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Background: Iatrogenic hypoglycemia is an unintended, though common, occurrence in individuals with diabetes. There is a clear association between hypoglycemia exposure and an increase in mortality in individuals with type 2 diabetes (T2DM). It is well-established that recurrent hypoglycemic episodes impair the counterregulatory hormone responses; however, it is yet to be determined if in T2DM there are more global effects of hypoglycemia on autonomic control of cardiovascular function (baroreflex sensitivity, BRS), as has been shown in healthy individuals. This is a clinically relevant knowledge gap as decreases in BRS are pro-arrhythmogenic and associated with decreases in mortality in individuals with diabetes.?Objective: We tested the hypothesis that in individuals with T2DM, hypoglycemia impairs baroreflex sensitivity (BRS), a robust measure of cardiovascular autonomic control.?Methods: Individuals with well-controlled T2DM and without known cardiovascular disease were exposed to two 90-minute episodes of experimental hypoglycemia (50 mg/dl) in the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). BRS was assessed using the modified Oxford method (sequential administration of nitroprusside and phenylephrine) before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 minutes of hypoglycemia, and the following day.?Results: The study included 16 individuals with a diagnosis of T2DM (6 men and 10 women) with the following characteristics (mean ± SD): age 45 ± 11 years, BMI 32 ± 6 kg/m2, hemoglobin A1c 6.4 ± 0.9%, and diabetes duration 8 ± 5 years. At baseline, individuals with T2DM had a BRS of 7.7 ± 3.6 ms/mmHg, which is reduced compared to a BRS of 21.3 ± 13.8 ms/mmHg in a historical healthy control group of 54 subjects (p&lt;0.001). A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on BRS (p=0.008). Pairwise comparisons revealed a significant decrease in BRS during the PM clamp as compared with BRS assessed at baseline (5.5 ± 5.0 vs 7.7 ± 3.6 ms/mmHg, p=0.045), during the AM clamp (5.5 ± 5.0 vs 10.5 ± 5.6 ms/mmHg, p=0.43), and the following day (5.5 ± 5.0 vs 8.6 ± 3.8 ms/mmHg, p=0.33). Of note, there was no significant difference between BRS at baseline and during the AM clamp (p=0.44). Additionally, insulin levels positively and strongly correlated with BRS at baseline (R2 0.52) and during the AM clamp (R2 0.67).?Discussion: Insulin may have a stimulatory effect on BRS during a hyperinsulinemic hypoglycemic clamp that counters the inhibitory effect of hypoglycemia during the first episode of hypoglycemia. However, with exposure to a second hypoglycemic clamp, BRS decreases. ?Conclusion: Individuals with T2DM have low BRS at baseline, which is further reduced after 2 episodes of hypoglycemia.??? 

ENDO 2021

Hypoglycemia Impairs Baroreflex Sensitivity: Implications for Autonomic Control of Cardiovascular Function in Diabetes

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

Background: Iatrogenic hypoglycemia is an unintended, though common, occurrence in individuals with diabetes. There is a clear association between hypoglycemia exposure and an increase in mortality in individuals with type 2 diabetes (T2DM). It is well-established that recurrent hypoglycemic episodes impair the counterregulatory hormone responses; however, it is yet to be determined if in T2DM there are more global effects of hypoglycemia on autonomic control of cardiovascular function (baroreflex sensitivity, BRS), as has been shown in healthy individuals. This is a clinically relevant knowledge gap as decreases in BRS are pro-arrhythmogenic and associated with decreases in mortality in individuals with diabetes.?Objective: We tested the hypothesis that in individuals with T2DM, hypoglycemia impairs baroreflex sensitivity (BRS), a robust measure of cardiovascular autonomic control.?Methods: Individuals with well-controlled T2DM and without known cardiovascular disease were exposed to two 90-minute episodes of experimental hypoglycemia (50 mg/dl) in the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). BRS was assessed using the modified Oxford method (sequential administration of nitroprusside and phenylephrine) before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 minutes of hypoglycemia, and the following day.?Results: The study included 16 individuals with a diagnosis of T2DM (6 men and 10 women) with the following characteristics (mean ± SD): age 45 ± 11 years, BMI 32 ± 6 kg/m2, hemoglobin A1c 6.4 ± 0.9%, and diabetes duration 8 ± 5 years. At baseline, individuals with T2DM had a BRS of 7.7 ± 3.6 ms/mmHg, which is reduced compared to a BRS of 21.3 ± 13.8 ms/mmHg in a historical healthy control group of 54 subjects (p<0.001). A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on BRS (p=0.008). Pairwise comparisons revealed a significant decrease in BRS during the PM clamp as compared with BRS assessed at baseline (5.5 ± 5.0 vs 7.7 ± 3.6 ms/mmHg, p=0.045), during the AM clamp (5.5 ± 5.0 vs 10.5 ± 5.6 ms/mmHg, p=0.43), and the following day (5.5 ± 5.0 vs 8.6 ± 3.8 ms/mmHg, p=0.33). Of note, there was no significant difference between BRS at baseline and during the AM clamp (p=0.44). Additionally, insulin levels positively and strongly correlated with BRS at baseline (R2 0.52) and during the AM clamp (R2 0.67).?Discussion: Insulin may have a stimulatory effect on BRS during a hyperinsulinemic hypoglycemic clamp that counters the inhibitory effect of hypoglycemia during the first episode of hypoglycemia. However, with exposure to a second hypoglycemic clamp, BRS decreases. ?Conclusion: Individuals with T2DM have low BRS at baseline, which is further reduced after 2 episodes of hypoglycemia.??? 

technical paper

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein that is being assessed for the treatment of diabetes mellitus. The presented study evaluated the safety and efficacy of BIF compared to insulin degludec over 32 weeks in patients with T2DM previously treated with oral antidiabetic drugs and a basal insulin. The study design included 2 different dosing algorithms for BIF (BIF-A1 and BIF-A2) with two different fasting glucose (FG) targets of ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Insulin degludec was titrated to a FG target of ≤100mg/dL using a modified Riddle treat-to-target algorithm. Study participants (N=399) were randomized in a 1:1:1 ratio to 1 of 3 parallel treatment groups. The average age of participants was 60.2 years, baseline HbA1c was 8.1% and duration of diabetes 14.7 years. There were no statistically significant differences in demographics or baseline characteristics across the 3 treatment groups. Both BIF groups achieved non-inferiority (non-inferiority margin = 0.4%) for the primary endpoint of HbA1c change from baseline to Week 32 with a mean±SE reduction for BIF-A1, BIF-A2 and insulin degludec of 0.6±0.1%, 0.6±0.1% and 0.7±0.1%, respectively. In line with the different fasting serum glucose (FSG) targets, insulin degludec achieved greater FSG lowering from baseline as compared to the BIF arms. Similarly, both BIF dosing groups showed significantly fewer hypoglycemic events compared to insulin degludec (all documented events as well as nocturnal events) when assessing events ≤70 mg/dL (3.9 mmol/L). Hypoglycemic events <54 mg/dL (3.0 mmol/L - all documented events as well as nocturnal events) were not significantly different between the three dosing groups. Two severe hypoglycemic events were reported in BIF-A2. The reported treatment-emergent adverse events and serious adverse events were balanced across the 3 treatment groups. Both BIF groups had a statistically significantly smaller increase in body weight compared to insulin degludec from baseline to Week 32. In summary, BIF, when administered weekly according to either dosing algorithm, was noninferior to insulin degludec for glycemic control as measured by change in HbA1c after 32 weeks with a lower rate of documented and nocturnal hypoglycemia ≤70 mg/dL and less weight gain. Additionally, no safety signals were detected. While higher FG targets were chosen in this first Phase 2 study with BIF, the safety and tolerability results allow assessment of lower target glucose ranges in future trials. The results from this study support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.?? 

Once Weekly Basal Insulin Fc (BIF) is Safe and Efficacious in Patients with Type 2 Diabetes Mellitus (T2DM) Previously Treated With Basal Insulin

Efficacy of High-intensity Interval Training for Improving Cardio-Metabolic Health in Women With Polycystic Ovary Syndrome

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Do GLP-1 receptor agonists increase the risk of breast cancer? A systematic review and meta-analysis

Background: 17α-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen introduced in the 1950s to treat habitual and threatened abortion in pregnant women. Although 17-OHPC is still available (tradename Makena), little is known about its effects on health of adult offspring, and questions concerning safety and effectiveness remain. For example, progestogens have been implicated in cancer, and trends in the use of 17-OHPC in early pregnancy during the 1950s and 60s parallel increasing incidence rates of certain cancers in young adults, such as early-onset colorectal cancer, born during that time. Methods: We examined the effect of 17-OHPC exposure in utero on risk of cancer in adult offspring in the Child Health and Development Studies, a cohort of women receiving prenatal care between June 1959 and September 1966, with deliveries through June 1967 (n=18,751 live births excluding neonatal deaths among 14,507 mothers). Diagnosed conditions and prescribed medications were abstracted from mothers’ medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received 17-OHPC (tradenames Delalutin and Proluton) in early pregnancy, defined as day 1 - 140 of gestation. Incident cancers diagnosed in offspring through 2018 were ascertained by linkage with the California Cancer Registry. Results: Among 18,751 live births, 954 cancers were diagnosed at ages 18 - 58 years. The most frequent cancers were breast (20.9%), cervical (10.9%), colorectal (7.1%), and prostate (5.9%) cancer and melanoma (9.2%). Although few mothers (n=181, 1.0%) received 17-OHPC in early pregnancy, in utero exposure was more common in offspring diagnosed with cancer (n=18, 1.9%) compared to those without cancer (n=163, 0.9%). Conditions indicating 17-OHPC included threatened abortion (54.0%), amnionitis (9.4%), and incompetent cervix (3.0%). 17-OHPC increased risk of any cancer in offspring (OR 2.08, 95% CI 1.27, 3.40), with particularly striking associations for colorectal (OR 4.78, 95% CI 1.49, 15.41) and prostate (OR 3.83, 95% CI 0.93, 15.83) cancer. There was no association between conditions indicating 17-OHPC and risk of any cancer in offspring (threatened abortion: n=1,891 mothers, OR 1.07, 95% CI 0.87, 1.32), or with use of other progestogens within 6 months prior to pregnancy (medroxyprogesterone acetate: n=50 mothers, OR 0.38, 95% CI 0.05, 2.76). Conclusions: Findings support susceptibility of multiple organ systems to endocrine disruption during early development and risk of cancer decades later - and may partly explain increasing rates of early-onset colorectal cancer. Even before mechanisms of carcinogenesis are elucidated, caution using 17-OHPC and other endocrine-active pharmaceuticals in early pregnancy is warranted, especially in the absence of a clear short-term benefit, and given the possible effect on risk of cancer in adult offspring.?? 

In Utero Exposure to 17α-Hydroxyprogesterone Caproate May Contribute to Increasing Incidence Rates of Early-Onset Cancer

Nitrate and perchlorate competitively inhibit iodide uptake in thyrocytes and disrupt thyroid function in rodents and humans. Our previous data indicated that the intrauterine exposure to perchlorate or nitrate induced thyroid dysfunction in the offspring rats during adult life. Therefore, this study aimed to investigate the effects of these endocrine disruptors during the embryonic period on the endoderm and thyroid development. Additionally, it was also investigated the role of epigenetic modifications in the programming of gene expression of the evaluated tissues. For this purpose, CD1 pregnant female mice received filtered water (control) or filtered water supplemented with sodium perchlorate (0.3 or 1 ppm) or sodium nitrate (20 or 50 ppm). At gestational day 16.5 (GD16.5), the embryonic thyroid lobes were collected and processed for molecular analysis. Besides the in vivo model, the effect of these thyroid disruptors was also evaluated during the differentiation of mouse embryonic stem cells (mESc) into endoderm and thyroid cells. Endoderm cells differentiation was achieved through the treatment of mESc with several growth factors. During the entire protocol the cells were exposed or not to sodium perchlorate or sodium nitrate (10-5 or 10-7 M). The effects of perchlorate and nitrate were also evaluated during the differentiation of mESC into thyroid cells. For this purpose, mESC-derived endoderm cells were transiently transfected with Pax8/Nkx2.1 expressing vectors. During the endoderm-to-thyrocytes differentiation protocol, the cells were also exposed or not to perchlorate or nitrate (10-5 or 10-7 M). The results demonstrated that both thyroid disruptors reduced the mRNA and protein expression of several endoderm markers (Foxa1, Gata4, Sox17) in the mESc-derived endoderm cells. Moreover, perchlorate or nitrate treatment also reduced the expression of thyroid transcription factors (Pax8, Nkx2.1, Foxe1) and thyroid differentiation markers (Slc5a5, Tpo, Tshr, Tg) both in the embryonic thyroid lobes and in the mESc-derived thyrocytes. Epigenetic mechanisms related to transcription repression seem to be involved in the gene expression downregulation both in vivo and in vitro, since perchlorate and nitrate increased the mRNA expression of Dnmt1, Dnmt3, Hdac and reduced the expression of Hat. Additionally, the methylation of histone H3 was increased, and the acetylation status of this histone was decreased in perchlorate- or nitrate-exposed thyroid lobes and mESc-derived endoderm/thyroid cells. In conclusion, our data strongly suggest that the programming of thyroid dysfunction induced by intrauterine exposure to perchlorate or nitrate involve the disruption of the endoderm and thyroid development during embryonic life through epigenetic mechanisms.?? 

Perchlorate and Nitrate Treatments Disrupt the Endoderm and Thyroid Development Through Epigenetic Mechanisms

The presence of progesterone receptor (PR)-interacting compounds in the environment may have serious health consequences for humans and wildlife, but the methods for their detection and monitoring are limited. Here we report the development and testing of a cell line expressing a chimeric construct containing ligand-binding domain of progesterone receptor and green fluorescent protein-tagged domain of the glucocorticoid receptor (GFP-GR-PR) under tetracycline regulation. Unlike the constitutively nuclear PR, this chimera is cytoplasmic in the absence of the ligand and translocates to the nucleus in response to the hormone or its analogues. The GFP-GR-PR chimera maintains specificity for binding to progesterone and does not cross-react with GR-activating hormones. A concentration- and time-dependent translocation in response to progesterone confirmed picomolar sensitivity for detecting PR ligands. Importantly, the assay can detect both agonist and antagonist activities and thus can be used for screening environmental samples for contamination with endocrine disruptors and for drug development. Using this approach, we screened water samples collected at 23 sites along 2 major rivers in Virginia: Mattaponi and Rappahannock Rivers. We detected a low, but reproducible PR-binding activity in 34.8 % of the sites tested. The calculated progesterone equivalent concentration (EQ) in some of these sites reached ~ 0.8 ng/L. The assay provides an effect-based approach for screening PR-interacting endocrine disrupting chemicals regardless of whether they exert agonist or antagonist activities. Either one could be seriously disruptive for the health of humans and wildlife.?? 

Novel Assay for Detection of Progesterone Receptor-Interacting Endocrine Disruptors

Endocrine disruptors (EDs) interfere with hormonal signalling and, given that multiple developmental processes are hormone-driven, the prenatal period is a window of increased sensitivity. Maternal smoking is a real-life model of in utero exposure to a complex mixture of EDs. Cigarette smoke contains of >7,000 pollutants, including polycyclic aromatic hydrocarbons (PAHs), which are AhR ligands and cross-talk with the estrogen receptor (ER) system. Prenatal exposure to cigarette smoke is associated with adverse outcomes, including intrauterine growth restriction and increased risk of metabolic syndrome later in life. We aimed to evaluate ED effects associated with smoke exposure in human fetuses.Fetal tissues (plasma, n=48; placenta, n=30; liver, n=29) from elective terminations of normally progressing pregnancies, ranging from 10 to 20 gestation weeks, were collected (SAFeR and FEGO studies: REC 15/NS/0123, REC 04/S0802/21). PAHs and PAH-like compounds were extracted from placenta and fetal liver. Bioactivity levels in plasma, placenta and liver extracts were determined using ER and androgen receptor (AR) transactivation reporter gene assays. PAH burden was evaluated using the AhR-responsive DRhp-CALUX assay. Smoke exposure was associated with a 1.3-fold increase in plasma estrogenic activity. The developmental trajectory of androgenic activity was altered in plasma of smoke-exposed fetuses, with significant anti-androgenic activity in older fetuses (>16 weeks of gestation). In males, plasma androgenic activity was positively associated with testes weight and anogenital distance. In contrast, placentas from smoking mothers had significantly increased androgenic potential. Furthermore, AhR-like activity was 2.9-fold higher in smoke-exposed placentas compared to controls, and 2.3-fold higher in female compared to male fetal livers. Overall, all bioactivity levels were higher in placentas compared to fetal liver.Prenatal exposure to cigarette smoke is associated with higher placental AhR activation, indicative of increased xenotoxicants burden. We also report that smoke-exposed fetuses showed increased circulating estrogenic activity and disrupted androgenic potential, across 10-20 weeks of gestation, in both fetal plasma and placenta. This demonstrates that EDs present in cigarette smoke are able to interfere with hormonal signalling and alter dynamic endocrine activity profiles, which are critical to ensure appropriate, sex-specific, development. These ED effects are likely to disturb placental function and reprogramme fetal development and thus impacting on life-long health.?? 

Disruption of Estrogenic and Androgenic Bioactivities in Human Fetuses Exposed to Maternal Smoking

Background: A unique feature of muscle during aging, obesity and type 2 diabetes is the appearance of adipose tissue between skeletal muscle fibers, the intramuscular adipose tissue (IMAT). IMAT is generally associated with systemic insulin resistance, decreased muscle strength and, in older adults, impaired mobility. A large body of work over the last years have addressed the origin of IMAT. Skeletal muscle contains preadipocyte progenitors termed fibro/adipogenic progenitors (FAPs) that normally do not form adipocytes, but proliferate during muscle injury to support the commitment of myogenic progenitor cells during muscle repair. However, under the conditions outlined above, FAPs differentiate to adipocytes and give rise to IMAT. The molecular cues that trigger this pathogenesis are unknown and strategies that can modulate the fate of FAPs and their propensity to differentiate to adipocytes in disease states are urgently needed. Methods: We have used molecular cloning and genome editing techniques together with a variety of biochemical, molecular, genomic, transcriptomic and proteomic analyses in pre-adipocyte and muscle cell lines, primary cells isolated from human and mouse skeletal muscle, human skeletal muscle biopsies, and animal models. Results: Using multiple screening assays upstream and downstream of a master regulator of myogenesis, microRNA (miR)-29a, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. We identified FGF-2 as an upstream regulator that increases miR-29a promoter activity and gene expression via MEK1/2/MAPK signaling and consequently decreases the conserved miR-29a target SPARC. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. CRISPR/Cas9-mediated genomic deletions of miR-29a recognition elements located in the Sparc 3´UTR of muscle cells and AAV-mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of FAPs in vitro and IMAT formation in vivo. Skeletal muscle from human donors aged > 75 years versus < 55 years showed activation of FGF-2-dependent signaling and increased IMAT. Conclusion: FGF-2 not only stimulates muscle growth, but also promotes intramuscular adipogenesis via targeting the fate of FAPs. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a novel pathway, which has the potential to provide innovative diagnostic and therapeutic approaches to combat fat accumulation in aged human skeletal muscle.?? 

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Hypoglycemia Impairs Baroreflex Sensitivity: Implications for Autonomic Control of Cardiovascular Function in Diabetes

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Once Weekly Basal Insulin Fc (BIF) is Safe and Efficacious in Patients with Type 2 Diabetes Mellitus (T2DM) Previously Treated With Basal Insulin

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