Efficacy and safety of basal-first titration order in individuals with type 2 diabetes receiving short-term intensive insulin therapy: An exploratory analysis of BEYOND V.

AIMS: To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short-term intensive insulin therapy (SIIT) during study run-in (prior to randomization) using a basal-first insulin titration method. MATERIALS AND METHODS: This was exclusively an exploratory analysis of the 7- to 10-day run-in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once-daily insulin glargine and three-times-daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre-meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2-hour postprandial blood glucose (PBG) targets. RESULTS: Overall, 397 entered the run-in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2-hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2-hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2-hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia. CONCLUSIONS: Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia.

Efficacy and safety of a basal insulin + 2-3 oral antihyperglycaemic drugs regimen versus a twice-daily premixed insulin + metformin regimen after short-term intensive insulin therapy in individuals with type 2 diabetes: The multicentre, open-label, randomized controlled BEYOND-V trial.

AIM: To compare the efficacy and safety of basal insulin glargine 100 units/ml (Gla) + 2-3 oral antihyperglycaemic drugs (OADs) with twice-daily premixed insulin aspart 70/30 (Asp30) + metformin (MET) after short-term intensive insulin therapy in adults with type 2 diabetes in China. MATERIALS AND METHODS: This open-label trial enrolled insulin-naïve adults with type 2 diabetes and an HbA1c of 7.5%-11.0% (58-97 mmol/mol) despite treatment with 2-3 OADs. All participants stopped previous OADs except MET, then received short-term intensive insulin therapy during the run-in period, when those with a fasting plasma glucose of less than 7.0 mmol/L and 2-hour postprandial glucose of less than 10.0 mmol/L were randomized to Gla + MET + a dipeptidyl peptidase-4 inhibitor or twice-daily Asp30 + MET. If HbA1c was more than 7.0% (>53 mmol/mol) at week 12, participants in the Gla group were added repaglinide or acarbose, at the physician's discretion, and participants in the Asp30 group continued to titrate insulin dose. The change in HbA1c from baseline to week 24 was assessed in the per protocol (PP) population (primary endpoint). RESULTS: There were 384 enrollees (192 each to Gla and Asp30); 367 were included in the PP analysis. The threshold for non-inferiority of Gla + OADs versus Asp30 + MET was met, with a least squares mean change from baseline in HbA1c of -1.72% and -1.70% (-42.2 and -42.1 mmol/mol), respectively (estimated difference -0.01%; 95% CI -0.20%, 0.17% [-0.1 mmol/mol; 95% CI -2.2, 1.9]). Achievement of HbA1c less than 7.0% (<53 mmol/mol) was comparable between the groups (60% vs. 57%). The proportion of participants with any (24% vs. 38%; P = .003), symptomatic (19% vs. 31%; P = .007) or confirmed hypoglycaemia (18% vs. 33%; P < .001) was lower in the Gla + OADs group. CONCLUSIONS: Compared with Asp30 + MET, Gla + 2-3 OADs showed similar efficacy but a lower hypoglycaemia risk in Chinese individuals with type 2 diabetes who had undergone short-term intensive insulin therapy.

Short-term intensive insulin therapy at diagnosis in type 2 diabetes: plan for filling the gaps.

Short-term intensive insulin therapy is unique amongst therapies for type 2 diabetes because it offers the potential to preserve and improve beta-cell function without additional pharmacological treatment. On the basis of clinical experience and the promising results of a series of studies in newly diagnosed patients, mostly in Asian populations, an expert workshop was convened to assess the available evidence and the potential application of short-term intensive insulin therapy should it be advocated for inclusion in clinical practice. Participants included primary care physicians and endocrinologists. We endorse the concept of short-term intensive insulin therapy as an option for some patients with type 2 diabetes at the time of diagnosis and have identified the following six areas where additional knowledge could help clarify optimal use in clinical practice: (1) generalizability to primary care, (2) target population and biomarkers, (3) follow-up treatment, (4) education of patients and providers, (5) relevance of ethnicity, and (6) health economics.

Plasma extrachromosomal circular DNA is a pathophysiological hallmark of short-term intensive insulin therapy for type 2 diabetes.

BACKGROUND: Extrachromosomal circular DNA (eccDNA) has emerged as a promising biomarker for disease diagnosis and prognosis prediction. However, its role in type 2 diabetes remains unexplored. OBJECTIVE: To investigate the characteristics and dynamics of circulating eccDNAs in newly diagnosed type 2 diabetes mellitus (T2DM) patients undergoing short-term intensive insulin therapy (SIIT), a highly effective treatment for inducing long-term glycemic remission. METHODS: We conducted Circle-Seq analysis on plasma samples from 35 T2DM patients at three time points: pre-SIIT, post-SIIT, and 1-year post-SIIT. Our analysis encompassed the characterization of eccDNA features, including GC content, eccDNA length distribution, genomic distribution, and the genes in eccDNAs. RESULTS: Following SIIT, we observed an increase in plasma eccDNA load, suggesting metabolic alterations during therapy. Notably, a correlation was identified between eccDNA profiles and glycemia in T2DM, both quantitatively and genetically. Our analysis also revealed the frequent presence of metabolism-related genes within T2DM plasma eccDNAs, some of which spanned gene exons and/or fractions. CONCLUSION: This study represents the first report of cell-free eccDNA in T2DM and underscores a compelling association between cell-free eccDNA and profound glycemic changes. These findings highlight the potential of eccDNAs as crucial players in the context of T2DM and glycemic control.

Evaluating the role of time in range as a glycemic target during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Tight glycemic control during short-term intensive insulin therapy (SIIT) is critical for inducing diabetes remission in patients with newly diagnosed type 2 diabetes (T2D). This work aimed to investigate the role of time in range (TIR) during SIIT as a novel glycemic target by predicting clinical outcomes. METHODS: SIIT was given to 116 patients with newly diagnosed T2D, with daily eight-point capillary glucose monitored. Glycemic targets (fasting/premeal glucose, 3.9-6.0 mmol/L; 2 h postprandial blood glucose, 3.9-7.8 mmol/L) were achieved and maintained for 2 weeks. TIRPIR was calculated as the percentage of glucose points within these glycemic targets during the maintenance period and was compared to TIR3.9-7.8mmol/L and TIR3.9-10.0mmol/L . Acute insulin response (AIR), HOMA-IR, HOMA-B, and disposition index (DI) were measured. Patients were followed up for 1 year to observe clinical outcomes. RESULTS: TIRPIR , TIR3.9-7.8mmol/L , and TIR3.9-10.0mmol/L were 67.2 ± 11.2%, 80.8 ± 9.2%, and 90.1 ± 6.2%, respectively. After SIIT, ß-cell function and insulin sensitivity improved remarkably, and the 1-year remission rate was 55.2%. △AIR and △DI were positively correlated with all the TIR values, whereas only TIRPIR was correlated with △HOMA-IR (r = -0.22, p = 0.03). Higher TIRPIR but not TIR3.9-7.8mmol/L or TIR3.9-10.0mmol/L was robustly associated with diabetes remission; patients in the lower TIRPIR tertile had an elevated risk of hyperglycemia relapse (hazard ratio 3.4, 95% confidence interval 1.6-7.2， p = .001). Only those with TIRPIR ≥ 65% had a one-year remission rate of over 60%. CONCLUSIONS: These findings advocate TIRPIR ≥ 65% as a novel glycemic target during SIIT for clinical decision-making.

The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Diabetes mellitus was a chronic low-grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short-term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). METHODS: Thirty-three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. RESULTS: Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin-6 receptor (IL-6R), regulated upon activation normal T-cell expressed and secreted (RANTES), intercellular adhesion molecule-1 (ICAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and platelet-derived growth factor type BB (PDGF-BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL-6R, RANTES, and ICAM-1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM-1, IL-6R, RANTES, TIMP-1, TIMP-2, macrophage inflammatory protein-1 beta (MIP-1ß), PDGF-BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor-kappa B (NF-κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. CONCLUSIONS: A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL-6R, RANTES, and ICAM-1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL-6R, TIMP-2, PDGF-BB, and TNF RII decreased after the CSII therapy.

Predicting and understanding the response to short-term intensive insulin therapy in people with early type 2 diabetes.

OBJECTIVE: Short-term intensive insulin therapy (IIT) early in the course of type 2 diabetes acutely improves beta-cell function with long-lasting effects on glycemic control. However, conventional measures cannot determine which patients are better suited for IIT, and little is known about the molecular mechanisms determining response. Therefore, this study aimed to develop a model that could accurately predict the response to IIT and provide insight into molecular mechanisms driving such response in humans. METHODS: Twenty-four patients with early type 2 diabetes were assessed at baseline and four weeks after IIT, consisting of basal detemir and premeal insulin aspart. Twelve individuals had a beneficial beta-cell response to IIT (responders) and 12 did not (nonresponders). Beta-cell function was assessed by multiple methods, including Insulin Secretion-Sensitivity Index-2. MicroRNAs (miRNAs) were profiled in plasma samples before and after IIT. The response to IIT was modeled using a machine learning algorithm and potential miRNA-mediated regulatory mechanisms assessed by differential expression, correlation, and functional network analyses (FNA). RESULTS: Baseline levels of circulating miR-145-5p, miR-29c-3p, and HbA1c accurately (91.7%) predicted the response to IIT (OR = 121 [95% CI: 6.7, 2188.3]). Mechanistically, a previously described regulatory loop between miR-145-5p and miR-483-3p/5p, which controls TP53-mediated apoptosis, appears to also occur in our study population of humans with early type 2 diabetes. In addition, significant (fold change > 2, P < 0.05) longitudinal changes due to IIT in the circulating levels of miR-138-5p, miR-192-5p, miR-195-5p, miR-320b, and let-7a-5p further characterized the responder group and significantly correlated (|r| > 0.4, P < 0.05) with the changes in measures of beta-cell function and insulin sensitivity. FNA identified a network of coordinately/cooperatively regulated miRNA-targeted genes that potentially drives the IIT response through negative regulation of apoptotic processes that underlie beta cell dysfunction and concomitant positive regulation of proliferation. CONCLUSIONS: Responses to IIT in people with early type 2 diabetes are associated with characteristic miRNA signatures. This study represents a first step to identify potential responders to IIT (a current limitation in the field) and provides important insight into the pathophysiologic determinants of the reversibility of beta-cell dysfunction. ClinicalTrial.gov identifier: NCT01270789.

Lower mean blood glucose during short-term intensive insulin therapy is associated with long-term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence-based recommendations for standardization.

AIMS/INTRODUCTION: Optimal glycemic targets during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes. MATERIALS AND METHODS: A total of 95 individuals with newly diagnosed type 2 diabetes were enrolled. Short-term intensive insulin therapy was carried out using an insulin pump to achieve and maintain glycemic targets (fasting blood glucose ≤6.0 mmol/L, 2-h postprandial blood glucose ≤7.8 mmol/L) for 14 days, with daily eight-point capillary blood glucose profiles recorded. Patients were followed up for 1 year after discharge. RESULTS: In most participants, the mean blood glucose and glycemic excursion parameters during the therapy were controlled within the normal range. Mean blood glucose was independently associated with amelioration of acute insulin response (r = -0.25, P = 0.015) and 1-year remission (odds ratio 0.12, 95% confidence interval 0.034-0.426), but negatively associated with more level 1 hypoglycemia (r = -0.34, P = 0.001), although major hypoglycemia was rare. Among mean blood glucose tertiles, patients in the middle (68.7%) and lower (75.0%) tertiles had a higher 1-year remission rate compared with the upper tertile (32.3%, both P < 0.001), whereas only the middle tertile did not have increased hypoglycemia compared with the upper tertile (8.1 ± 5.4 vs 7.2 ± 3.9 events/person, P = 0.48). CONCLUSIONS: Stricter glycemic control during short-term intensive insulin therapy produced more remission despite self-manageable hypoglycemia. Based on glycemic parameters in the middle mean tertile, we propose new glycemic targets that are approximately 0.4 mmol/L lower than current the targets, as long-term benefit outweighs short-term risks.