALBDM.

Methodology: We assessed the glucagon and incretin (GLP-1, GIP, and Oxyntomodulin) responses to an oral glucose tolerance test (OGTT) in patients with ALBDM. Ten male subjects demonstrating features of ALBDM (n=10, age 33±8.3 years, BMI 18.5±1.1 kg/m2, HbA1c 7.5±0.7%) were compared with 7 healthy BMI-matched normoglycemic (HbA1c: 5.0±0.3%) controls. All subjects underwent an OGTT, with blood sampling for C-peptide and incretin levels at nine specific time points. Insulin secretion rate (ISR) was calculated by C-peptide deconvolution using ISEC software, and total secretion rate for incretins were calculated as area under the curve (AUC) using the Trapezoid method with linear interpolation.

Results: As we previously reported, ALBDM subjects displayed impaired insulin secretion (50% reduction in post-OGTT insulin AUC, p=0.007). There was a profound reduction of OGTT-stimulated rise in the incretins GLP-1 (80% reduction; p=0.055), GIP (79% reduction; p=0.02) and oxyntomodulin (75% reduction; p=0.007) in ALBDM subjects compared to controls. In ALBDM subjects, mild hyperglucagonemia was observed in the early postprandial phase at 15 min of the OGTT followed by slow postprandial suppression.

Conclusions: Significant reductions in levels of GLP-1, GIP and Oxyntomodulin and an accompanying early phase of hyperglucagonemia suggest potential defects in development and/or function of enteroendocrine cells, which may contribute to defective insulin secretion and hyperglycemia in patients with Atypical Low BMI Diabetes Mellitus.

Disclosure

F.Jebasingh: None. N.Jiang: None. M.Hawkins: None. N.Thomas: None. S.Anoop: None. M.E.Kurian: None. V.N.Sandeep: None. F.Christina: None. S.Jennifer: None. A.Jose: None. P.Christudoss: None. G.Rebekah: None.

Funding

Endocrine Society of India
356-OR: Accuracy Evaluation of an Implantable CGM with Chemistry Improvements in a 365-Day Feasibility Study
Authors: AL-KHAWI LUJAIN , SANCHEZ PATRICIA , HUFFSTETLER PHILIP , VELVADAPU VENKATA N. , MASCIOTTI JAMES M. , TWEDEN KATHERINE S. , KAUFMAN FRANCINE R.
Published: June 2023

Background: The prospective, multi-center PROMISE study demonstrated safety and accuracy of the 180-day Eversense E3 CGM System in adults with diabetes. Subsequently, the implantable E3 CGM sensor material and protective chemistries were advanced to improve the sensor signal maintenance. This analysis compares this Modified CGM System accuracy obtained from a feasibility study to that of the E3 CGM System using data from the PROMISE study.

Methods: A 365-day feasibility study was conducted to assess accuracy of CGM to SMBG measurements using the CONTOUR Next One meter for 32 Modified E3 sensors inserted in 32 subjects through 365 days. Results were compared to the CGM-SMBG pairs of E3 sensors from 30 subjects evaluated in the PROMISE study through 180 days.

Results: Modified E3 CGM System accuracy to SMBG through day 365 was equivalent to that of the E3 CGM System through day 180 as shown in the Table below.

Table: Accuracy to SMBG measurements of the Modified E3 sensors compared to that of E3 control sensors (Mean MARD increase of ~1.4% when SMBG is used as reference compared to YSI)

Conclusion: Modifications to the E3 sensor prolonged the longevity of the sensor from 180 days to 365 days while maintaining accuracy, suggesting that a fully implanted CGM System could provide accurate data over a one-year time period.

Disclosure

L.Al-khawi: Employee; Senseonics. P.Sanchez: Employee; Senseonics. P.Huffstetler: None. V.N.Velvadapu: None. J.M.Masciotti: None. K.S.Tweden: Employee; Senseonics. F.R.Kaufman: Consultant; MannKind Corporation, Twin Health, Stock/Shareholder; Senseonics.