United States

Context: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of &lt;200 ng/dL is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study investigating whether baseline T levels also influences body composition and metabolic response to T therapy.Objective: To determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with baseline T level of &lt; 264 ng/dL compared to those with levels ≥264ng/dLMethods: Secondary analysis of single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011-2016 involving 105 men (40-74 years old), with average morning T &lt; 300 ng/dL, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of &lt; 264 ng/dL (N=43) and those with ≥264 ng/dL (N=57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, sclerostin), adiponectin, and leptin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD, and body composition by dual-energy x-ray absorptiometry (DXA).Results: Men with T &lt; 264 ng/dL showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dL (4.2±4.1 vs 2.7±3.8%; p=0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7±11.5 vs 4.4±4.3%, 7.3±11.6 vs 2.4±6.8 %; p=0.033 and p=0.043, respectively). Men with T ≥ 264 ng/dL showed significant decreases in HbA1c at 12 months (-3.1±9.2 vs 3.2±13.9%; p=0.005), fasting glucose at 18 months (-4.2±31.9 vs 13.0±57.3%; p=0.040), LDL at 6 months (-6.4±27.5 vs 12.8±44.1%; p=0.034), leptin at 18 months (-40.2±35.1 vs -27.6±31.0%; p=0.034) compared to those with T &lt; 264 ng/dL. No significant differences in BMD and bone turnover markers were observed.Conclusion: T therapy results in improvement in body composition irrespective of baseline T levels but T &lt;264 ng/dL is associated with greater improvement in FFM, whereas T level of ≥264 ng/dL favors improvement in metabolic profile

ENDO 2022

Testosterone Therapy Results in Greater Improvement in Body Composition and Metabolic Profile in Hypogonadal Men with Testosterone Levels of &lt; 200 ng/dL Compared To Those with ≥200 ng/dL

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Context: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dL is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study investigating whether baseline T levels also influences body composition and metabolic response to T therapy.Objective: To determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with baseline T level of < 264 ng/dL compared to those with levels ≥264ng/dLMethods: Secondary analysis of single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011-2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dL, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of < 264 ng/dL (N=43) and those with ≥264 ng/dL (N=57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, sclerostin), adiponectin, and leptin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD, and body composition by dual-energy x-ray absorptiometry (DXA).Results: Men with T < 264 ng/dL showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dL (4.2±4.1 vs 2.7±3.8%; p=0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7±11.5 vs 4.4±4.3%, 7.3±11.6 vs 2.4±6.8 %; p=0.033 and p=0.043, respectively). Men with T ≥ 264 ng/dL showed significant decreases in HbA1c at 12 months (-3.1±9.2 vs 3.2±13.9%; p=0.005), fasting glucose at 18 months (-4.2±31.9 vs 13.0±57.3%; p=0.040), LDL at 6 months (-6.4±27.5 vs 12.8±44.1%; p=0.034), leptin at 18 months (-40.2±35.1 vs -27.6±31.0%; p=0.034) compared to those with T < 264 ng/dL. No significant differences in BMD and bone turnover markers were observed.Conclusion: T therapy results in improvement in body composition irrespective of baseline T levels but T <264 ng/dL is associated with greater improvement in FFM, whereas T level of ≥264 ng/dL favors improvement in metabolic profile

Testosterone Therapy Results in Greater Improvement in Body Composition and Metabolic Profile in Hypogonadal Men with Testosterone Levels of < 200 ng/dL Compared To Those with ≥200 ng/dL

technical paper

Prostate cancer is the second leading cause of male cancer death in the United States. While localized disease can be cured by radiation or surgery, metastatic prostate cancer presents a clinical challenge. Metastatic prostate cancer can initially be controlled by endocrine therapies that target the androgen receptor (AR), however, these tumors will inevitably develop resistance. This stage of the disease, termed castration-resistant prostate cancer (CRPC), is responsible for the majority of prostate cancer-specific deaths. Truncated AR variant (AR-V) proteins are broadly enriched in CRPC cell lines and clinical samples, and can function as ligand-independent, constitutively active transcription factors. We found that blocking an alternative poly(A) site located in AR intron 3 reduced expression of multiple AR-V mRNA and protein species and increased expression of full-length (FL) AR mRNA and protein in 22Rv1 and LNCaP95 CRPC cells. We found the cleavage and polyadenylation specificity factor (CPSF) component, CPSF1, regulates selection of this alternative poly(A) site based on the finding that knockdown of CPSF1 also reduced expression of AR-Vs and increased expression of FL-AR in 22Rv1 and LNCaP95 cells. Further, knockdown of CPSF1 inhibited growth of these CRPC cell lines, as well as androgen-dependent LNCaP cells. To define how CPSF1 regulates alternative polyadenylation of AR and to determine novel pathways that are manipulated by CPSF1 in prostate cancer, we identified CPSF1-dependent gene expression using RNA-seq and CPSF1-dependent poly(A) site usage using poly(A)-ClickSeq (PAC-Seq). Gene set enrichment analysis of RNA-seq data revealed the Glycolysis Hallmark gene was positively regulated by CPSF1, and nominated multiple differentially-expressed genes encoding regulators of glycolysis as CPSF1 targets. These results highlight AR independent pathways that are also regulated by CPSF1 in prostate cancer. We are currently integrating RNA-Seq and PAC-seq datasets to define novel CPSF1 regulated pathways that can be targeted therapeutically in prostate cancer. This research will determine trans-acting factors and cis-regulatory elements that drive alternative polyadenylation of AR mRNA transcripts to promote CRPC progression. This research will also identify AR independent targets of CPSF1 that could be exploited for development of new therapies for CRPC.

Alternative Polyadenylation as a Therapeutic Vulnerability in Prostate Cancer

Background: Phosphorylation of the mineralocorticoid receptor (MR) at serine 843 inhibits its activity. mTOR phosphorylation of ULK1 prevents this MR phosphorylation.
Purpose: To study the relationship between mTOR and MR and its role in the modulation of aldosterone signaling.
Methods: Mouse cortical collecting duct M1 cells stably expressing the rat wild type MR or mutated MR (mu/S843A) and a Gaussia luciferase gene reporter under a hormone response promoter tyrosine aminotransferase (TAT) were incubated with mTOR activator and inhibitors in the presence and absence of aldosterone or corticosterone. Co-immunoprecipitation was performed to study protein interactions with the MR, and a phospho-serine antibody was used to demonstrate MR and ULK1 phosphorylation. Effects of mTOR knockdown in M1 cells by lentiviral transduction with CRISPR/gRNA for Raptor and Rictor were also studied.
Results: mTOR and the adaptor proteins of mTOR complex 1 and 2, Raptor and Rictor, respectively, co-precipitated with the MR of M1-rMR cells. Expression levels of these proteins were not changed by aldosterone. mTOR inhibitors significantly reduced ligand-induced MR reporter gene transactivation, however the mTOR activator MHY1485 had no effect. CRISPR/gRNA gene knockdown of Raptor or Rictor also inhibited MR activation stimulated by ligands, supporting a role of mTOR in maintaining the active MR. The mTOR inhibitor AZD8055 attenuated ligand-mediated MR gene transcription assessed by the reporter gene product and measurement of products of the endogenous MR target genes ACSBG1, LCN2 and Psca. AZD8055 also decreased phospho-ULK1 levels in a dose-dependent manner. We thus assumed that mTOR decreases ULK1 activity and prevents ULK1 phosphorylation of the MR at Serine (S843). Indeed, phosphorylation of the MR was increased in M1-rMR cells treated with AZD8055. However, AZD8055 still inhibited ligand-induced MR activity in cells carrying the mutated MR in which the Serine at 843 was replaced with an Alanine. These results suggest that mTOR has an additional role in MR activity unrelated to the specific phosphorylation at S843 by ULK1. This merits further investigation.

mTOR Interacts with the Mineralocorticoid Receptor to Regulate its Activation by Ligand

Ubiquitin specific protease 19 (USP19) is a deubiquitinating enzyme involved in metabolism.  Its expression is upregulated in skeletal muscle in many conditions of muscle wasting. Genetic inactivation of USP19 (USP19KO) in mice protects from muscle atrophy and diet induced obesity and insulin resistance. We previously reported that the protection against muscle atrophy in USP19KO is due at least in part to reduction in muscle glucocorticoid receptor (GR) levels and signaling.  Here, we report that USP19KO mice show > 50% decrease in GR protein level in multiple tissues with no observed changes in GR mRNA levels. Overexpression of the endoplasmic reticulum or cytosol-localized isoforms of USP19 in cells resulted in increased GR protein levels, while knockdown by siRNA or knockout by CRISPR-Cas9 resulted in decreased GR protein levels. Intriguingly, GR was not more ubiquitinated in the absence of USP19. Furthermore, expression of a catalytically inactive form of USP19 also increased GR protein levels and exposure of cells to a small molecule inhibitor of USP19 enzymatic activity had no effects on levels of GR.  Deletion analysis revealed that the N-terminal CS domains of USP19, which are structurally similar to the p23 co-chaperone of HSP90, were required for increasing levels of GR.  Since HSP90 is known to regulate GR folding and stability, this suggested that USP19 may function as a p23 like co-chaperone. Indeed, overexpression of USP19 not only increased GR levels, but translocation to the nucleus and transcriptional activity of a reporter gene. Using a novel BRET assay, we observed that USP19 interacts indirectly with GR through binding with HSP90. This interaction with HSP90 is critically dependent on the CS2 domain of USP19 and can be competed by expression of the p23 co-chaperone of HSP90. We have therefore identified a novel co-chaperone-like mechanism through which USP19 regulates GR protein stability independent of its catalytic activity. Targeting the interaction of USP19 with the GR-HSP90 complex could be a strategy to decrease GR levels, reduce glucocorticoid signalling and prevent muscle atrophy.

USP19 Deubiquitinating Enzyme Functions as a Novel Co-Chaperone of Hsp90 to Regulate Glucocorticoid Receptor Levels

Critically ill patients are thought to develop maladaptive glucocorticoid-resistance which convinces many clinicians to administer stress doses of glucocorticoids to overcome this state of glucocorticoid-resistance. However, supportive data arises mainly from whole blood cells. It is currently not known if the observed changes in regulators and markers of glucocorticoid signaling and activity are also present in other cell and tissue types with a role in critical illness. We quantified regulators and markers of glucocorticoid signaling and activity in several cell and tissue types in critically ill humans and animals and in healthy controls. We found that throughout critical illness, glucocorticoid activity appeared suppressed in neutrophils, but upregulated in monocytes and skeletal muscle. Also in vital tissues GRα-signaling was altered in a tissue-specific, largely time-independent manner. Increasing systemic glucocorticoid availability increased glucocorticoid activity in adipose tissue, diaphragm and lung, whereas in immune cells and other tissues regulatory pathways counteracted. These data argue against glucocorticoid-treatable generalized glucocorticoid resistance and rather point towards an adaptive response in each specific cell or tissue type to optimally guide the beneficial actions of glucocorticoids to the tissues that need it while protecting collateral undesirable effects in tissue that are harmed by elevated systemic glucocorticoid availability.

Glucocorticoid Receptor Expression and Signaling During Critical Illness, in Relation to the Duration of Illness and the Systemic Glucocorticoid Availability: A Prospective, Observational, Cross-Sectional Human and a Translational Mouse Study

The adrenal gland is the site of steroid hormone synthesis. These hormones regulate many physiological processes including metabolism, blood pressure and volume, and sexual characteristic development. While signaling pathways, steroidogenic enzymes, and transcription factors have all been well characterized, little is known about the contribution of RNA-binding proteins (RBPs) in regulating steroidogenesis. We recently demonstrated that regulated RNA decay controls the timing of the steroidogenic gene expression response and identified 9 RBPs that regulate aldosterone production in an immortalized human cell line model for steroidogenesis, H295R. One of the RBPs we identified was Musashi-2 (MSI2), which is required for development of other steroidogenic tissues such as ovary and testis in mice. We found that MSI2 mRNA is enriched in human adrenal glands relative to other tissues, positively correlates in expression with mRNAs encoding steroidogenic enzymes, and abundantly expressed in H295R cells. Staining of normal human adrenal gland sections demonstrated that MSI2 protein is expressed in all three layers of the human adrenal cortex. Taken together, we hypothesized that MSI2 promotes steroidogenesis through regulating expression of target mRNAs encoding. Using the selective MSI2 inhibitor Ro-08-2750 (Ro) we found that aldosterone and cortisol production is decreased in a dosage dependent manner in H295R cells, which is consistent with siRNA knockdown of MSI2. We performed RNA-immunoprecipitation and sequencing and identified 1428 mRNA targets of MSI2 in H295R cells. A target of interest was Stearoyl-CoA Desaturase (SCD), which functions to convert saturated fatty acids to unsaturated fatty acids that promote formation of lipid droplets. Cholesterol esters in lipid droplets are a source of cholesterol used to produce all steroid hormones. Ro treatment of H295R cells resulted in a suppression of SCD mRNA and protein induction. Furthermore, inhibition of SCD with A939572 caused a dosage dependent decrease in aldosterone production. These data suggest that potentiation of stimulation dependent SCD induction is one mechanism by which MSI2 promotes steroidogenesis. It will be important to determine if and how MSI2 promotes steroidogenesis in primary human adrenal cells and mouse models. Since it is possible to deliver oligonucleotides to the adrenal cortex, disruption of MSI2-SCD mRNA regulatory interactions may open new therapeutic avenues for modulate aldosterone production.

Musashi-2 Regulatory Interactions Promote Adrenal Steroidogenesis

Aberrant macrophage function is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcriptional and epigenomic programs driving macrophage polarization toward distinct phenotypic states are not well understood. Macrophage phenotypes exist on a spectrum, with pro-inflammatory (M1-like) and homeostatic, tissue repair (M2-like) states viewed as polar opposites and relatively stable. The main driver of the M2-like program is a type-2 cytokine, IL4 which signals to STAT6 followed by the Krüppel-like factor 4 (KLF4), a master regulator for numerous M2-specific genes. Reportedly, glucocorticoid (GC) hormones also promote the M2-like state, although the extent to which the phenotypes elicited by such disparate signals overlap is unknown. Interestingly, we discovered that GRIP1, a well-known cofactor for nuclear receptors including GR, serves as a KLF4 coactivator, suggesting that GRIP1 could mediate transcriptional and phenotypic convergence of the IL4- and GC-driven pathways. Gene expression profiling on differentially polarized macrophages revealed a highly significant overlap between M2IL4 and M2GC transcriptomes which was mirrored by the H3K27ac de novo enhancer landscape. Notably, loss of GRIP1 blunted both up-regulation of M2- and downregulation of M1-associated genes irrespective of the signal driving M2 polarization. At the cellular level, polarization with either IL4 or GCs enhanced macrophage phagocytosis relative to non-polarized M0, and did so in a GRIP1-dependent manner. Finally, in the dextran sulphate sodium (DSS)-induced colitis model of intestinal inflammation and tissue damage, GRIP1-cKO mice lacking GRIP1 in myeloid cells, including macrophages, displayed more severe destruction of the colonic mucosa and greater immune cell infiltration into the mucosa and submucosa. Moreover, in total colon RNA, the abundance of many characteristic M2 transcripts was reduced in the cKO mice. Surprisingly, the expression of proinflammatory mediators such as TNF, IL1b and IL23 was unaffected by GRIP1 deletion, suggesting that the more severe disease in the cKO stems primarily from the failure of M2-like resolving macrophage to efficiently mitigate tissue destruction and repair the damage. Together, these findings point to GRIP1 as a crucial regulator of macrophage polarization to the homeostatic state in vitro and in vivo.

The Role Of Nuclear Receptor Coregulator Grip1 In Homeostatic Programming Of Macrophages

OBJECTIVE: Despite recent advances in diabetes technology, the distribution of healthcare resources is often unequal among racial and socio-economic groups. A recent multicenter study looking at technology use amongst young adults with T1D demonstrated that socioeconomic status (SES) was not the sole driver of racial/ethnic disparities and that adjustment for income, insurance level, and health literacy did not significantly attenuate disparities. Here we present a retrospective cohort study looking at racial/ethnic disparities in insulin pump and CGM use in adults with T1D at an urban university hospital system.
METHODS: We reviewed the charts of all adults aged 18 to 89 with T1D who attended the University of Maryland Center for Diabetes and Endocrinology (UMCDE) between 1/2019 and 12/2019. Age, gender, race/ethnicity, type of insurance, ZIP code, BMI, A1c, method of insulin delivery, and type of glucose monitoring device were obtained from each chart. We utilized the 2019 US Census data to determine the median income for each ZIP code. Patient charts were re-accessed in 2021 to check for changes in diabetes technology use from 1/2020 until 12/2021. Logistic regression modeling was done in PRISM to control for age, gender, race, insurance type, ZIP code, last known provider, BMI, and A1c. Hosmer-Lemeshow test was done to evaluate goodness of fit. Stratified analysis was done for potential confounders such as insurance type and income. The Breslow-Day test and Likelihood Ratio test for nested models were used to evaluate their degree and significance.
RESULT: A total of 532 adults were included in the study; 277 identified as non-Hispanic (NH) White, 204 identified as NH Black, 7 identified as Hispanic, and 44 identified as other racial/ethnic groups. NH White adults had a significantly higher insulin pump use when compared to NH Black (adjusted ratio 54.0% vs. 18.4%, OR 2.43 after regression, 95%CI [1.41-4.22]). Similarly, NH White adults had significantly higher CGM use when compared to NH Black (66.5% vs. 35.2%, OR 2.00 after regression, 95%CI [1.24-3.22]). Disparities between NH White and NH Black patients did not resolve throughout 2020-2021. Insurance type was a potential effect modifier for CGM prescriptions between NH White and NH Blacks (Crude OR 4.04, Commercial Strata OR 2.68, Medicaid 1.79, Medicare 2.79, Other/Self-pay 25.7, p=0.039 on Breslow-Day test). There was large heterogeneity in the rate of Pump or CGM prescriptions between providers.
CONCLUSION: NH White adults with T1D were significantly more likely to have been prescribed diabetes-related technologies when compared to other racial/ethnic groups, and this difference did not resolve over 2 years of follow-up. Future directions include a comprehensive survey of our population regarding patient-derived and patient-perceived factors driving disparities beyond socioeconomic status.

Racial and Ethnic Disparities in Diabetes Technology Use amongst Persons with Type 1 Diabetes

Background: Insulin pump use provides many advantages for the management of type 1 diabetes (T1D), but studies have shown racial, ethnic, and socioeconomic inequities in the use of this technology. As the prevalence of insulin pump use has increased over the past two decades, we aimed to determine whether these inequities have increased or diminished over time.
Methods: We used data from the population-based SEARCH for Diabetes in Youth study to perform a serial cross-sectional analysis to evaluate changes over time in insulin pump use in participants <20 years old with T1D by racial and ethnic group, health insurance, household income, and formal parental education across 4 phases of the study (Phase 1: 2001-2005, Phase 2: 2006-2010, Phase 3: 2011-2015 and Phase 4: 2016-2019). Data from the last study visit were analyzed for those with multiple visits within a phase. Multivariable generalized estimating equations with a binomial distribution were used to assess probability of insulin pump use, and models were further adjusted for the other predictors--age at visit, diabetes duration, sex and clinic site--with clustering for individuals.  An interaction effect between each primary predictor (race and ethnicity, health insurance, household income, education) and the phase variable was used to assess temporal changes.
Results: The prevalence of insulin pump use increased from 30% in Phase 1 to 58.3% in Phase 4 . Compared to those of non-Hispanic (NH) white race, odds of pump use in Hispanic participants was 0.08 (95% CI 0.01-0.63) in Phase 2 and 0.65 (95% CI 0.48-0.87) in Phase 4 with significantly reduced disparities over time (p=0.05). The disparities for Black participants and those of other races did not change over time, but was significantly lower than for white participants in all periods ( 0.28 (95%CI 0.21-0.37) and 0.43 (95%CI 0.26-0.71), respectively). Across all time periods, T hose with some high school/high school degree and those with some college had lower odds of pump use compared to those with at least a bachelor's degree 0.38 (95%CI 0.30-0.48) and 0.69 (95%CI 0.57-0.82). T hose with public insurance had lower odds for pump use compared to those with private insurance 0.84 (0.68-1.03). T hose with an income of < $25K, $25K-$49K, and $50K-74K had lower odds of pump use of 0.43 (95%CI 0.34-0.54), 0.57 (95%CI 0.46-0.71) and 0.80 (95%CI 0.65-0.97) compared to those with household incomes ≥ $75,000.
Conclusion: Over the past two decades, there have been no improvements in the ethnic, racial, and socioeconomic inequities in insulin pump use among youth with T1D.  Studies that evaluate barriers or test interventions to improve technology access are needed to address the persistent inequities in diabetes care.

Assessing Longitudinal Disparities in Insulin Pump Use Among Youth with Type 1 Diabetes

BACKGROUND:  Diabetic kidney disease (DKD) develops in approximately 40% of adults with diabetes and is the leading cause of chronic kidney disease (CKD). Less is known about early DKD, particularly in ethnically diverse populations that include Black, Hispanic/Latinx, and Asian Americans. Current guidelines recommend that patients with diabetes be screened annually for DKD. Albuminuria is the first sign of CKD and is associated with CKD progression, cardiovascular events, and death. This study characterizes ethnic differences in the prevalence of albuminuria in a diverse population of adults with diabetes with normal range eGFR.
METHODS:  This retrospective study was conducted in a large healthcare system where patients with diabetes are annually monitored for DKD. We identified adults with diabetes aged 45-74 years, eGFR ≥60 mL/min/m2 based on serum creatinine (using the CKD-EPI equation without race), and assessment of urine albumin-creatinine ratio (ACR), urine protein-creatinine ratio (PCR) and/or urine protein dipstick in 2015. Albuminuria was based on urine ACR (95%), otherwise, from urine PCR (1%) converted to ACR, and, if unavailable, from urine protein dipstick (4%) converted to ACR. The cohort was restricted to patients with diabetes onset after health plan enrollment to calculate diabetes duration. Hypertension was identified by clinical diagnosis. Modified Poisson regression with robust variance was used to examine the association of ethnicity and albuminuria, reporting relative risk (RR) with 95% confidence intervals (CI).
RESULTS: Among 79,184 adults with diabetes, eGFR ≥60, and urine albumin/protein assessment (age 60.5 ±7.7y, 54.0% male), 40.3% were non-Hispanic White, 9.6% Black, 26.3% Asian/Pacific Islander (PI), and 21.0% Hispanic/Latinx race/ethnicity. 69.9% had hypertension. Overall, 81.7%, 13.8%, and 4.6% had urine ACR <30 (normal), 30 to <300 (microalbuminuria), and ≥300 mg/g (macroalbuminuria), respectively, with albuminuria higher in males than females. By race/ethnicity, the prevalence of [micro/macroalbuminuria] was [15.7/5.4%] Asian/PI, [13.8/4.8%] Black, [13.1/4.5%] Hispanic/Latinx, and [12.8/4.1%] non-Hispanic Whites. Among Asian/PIs, prevalence ranged from [19.5/8.4%] Hawaiian/PI and [18.2/7.1%] Filipino to [14.5/3.6%] Chinese and [11.2/3.4%] South Asian. In multivariable analyses, adjusting for age, sex, diabetes duration, and hypertension, Asian/PI (RR 1.3, CI 1.2-1.3) was associated with higher risk of albuminuria compared to non-Hispanic White, but Black (RR 1.0) and Hispanic/Latinx (RR 1.0) were not. Among Asian/PIs, with Chinese as reference, Filipino (RR 1.3, CI 1.2-1.4) and Hawaiian/PI (RR 1.4, CI 1.3-1.6) had higher risk, South Asian had lower risk (RR 0.7, CI 0.7-0.8), and Japanese and Southeast Asian had similar risk of albuminuria.
CONCLUSIONS: The risk of albuminuria in adults with diabetes and normal range eGFR was higher in Asian/PI adults. Among Asian/PIs, the risk was higher among Filipino and Hawaiian/PI and lower in South Asian compared to Chinese adults, supporting the importance of disaggregating Asians when examining microvascular outcomes. Future studies should examine ACEI/ARB use and albuminuria progression.

Ethnic Differences in Albuminuria among Adults with Diabetes and Normal Range Estimated Glomerular Filtration Rate (eGFR).

Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight that were significantly greater compared with semaglutide in patients with type 2 diabetes on background metformin. In a pre-specified subgroup analysis, we evaluated the efficacy and safety of tirzepatide in the Hispanic or Latino population of SURPASS-2.
In this open-label, 40-week, Phase 3 study (N=1878; mean baseline HbA1c 8.28%; BMI 34.2 kg/m²; Hispanic or Latino ethnicity 70%) participants were randomized 1: 1: 1: 1 to tirzepatide (5, 10, 15 mg; doses were double-blinded) or semaglutide (1 mg). Efficacy analyses included all randomised patients who received ≥1 treatment dose (modified intention-to-treat [mITT] population) while patients were on treatment without rescue therapy and excluding patients who discontinued study drug due to inadvertent enrollment (efficacy estimand). Safety analyses were performed in the mITT population, including all data from the start of treatment to the end of the safety follow-up. The least square mean (LSM) change from baseline was calculated within each subgroup using a mixed model for repeated measurements (MMRM) with country, baseline value, treatment group, visit, and treatment-by-visit interaction as the fixed effect, and patient as the random effect. MMRM for weight change also included baseline HbA1c group (≤8.5%, >8.5%) as a covariate.
In patients of Hispanic or Latino ethnicity, the LSM change from baseline in HbA1c at 40 weeks was -2.11%, -2.46%, and -2.47% with tirzepatide 5, 10, and 15 mg, respectively, and -1.93% with semaglutide (all p<0.001). The respective changes in patients not of Hispanic or Latino ethnicity were -2.03%, -2.14%, -2.43%, and -1.69% (all p<0.001). Reductions in HbA1c were significantly greater for all tirzepatide doses compared with semaglutide in patients of both Hispanic or Latino and non-Hispanic or Latino ethnicity (all p≤0.027). In Hispanic or Latino patients, body weight change was -6.9 kg with tirzepatide 5 mg, -9.7 kg with 10 mg, -10.5 kg with 15 mg, and -5.6 kg with semaglutide (all p<0.001). In non-Hispanic or Latino patients, the changes from baseline in body weight were -9.9 kg, -11.6 kg, -17.1 kg, and -7.5 kg, for the tirzepatide doses and semaglutide, respectively, (all p<0.001). In both subgroups, reductions in body weight were significantly greater than semaglutide with all tirzepatide doses (all p≤0.013).
The most common adverse events were gastrointestinal in the tirzepatide and semaglutide arms, including nausea (Hispanic or Latino 11-17% and 13%; non-Hispanic or Latino 32-36% and 29%), diarrhoea (10-13% and 10%; 15-24% and 17%) and vomiting (4-7% and 7%; 10-16% and 12%).
Consistent with the primary SURPASS-2 results, in a Hispanic or Latino population with type 2 diabetes, tirzepatide demonstrated greater reductions from baseline in HbA1c and body weight than the selective GLP-1 receptor agonist semaglutide, with a comparable safety profile.

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Testosterone Therapy Results in Greater Improvement in Body Composition and Metabolic Profile in Hypogonadal Men with Testosterone Levels of < 200 ng/dL Compared To Those with ≥200 ng/dL

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