Daily Endocrinology Research Analysis

UNLABELLED: Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrated the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D, nonobese diabetic (NOD) mouse model, by suppressing glucagon secretion. This fraction promoted white adipocyte differentiation and browning, maintained healthy BAT, and enhanced glucose uptake in adipose tissue, skeletal muscle, and liver. We identified nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 failed to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2 beyond its traditional classification as an extracellular matrix protein. ARTICLE HIGHLIGHTS: Large embryonic brown adipose tissue-secreted proteins (CB-100) suppress glucagon and normalize glycemia in mice with type 1 diabetes (T1D) without changing insulin. CB-100 prevented T1D-induced whitening, promoted browning of adipose tissue, and enhanced glucose uptake via an insulin receptor-dependent pathway. Within CB-100, nidogen-2 regulated glucagon secretion and restored euglycemia in T1D. Nidogen-2 and CB-100 unveil a therapeutic strategy for diabetes management beyond insulin-centric paradigms by modulating glucagon secretion and enhancing glucose metabolism.

OBJECTIVE: The International Diabetes Federation recently endorsed a 1-h oral glucose tolerance test (OGTT) as more convenient than the conventional 2-h OGTT. In practice, women with hyperglycemia in pregnancy are advised to undergo a 2-h OGTT within 6 months after delivery, but this test is often not completed, partly owing to its inconvenience for busy mothers. Recognizing the potential advantage of the 1-h OGTT in this setting, we sought to compare 1-h and 2-h OGTT glucose measurements at 3 months postpartum as predictors of dysglycemia (prediabetes/diabetes) over the first 5 years postpartum. RESEARCH DESIGN AND METHODS: A total of 369 women across a range of glucose tolerance in pregnancy (from normoglycemia to gestational diabetes [GDM]) underwent multisample 2-h 75-g OGTTs at 3 months, 1 year, 3 years, and 5 years postpartum. Glucose measurements from the 3-month OGTT were ranked as predictors of dysglycemia (both criteria) by change in concordance index (CCI) of Cox proportional hazard regression models. RESULTS: At the 3-month OGTT, 1-h glucose identified all but 10 of 70 women concurrently diagnosed with dysglycemia by 2-h glucose, while diagnosing an additional 96 women. The cumulative incidence of dysglycemia progressively increased over 5 years by tertile of 1-h glucose on the 3-month OGTT (P < 0.0001). On regression analyses, the strongest predictor of dysglycemia was 1-h glucose (change in CCI: 16.1%), followed by 2-h glucose (14.9%). In women with GDM, 1-h glucose again emerged as strongest predictor of dysglycemia (13.0%), followed by 2-h glucose (12.8%). CONCLUSIONS: The 1-h OGTT may offer a strategy for increasing rates of postpartum reclassification following hyperglycemia in pregnancy.

IMPORTANCE: Few of the available therapies for type 2 diabetes (T2D) comprehensively address disease burden beyond glycemic control. Examining whether berberine ursodeoxycholate (HTD1801), a first-in-class gut-liver anti-inflammatory metabolic modulator, has the potential to treat the core aspects of metabolic disease is important. OBJECTIVE: To assess the safety and efficacy of HTD1801 in patients with T2D that is inadequately controlled with diet and exercise. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 double-blind, placebo-controlled, 12-week randomized clinical trial, conducted in China between March 2022 and January 2023, included patients with T2D who underwent 8 or more weeks of diet and exercise, had a hemoglobin A1c (HbA1c) level of 7.0% to 10.5%, and had a fasting plasma glucose (FPG) level less than 250.5 mg/dL. INTERVENTIONS: Patients were randomized 1:1:1 to placebo (n = 38), HTD1801 500 mg twice daily (n = 37), and HTD1801 1000 mg twice daily (n = 38). MAIN OUTCOMES AND MEASURES: The primary end point was the HbA1c level change from baseline to week 12. Secondary end points included glycemic, hepatic, and cardiometabolic parameters. The primary end point was analyzed using a mixed-effects model for repeated measures, with the HbA1c level change from baseline as the dependent variable. Treatment group, measurement time point, and interaction between treatment group and measurement time point were independent variables. RESULTS: The study included 113 patients with T2D (mean [SD] age, 54.3 [10.6] years; 72 male [63.7%]) who were randomized. Among these patients, the mean (SD) HbA1c level was 8.2% (0.8%); body mass index, 25.5 (3.7), calculated as weight in kilograms divided by height in meters squared; and FPG level, 160.7 (38.3) mg/dL. Baseline disease severity was balanced across treatment groups. The primary end point was achieved with significant dose-dependent reductions in the HbA1c level in both HTD1801 groups compared with the placebo group. The least-squares mean difference in the HbA1c level at week 12 was -0.4% (95% CI, -0.79% to -0.03%; P = .04) for the 500-mg group and -0.7% (95% CI, -1.10% to -0.35%; P < .001) for the 1000-mg group compared with the placebo group. HbA1c level reductions were paralleled with mean (SD) improvements in the FPG level in both the 500-mg group (-13.0 [38.2] mg/dL) and the 1000-mg group (-18.4 [21.8] mg/dL) groups. Reductions were observed in lipids and markers of liver injury in the 1000-mg group. HTD1801 was safe and well tolerated, with 110 patients (97.3%) completing the study. Treatment-emergent adverse events, generally mild, occurred in 59 patients (52.2%) overall. One patient (in the 500-mg group) experienced a serious adverse event of retinal hemorrhage, which was unlikely related to treatment. No patients discontinued due to an adverse event. CONCLUSIONS AND RELEVANCE: In this placebo-controlled randomized clinical trial, treatment with HTD1801 resulted in significant reductions in the HbA1c level and improvements in key cardiometabolic and liver parameters. HTD1801 was safe and well tolerated. These findings are being confirmed in ongoing phase 3 studies. The effects demonstrated by HTD1801 support an oral treatment option for T2D and its comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06411275.