Treatment Of Type 2 Diabetes Research Articles

226-OR: ADA Presidents’ Select Abstract: Exercise Training Promotes Mitochondrial Remodeling in Skeletal Muscle of Type 2 Diabetes Humans

Altered mitochondrial dynamics may contribute to impaired mitochondrial function and insulin sensitivity in type 2 diabetes (T2D). High intensity interval training (HIIT) can induce mitochondrial biogenesis in healthy humans, but its impact on mitochondrial remodeling in insulin resistant states is still unclear. To this end, this study examined the effect of HIIT on mitochondrial function and dynamics in T2D as well as in insulin resistant (IR) and sensitive (IS) glucose tolerant humans to elucidate the interplay between mitochondrial turnover and muscle insulin sensitivity. Twenty T2D, 11 IR and 12 IS humans age- and BMI-matched (HbA1c in %: 7.2 ± 0.2, 5.4 ± 0.1, 5.5 ± 0.1; M-value in mg*kg-1*min-1: 3.0 ± 0.4, 4.1 ± 0.3, 7.4 ± 0.4) performed a 12-week HIIT cycling protocol for 3 days/week. Before the intervention (baseline) and 72 h after the last exercise bout, whole-body insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, whereas mitochondrial respiration and dynamics were assessed by high resolution respirometry and immunoblotting of skeletal muscle biopsies. After HIIT, all participants showed improved cardiorespiratory fitness and increased muscle maximal oxygen uptake (p<0.001 vs. baseline), whereas insulin sensitivity increased only in T2D and IR (M-value; 4.3 ± 0.5 and 5.7 ± 0.6; p<0.01 vs. baseline). Moreover, HIIT doubled muscle citrate synthase activity in all groups, while biomarkers of mitochondrial fission (p<0.01), fusion (p<0.001) and mitophagy (p<0.001 for phospho-Parkin(Ser65) and p<0.05 for phospho-Pink(Thr257)) increased only in T2D. In conclusion, this study suggests that mitochondrial fusion and fission synergically respond to chronic exercise training and likely contribute to the exercise training response of insulin sensitivity at least in overt T2D. Targeting these mechanisms might help to better understand muscle insulin resistance and to identify novel therapeutic strategies for tailored prevention and treatment of T2D. Disclosure L. Mastrototaro: None. M. Apostolopoulou: None. D. Pesta: None. K. Strassburger: None. Y. Karusheva: None. S. Gancheva: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.

60-LB: Dendritic Cells Engineered with Tailored Multiepitopes-Encoding mRNA as Precision Medicine for Immunotherapy of Type 1 Diabetes

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by heterogeneity in genetic risk factors and immune profiles of patients and for which a cure or approved treatment is not yet available. Antigen-specific immunotherapy (ASIT) offers a targeted treatment of T1D that selectively inhibits autoreactive T cells. So far, ASIT trials showed limited efficacy, as only a subset of patients is responsive. Thus, approaches that consider the genetic and immunological heterogeneity of T1D patients to provide more tailored treatments are needed. Using mRNA encoding multiple epitopes tailored to the NOD mouse (model of T1D), we engineered bone marrow-derived dendritic cells (DCs) by mRNA electroporation (mRNA-DCs). The mRNA is designed to enable optimal presentation of epitopes to both CD4 and CD8 T cells. Antigen presentation persisted at least three days in vivo. Markers of anergy as well as IL-10 expression were found to be upregulated in antigen-specific CD4 and CD8 T cells after treating NOD mice with mRNA-DCs. T1D development was significantly suppressed with 3 biweekly treatments with 106 DCs containing 2 µg of antigen mRNA. Moreover, efficacy of the mRNA-DCs was enhanced when mRNAs encoding antigens and IL-27 were co-delivered into DCs by electroporation or when DCs were treated with rapamycin during differentiation. Endogenous expression of antigens may enable post-translational modifications and more prolonged presentation. Thus, we developed a promising and customizable ASIT platform to deliver multiple epitopes to exogenous tolerogenic DCs (or to endogenous APCs using a nanoparticle-based platform not covered here) that will consider the patient’s immune profile for a precision medicine treatment of T1D. Disclosure R. Fite: None. R. J. Creusot: None. Funding American Diabetes Association (1-19-PMF-022 to R.F.F.)

113-OR: Identification of Sorafenib for the Treatment of Type 1 Diabetes

Type 1 diabetes (T1D) is an immune-mediated disease characterized by impairment of pancreatic beta cells. To date, a comprehensive cure is not available. Th1 cell activation is considered a key mediator of the pathogenesis of T1D. IL-12-induced STAT4 activation is a paramount signaling pathway to instigate Th1 cell differentiation. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of T1D. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of T1D. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that sorafenib, an oral anti-cancer drug, is a top contender for inhibition of Th1 differentiation relative to induced toxicity. Sorafenib inhibited IL-12-induced Th1 cell differentiation in a dose-dependent manner without any change of CD4+ T-cell viability. Treatment of NOD mice with sorafenib significantly impeded the development of T1D and ameliorated insulitis, which coincided with a specifically decreased aggregate of Th1 cell population in pancreas but not in peripheral immune organs. Inflammatory cytokines and Th1 signature transcription factor Tbet mRNA expression in pancreas were decreased in sorafenib-treated NOD mice compared to vehicle-treated NOD mice. Mechanistically, sorafenib directly inhibited JAK2 activity and blocked IL-12-induced phosphorylations of JAK2 and STAT4. In conclusion, sorafenib administration inhibits the development of T1D by suppressing IL-12b/JAK2/STAT4 signaling-mediated Th1 cell differentiation specifically in pancreas in NOD mice. Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapeutic for T1D in humans. Disclosure Q. Zeng: None. J. Song: None. X. Sun: None. D. Wang: None. Y. Xiao: None. Z. Zhou: None. T. Deng: None.

ATTD 2021 Invited Speaker Abstracts.

ATTD 2021 Invited Speaker Abstracts.

Obesity in Patients with Type 1 Diabetes: Links, Risks and Management Challenges.

Obesity affects large numbers of patients with type 1 diabetes (T1D) across their lifetime, with rates ranging between 2.8% and 37.1%. Patients with T1D and obesity are characterized by the presence of insulin resistance, of high insulin requirements, have a greater cardiometabolic risk and an enhanced risk of developing chronic complications when compared to normal-weight persons with T1D. Dual treatment of obesity and T1D is challenging and no specific guidelines for improving outcomes of both glycemic control and weight management have been established for this population. Nevertheless, although evidence is scarce, a comprehensive approach based on a balanced hypocaloric diet, physical activity and cognitive behavioral therapy by a multidisciplinary team, expert in both obesity and diabetes, remains as the best clinical practice. However, weight loss responses with lifestyle changes alone are limited, so in the “roadmap” of the treatment of obesity in T1D, it will be helpful to include anti-obesity pharmacotherapy despite at present there is a lack of evidence since T1D patients have been excluded from anti-obesity drug clinical trials. In case of severe obesity, bariatric surgery has proven to be of benefit in obtaining a substantial and long-term weight loss and reduction in cardiovascular risk. The near future looks promising with the development of new and more effective anti-obesity treatments and strategies to improve insulin resistance and oxidative stress. Advances in precision medicine may help individualize and optimize the medical management and care of these patients. This review, by gathering current evidence, highlights the need of solid knowledge in all facets of the treatment of patients with obesity and T1D that can only be obtained through high quality well-designed studies.

977-P: Trends in First-Line Glucose-Lowering Drug Use in Adults with Type 2 Diabetes in Light of Emerging Evidence for SGLT2i and GLP-1RA

Recent utilization trends and predictors of first-line antidiabetic treatment in patients with type 2 diabetes (T2D) remain unexplored. Using Medicare and a large U.S. health insurance database of commercially-insured patients (Clinformatics), we identified adult patients with T2D who initiated first-line antidiabetic treatment during 2013-2019. Quarterly utilization trends were plotted overall and by cardiovascular disease (CVD). We estimated predictors of first-line antidiabetic treatment, using metformin, the recommended first-line treatment for T2D, as the common referent. Metformin was the most frequently initiated medication (80.6% in Medicare and 83.1% in Clinformatics) (Figure). Sulfonylureas were used by 8.7% in Medicare and by 4.7% in Clinformatics. Both populations had low use of SGLT-2 inhibitors (SGLT-2i, 0.8% [Medicare] and 1.7% [Clinformatics]) and GLP-1 receptor agonists (GLP-1RA, 1.0% [Medicare] and 3.5% [Clinformatics]), with increasing trends over time (P Among adult patients with T2D, metformin was the most frequent first-line treatment. The use of SGLT-2i and GLP-1RA remained low, though with a greater use among patients with CVD. Disclosure H. Shin: None. S. Schneeweiss: Other Relationship; Self; Aetion. R. Glynn: Research Support; Self; AstraZeneca, Kowa Research Institute, Inc., Novartis AG, Pfizer Inc. E. Patorno: Research Support; Self; Boehringer Ingelheim International GmbH, National Institutes of Health. Funding Brigham and Women’s Hospital; National Institute on Aging (K08AG055670 to E.P.)

Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes

Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.

684-P: Trends in Type 2 Diabetes Pharmacotherapy and Evolving Use of the Newer Agents

Background: Newer treatment options for type 2 diabetes (T2D) and emerging evidence of treatment-specific benefits for ASCVD, CKD, heart failure (HF), hypoglycemia, and obesity provide opportunities for individualizing treatment choices. We used claims data to examine how T2D treatment patterns have changed in recent years as clinical trial data and updated guidelines have emerged. Method: A retrospective observational study of T2D patients in a health insurance claims database (IBM® MarketScan® 2007 to 2019 Commercial and Medicare Databases). Medication use by class was examined from Jan 2015 through Dec 2019. Data since 2007 were used to establish disease history and categorize individuals according to the ADA/EASD Consensus Statement (2019): ASCVD, CKD, HF, hypoglycemia, and obesity defined risk groups. Alignment of risk group with treatment recommendation was evaluated by comparing use rates in the groups with and without risk. A GEE model was fit with guideline alignment as the dependent variable. The slope parameter and the area under the curve were calculated on the probability scale. Results: Use of guideline-recommended therapies in the risk groups increased in both cohorts from 2015 to 2019. The Commercial cohort showed better alignment vs. the Medicare cohort over all years. Guideline-recommended therapy use in 2019 was highest in the Commercial CKD and obesity groups (39.2%; 37.6 %) with 5 year growth rates of 74.5% and 54.9%; and lowest in Medicare HF and CKD groups (16.6%; 18.5% ), but showing rapid 5 year growth (145.5% and 132.2% respectively). Use of SU in the hypoglycemia risk group decreased over time, but at comparable rates to those without the risk. The HF risk group was less likely to receive guideline recommended therapies vs. no HF risk. Conclusion: The data suggest there is considerable room for improvement in individualizing therapies according to ADA risk grouping. Improving alignment through more targeted prescribing could further enhance outcomes without increasing overall use. Disclosure J. P. Bae: Employee; Self; Eli Lilly and Company. D. Liu: Employee; Self; Eli Lilly and Company. C. Chinthammit: Employee; Self; Eli Lilly and Company. Z. A. Kadziola: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. Boye: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company. K. J. Mather: Employee; Self; Eli Lilly and Company.

164-OR: Brown Adipose Tissue as a Novel Site for Islet Transplantation

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells. While islet transplantation is a promising alternative to insulin therapy for T1D treatment, finding ideal transplant sites that are readily accessible, exhibit glucose regulation, are immune-privileged, and promote vascularization for islet survival has remained a challenge. A novel site which exhibits these traits is the brown adipose tissue (BAT). BAT functions as a thermogenic adipose tissue that maintains body temperature and regulates metabolism. We hypothesize that murine islets transplanted into BAT will display normal islet graft and BAT function while providing immunological protection. Syngeneic transplant of 250 NOD.scid islets into the BAT of streptozotocin-treated diabetic NOD.scid mice restored euglycemia for over ten weeks, which was comparable to kidney capsule transplant controls. BAT histology and mRNA analysis assessed ten weeks after transplantation showed engrafted islets maintain expression of hallmark hormones, like insulin and glucagon, and critical transcription factors. Evaluation of BAT function after transplantation revealed no impairments in glucose and insulin tolerance, cold tolerance, or whole-body energy expenditure. Flow cytometry analysis displayed an enrichment of immunomodulatory T regulatory cells and anti-inflammatory M2 macrophages in BAT compared to kidney, possibly allowing greater immunoprotection for engrafted islets. Strikingly, adoptive transfer and allogeneic transplant studies revealed that islets transplanted into BAT showed significant delays in autoimmune and allograft rejection compared to islets transplanted under the kidney capsule. Overall, our data suggest BAT as a novel and efficacious site for islet transplantation to potentially combat T1D. Disclosure J. Kepple: None. J. Barra: None. C. S. Hunter: None. H. M. Tse: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK099550 to H.M.T.), (DK111483 to C.S.H.), (DK126456 to H.M.T., C.S.H.), (F31DK121414 to J.K.); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B to H.M.T.); National Institute of General Medical

914-P: The Impact of Racial and Ethnic Health Disparities in Diabetes Management on Clinical Outcomes: A Reinforcement Learning Analysis of Health Inequity

It is not known how racial/ethnic disparities in pediatric type 1 diabetes (T1D) treatment regimens contribute to the disparate clinical outcomes across racial/ethnic subgroups. Data were analyzed from the SEARCH for Diabetes in Youth study (diagnosed 2002-2005, 47.5% female, 77.5% non-Hispanic white (NHW), mean age at diagnosis=12.8±2.4 years). Youth were classified as nonwhite race/Hispanic ethnicity (nonwhite youth) or NHW race (white youth). Multivariate propensity scores estimated T1D treatment regimens (i.e., insulin delivery and glucose monitoring modality) in white versus nonwhite subgroups. Reinforcement learning, a machine learning technique, estimated the effect of each treatment regimen on HbA1c over time for nonwhite youth. Observed mean HbA1c over available visits for each individual was 9.0% and 8.2% for the nonwhite and white subgroups, respectively, difference=0.8%. Estimated mean HbA1c decreased by 0.33% (95%CI: -0.45%, -0.21%; p Disclosure A. Kahkoska: Other Relationship; Self; Novo Nordisk A/S. A. K. Mottl: Advisory Panel; Self; Bayer U. S. C. Pihoker: None. S. Saydah: None. M. R. Kosorok: None. E. J. Mayer-davis: None. T. Pokaprakarn: None. G. Alexander: None. T. L. Crume: None. D. Dabelea: None. J. Divers: None. L. M. Dolan: None. E. T. Jensen: None. S. M. Marcovina: None. Funding National Institutes of Health (1UC4DK108173, F30DK113728); Centers for Disease Control and Prevention (00097, DP-05-069, DP-10-001)

Evaluation of Consistency of Treatment Response Across Regions-the LEADER Trial in Relation to the ICH E17 Guideline.

The US Food and Drug Administration in 2008 required new type 2 diabetes (T2D) medications to be subject to cardiovascular outcomes safety requirements. Accordingly, the global LEADER trial investigated cardiovascular outcomes of T2D treatment with liraglutide, a glucagon-like peptide-1 receptor agonist. LEADER (NCT01179048) was a multiregional clinical trial (MRCT) conducted from 2010 to 2016, thus completed before publication of the International Council for Harmonization (ICH) E17 guideline on MRCTs in 2017. Novo Nordisk pre-specified analysis of regional cardiovascular outcomes of LEADER participants. This paper assesses the pre-specified regional outcomes based on the ICH E17 guidelines on consistency evaluation. Regional LEADER participant numbers were broadly aligned with ICH E17 guidance and equally balanced across Europe, Asia, North America, and rest of the world. Overall primary major adverse cardiovascular events (MACE) composite outcome for the trial: hazard ratio (HR) (95% CI) 0.87 (0.78; 0.97); regional results varied, ranging from HR (95% CI) 0.62 (0.37; 1.04) (Asia) to 1.01 (0.84; 1.22) (North America). However, pre-specified Cox proportional-hazard regression analyses did not show clear evidence of interaction between regions and primary outcome (p = 0.20). Furthermore, post hoc analysis of the US population in the North American region found that adjusting for extrinsic or intrinsic factors did not account for this difference [HR (95% CI) 1.03 (0.84; 1.25)]. LEADER data evaluation demonstrated general consistency in cardiovascular safety across regions, except for US participants. Discrepancies in the North American region may relate to drug exposure or chance, but, as these were post hoc findings, the overall primary result is valid, aligned with ICH E17 guidelines.

Clinical Characteristics of Withdrawal of Basal Insulin Therapy Among Japanese Patients with Type 2 Diabetes: A Multicenter Retrospective Observational Study.

IntroductionThis study aimed to examine retrospectively the clinical backgrounds of Japanese patients with type 2 diabetes (T2D) who successfully withdrew from insulin use after being started on basal insulin in an outpatient setting.MethodsThe study population comprised 376 insulin-naïve patients who were started on basal insulin (glargine U100, glargine U300, or degludec) for the management of T2D and followed the treatment regimen for at least 6 months in 13 institutions in Japan. The clinical courses of the study participants were compared based on outpatient clinic medical records for the three different types of basal insulin prescribed by categorizing the participants into two groups retrospectively: those who successfully withdrew from insulin therapy and those who did not, during a 6-month observation period. The clinical determinants for insulin withdrawal were assessed using a Cox proportional hazard model.ResultsGlycated hemoglobin was improved in all participants regardless of basal insulin type. Of the 376 study participants, 61 successfully withdrew from basal insulin therapy. After adjustment was made for several confounders, the positive determinant factors for successful withdrawal of insulin were short duration of diabetes and high body mass index at the start of study, and the negative determinant factor was use of insulin secretagogues at the start. The types of basal insulin used by the study participants were not significant determinants of successful insulin withdrawal in this study.ConclusionsUse of basal insulin is a powerful option for the treatment of T2D. In patients with high BMI and/or short duration of diabetes, short-term insulin therapy is a promising strategy for the treatment of T2D before the initiation of insulin secretagogues, since such patients have the potential to successfully withdraw from basal insulin use even in an outpatient setting.

Oral Salmonella msbB Mutant as a Carrier for a Salmonella-Based Vaccine for Prevention and Reversal of Type 1 Diabetes.

A therapy that includes an oral vaccine for type 1 diabetes (T1D) using live attenuated Salmonella MvP728 (ΔhtrA/ΔpurD), cytokines (IL10 and TGFβ) and preproinsulin (PPI) antigen in combination with a sub-therapeutic dose of anti-CD3 mAb was developed by our team. The vaccine combination therapy reduced insulitis and prevented and reversed diabetes in non-obese diabetic (NOD) mice. Here, we show the effectiveness of an alternative Salmonella mutant (ΔmsbB) as a carrier strain, which is anticipated to have lower risks of an inflammatory response and septicemia as a result of modification in the lipopolysaccharide (LPS) via detoxification of lipid A. This mutant strain proved to have highly reduced pathogenic side effects. Salmonella strain ΔmsbB expressed autoantigens and in combination with cytokines and anti-CD3 mAb, successfully prevented and reversed T1D to levels comparable to the previously used carrier strain ΔhtrA/ΔpurD. Additionally, the Salmonella msbB mutant resulted in higher rates of host cell infection. These results further demonstrate the potential of an oral Salmonella-based combined therapy in the treatment of early T1D.

Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.

Self-Assembled Nanochaperones Inhibit the Aggregation of Human Islet Amyloid Polypeptide Associated with Type 2 Diabetes

Human islet amyloid polypeptide (hIAPP) aggregation is closely associated with dysfunction and apoptosis of pancreatic β-cells in type 2 diabetes (T2D). Accordingly, hIAPP amyloid inhibitors have shown promise against T2D. Here, by mimicking the function of natural molecular chaperones, nanochaperones (nChaps) based on self-assembled polymeric micelles with tunable surface microdomains for T2D treatment are reported. By capturing the aggregation-prone species of hIAPP onto the hydrophobic microdomains and segregating them by hydrophilic PEG chains, this kind of nChaps could effectively prevent hIAPP aggregation, block cell adhesion of hIAPP, facilitate hIAPP aggregates degradation and reduce hIAPP-related cytotoxicity. Therefore, our work will provide useful insights to develop a biomimetic strategy for the treatment of T2D.

Role of High Energy Breakfast "Big Breakfast Diet" in Clock Gene Regulation of Postprandial Hyperglycemia and Weight Loss in Type 2 Diabetes.

Postprandial hyperglycemia (PPHG) is strongly linked with the future development of cardiovascular complications in type 2 diabetes (T2D). Hence, reducing postprandial glycemic excursions is essential in T2D treatment to slow progressive deficiency of β-cell function and prevent cardiovascular complications. Most of the metabolic processes involved in PPHG, i.e., β-cell secretory function, GLP-1 secretion, insulin sensitivity, muscular glucose uptake, and hepatic glucose production, are controlled by the circadian clock and display daily oscillation. Consequently, postprandial glycemia displays diurnal variation with a higher glycemic response after meals with the same carbohydrate content, consumed at dusk compared to the morning. T2D and meal timing schedule not synchronized with the circadian clock (i.e., skipping breakfast) are associated with disrupted clock gene expression and is linked to PPHG. In contrast, greater intake in the morning (i.e., high energy breakfast) than in the evening has a resetting effect on clock gene oscillations and beneficial effects on weight loss, appetite, and reduction of PPHG, independently of total energy intake. Therefore, resetting clock gene expression through a diet intervention consisting of meal timing aligned to the circadian clock, i.e., shifting most calories and carbohydrates to the early hours of the day, is a promising therapeutic approach to improve PPHG in T2D. This review will focus on recent studies, showing how a high-energy breakfast diet (Bdiet) has resetting and synchronizing actions on circadian clock genes expression, improving glucose metabolism, postprandial glycemic excursions along with weight loss in T2D.

Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes.

Apoptosis is a naturally occurring process generating plenty of apoptotic vesicles (apoVs), but the feature, fate and function of apoVs remain largely unknown. Notably, as an appealing source for cell therapy, mesenchymal stem cells (MSCs) undergo necessary apoptosis and release apoVs during therapeutic application. In this study, we characterized and used MSC‐derived apoVs to treat type 2 diabetes (T2D) mice, and we found that apoVs were efferocytosed by macrophages and functionally modulated liver macrophage homeostasis to counteract T2D. We showed that apoVs can induce macrophage reprogramming at the transcription level in an efferocytosis‐dependent manner, leading to inhibition of macrophage accumulation and transformation of macrophages towards an anti‐inflammation phenotype in T2D liver. At the molecular level, we discovered that calreticulin (CRT) was exposed on the surface of apoVs to act as a critical ‘eat‐me’ signal mediating apoV efferocytosis and macrophage regulatory effects. Importantly, we demonstrated that CRT‐mediated efferocytosis of MSC‐derived apoVs contributes to T2D therapy with alleviation of T2D phenotypes including glucose intolerance and insulin resistance. These findings uncover that functional efferocytosis of apoVs restores liver macrophage homeostasis and ameliorates T2D.

Effect of whole body vibration on clinical and metabolic outcomes in adults with type 2 diabetes: an observational pilot trial

AbstractThe objective of this trial was to evaluate the effect of 28Hz whole body vibration on glycaemic control and other metabolic parameters in adults with type 2 diabetes (T2D).Twenty‐four adults with T2D on oral antidiabetic agents, with a baseline glycated haemoglobin (HbA1c) 6.5–9.0% (48–75mmol/mol), were randomised into two groups. The control group (CG) was advised to adopt lifestyle modifications, and the intervention group (IG) received the same orientations plus a vibrating platform for daily use for 12 weeks.Data from 22 patients were analysed (one from each group was excluded). Baseline characteristics of both groups were similar except for triglycerides, which were higher in the CG (111.8±39.9 vs 188.9±68.8mg/dL [1.26±0.45 vs 2.13±0.78mmol/L], p<0.05). After 12 weeks, there was a significant reduction in HbA1c in the IG (7.69±0.49 vs 7.17±0.77% [60.5±5.39 vs 54.9±8.74mmol/mol], p<0.05), not observed in the CG (8.05±0.98 vs 7.92±1.07% [64.5±10.78 vs 63.1±11.77mmol/mol], p=0.52). A non‐significant trend for weight loss in IG was observed (78.14±10.47 vs 77.14±11.08kg, p=0.06). There were no significant differences between the groups regarding fasting blood glucose or any other clinical and biochemical variables analysed.Daily use of the vibrating platform for 12 weeks resulted in improved HbA1c in adults with T2D. Further studies are needed to better define the role of whole body vibration as an adjuvant in T2D treatment. Copyright © 2021 John Wiley & Sons.

Germinal center checkpoint restrains anti-insulin B lymphocytes in type 1 diabetes-prone mice

Abstract Anti-insulin B lymphocytes (AIBCs) are key drivers of the autoimmune attack in type 1 diabetes (T1D) but their exact functions in T1D pathogenesis, and the point(s) during their development where tolerance is lost, are unknown. In the class-switch-competent anti-insulin B cell receptor transgenic non-obese diabetic (VH125SD.NOD) mice, 1–2% of B lymphocytes are insulin-specific, which accelerates diabetes development despite limited insulin autoantibody (IAA) production. Here we used VH125SD.NOD mice to determine where immune tolerance is lost throughout AIBC class-switch, germinal center entry, and antibody-secreting cell differentiation. We find an increased percentage of AIBCs enter germinal centers relative to non-insulin binding B lymphocytes in the same mice. In addition, an increased percentage of AIBCs are found within the pancreas, class-switch to IgG1, and proliferate relative to non-insulin binding B lymphocytes. We also find that AIBCs are activated in the gut to a greater extent than non-insulin binding B lymphocytes. These data suggest that AIBCs escape anergy and are able to class-switch, enter GCs, and proliferate, but maintain functional silencing preventing spontaneous IAA-production. Moreover, the escape from anergy may occur within the pancreas and/or the gastrointestinal tract. Our data has implications in immunotherapy treatments for T1D, as these GC checkpoints may provide an opportunity for T1D intervention.

Making sense of associations between type 2 diabetes, metformin, and breast cancer risk.

The relationship between type 2 diabetes (T2D), metformin, and breast cancer is complex. T2D may increase risk, but metformin used as first-line treatment of T2D may decrease breast cancer risk. This comment explores efforts to disentangle effects of T2D and metformin use on breast cancer risk in a prospective study.