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ObjectiveTo quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)-related hospitalization and illness severity in type 1 diabetes.Research design and methodsWe conducted a prospective cohort study to identify case subjects with COVID-19 across a regional health care network of 137 service locations. Using an electronic health record query, chart review, and patient contact, we identified clinical factors influencing illness severity.ResultsWe identified COVID-19 in 6,138, 40, and 273 patients without diabetes and with type 1 and type 2 diabetes, respectively. Compared with not having diabetes, people with type 1 diabetes had adjusted odds ratios of 3.90 (95% CI 1.75-8.69) for hospitalization and 3.35 (95% CI 1.53-7.33) for greater illness severity, which was similar to risk in type 2 diabetes. Among patients with type 1 diabetes, glycosylated hemoglobin (HbA1c), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity.ConclusionsDiabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA1c) had significant but modest impact compared with comparatively static factors (e.g., race and insurance) in type 1 diabetes, indicating an urgent and continued need to mitigate severe acute respiratory syndrome coronavirus 2 infection risk in this community.

Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET)-producing enzyme, promotes insulin sensitivity, and Cyp2c44 −/− mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SCD)-fed male Cyp2c44 −/− mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared with wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol (DAG) levels. Cyp2c44 −/− mice had impaired glucose tolerance and increased hepatic plasma membrane–associated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SCD and high-fat diet (HFD)-fed Cyp2c44 −/− mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SCD-fed Cyp2c44 −/− mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44 −/− hepatocytes. Finally, Cyp2c44 −/− HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, DAG accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling. Article Highlights: Loss of epoxygenase Cyp2c44 leads to glucose intolerance, characterized by an increase in hepatic lipids and hyperlipidemia. Cyp2c44 participates in the regulation of hepatic fatty acid accumulation by limiting the plasma membrane localization of FATP2 and, in turn, intracellular levels of diacylglycerol. Cyp2c44-mediated downregulation of intracellular diacylglycerol levels results in decreased plasma membrane–associated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. Methods: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. Results: We identified a 35‐gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non‐immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. Conclusions: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non‐immune populations in SAT and is shared with VAT, nuancing the current VAT‐centric concept of IR in humans. [ABSTRACT FROM AUTHOR]

This article discusses the case of a 74-year-old female with a history of hypertension who presented to the emergency department with severe abdominal pain. The patient was found to have an acute intramural hematoma of the descending thoracic aorta and bilateral renal artery stenosis. The patient underwent percutaneous renal artery revascularization, which resulted in improved blood pressure control and renal function. The article highlights the importance of recognizing and treating renal artery stenosis in patients with hypertension to prevent complications and preserve renal function. [Extracted from the article]

Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss–independent, GLP-1R–dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. Article Highlights: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss–independent, GLP-1 receptor (GLP-1R)–dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R–dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1. [ABSTRACT FROM AUTHOR]

Key Points: Question: Among patients with uncontrolled hypertension, does the aldosterone synthase inhibitor lorundrostat safely lower blood pressure? Findings: In this randomized clinical trial that included 200 participants, lorundrostat decreased blood pressure significantly more than placebo with 50-mg and 100-mg once-daily doses, and adverse events, including hyperkalemia, were uncommon. Meaning: Aldosterone synthase inhibition with lorundrostat showed potential for blood pressure lowering in patients with hypertension that was inadequately controlled despite background antihypertensive treatment. Importance: Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure. Objective: To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials. Design, Setting, and Participants: Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h. Interventions: Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily. Main Outcomes and Measures: The primary end point was change in automated office systolic blood pressure from baseline to study week 8. Results: Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of −14.1, −13.2, −6.9, and −4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mm Hg (90% CI, −15.8 to −3.4 mm Hg; P =.01) for the 50-mg once-daily dose and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P =.04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Conclusions and Relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies. Trial Registration: ClinicalTrials.gov Identifier: NCT05001945 This randomized clinical trial assesses the effect of 5 dosages of lorundrostat treatment vs placebo on 8-week systolic blood pressure change among adults with uncontrolled hypertension. [ABSTRACT FROM AUTHOR]