PRE1BRAZIL Protocol: A Randomized Controlled Trial to Evaluate the Effectiveness and Safety of the DPP-4 Inhibitor Alogliptin in Delaying the Progression of Stage 2 Type 1 Diabetes.

Background: The incidence of Type 1 Diabetes Mellitus (T1DM) is on the rise. Since there is no curative treatment, it is urgent to look for therapies that can delay disease progression and protect pancreatic ß-cells. Dipeptidyl peptidase-4 inhibitors (DPP-4i) have shown potential in modulating inflammation and preventing ß-cell destruction. This protocol describes an upcoming trial to evaluate the effectiveness of the DPP-4i alogliptin in delaying the progression of stage 2 (presymptomatic) to stage 3 (symptomatic) T1DM. Patients and Methods: We propose a two-year, two-arm, multicenter, randomized, open-label clinical trial targeting Brazilian patients aged 18 to 35 with stage 2 T1DM. The study, facilitated by the custom-developed "PRE1BRAZIL" web application, aims to enroll 130 participants. They will be randomly assigned in a 1:1 ratio to either a treatment group (alogliptin 25 mg daily plus regular clinical and laboratory assessments) or a control group (regular assessments only). The primary outcome is the rate of progression to stage 3 T1DM. Secondary outcomes include changes in A1c levels, glucose levels during a 2-hour oral glucose tolerance test (OGTT), C-peptide levels, exogenous insulin requirements, Insulin-Dose Adjusted A1c (IDAA1c), and the incidence of diabetic ketoacidosis (DKA) in those advancing to stage 3. Discussion: This protocol outlines the first randomized clinical trial (RCT) to investigate the impact of a DPP-4i in the presymptomatic stage of T1DM. The trial is designed to provide critical insights into the role of DPP-4i in the secondary prevention of T1DM. Utilizing the "PRE1BRAZIL" web application is expected to enhance participant enrollment and reduce operational costs. Registration: Brazilian Registry of Clinical Trials.

Glucose-Lowering and the Risk of Cardiovascular Events With Antidiabetic Therapies: A Systematic Review and Additive-Effects Network Meta-Analysis.

Aim: To assess the impact of the HbA1c levels achieved with antidiabetic therapies (ADTs) on the risk of MACE. Methods: A systematic search was performed in PubMed, Cochrane, and ClinicalTrials. gov for RCTs published up to March 2022 reporting the occurrence of MACE and all-cause mortality in individuals with T2DM treated with all marketed ADTs, including a sample size ≥100 individuals in each study arm and follow-up ≥24 weeks. A systematic review and additive-effects network meta-analysis with random effects and a multivariate meta-regression were utilized to assess the impact of achieved HbA1c on incident MACE. Results: We included 126 RCTs with 143 treatment arms, 270,874 individuals, and 740,295 individuals-years who were randomized to an active treatment vs. control group. Among all ADTs, only therapy with SGLT2i, GLP1-RA, or pioglitazone similarly reduced the risk of MACE compared to placebo. The achievement of HbA1c ≤ 7.0% in RCTs with the 3 drug classes in the active arm was associated with an adjusted HR of 0.91 (95% CI 0.80, 0.97; p = 0.017) compared with HbA1c>7.0%, without affecting all-cause mortality. These results, however, were not maintained among all ADTs. Conclusions: Achieving lower glucose levels with SGLT2i, GLP1-RA, or pioglitazone is linearly associated with a reduced risk of MACEs, without affecting all-cause mortality. Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213127, identifier: CRD42020213127.

Adipose tissue-derived stromal/stem cells + cholecalciferol: a pilot study in recent-onset type 1 diabetes patients

ABSTRACT Objective: Adipose tissue-derived stromal/stem cells (ASCs) and vitamin D have immunomodulatory actions that could be useful for type 1 diabetes (T1D). We aimed in this study to investigate the safety and efficacy of ASCs + daily cholecalciferol (VIT D) for 6 months in patients with recent-onset T1D. Materials and methods: In this prospective, dual-center, open trial, patients with recent onset T1D received one dose of allogenic ASC (1 x 106 cells/kg) and cholecalciferol 2,000 UI/day for 6 months (group 1). They were compared to patients who received chol-ecalciferol (group 2) and standard treatment (group 3). Adverse events were recorded; C-peptide (CP), insulin dose and HbA1c were measured at baseline (T0), after 3 (T3) and 6 months (T6). Results: In group 1 (n = 7), adverse events included transient headache (all), mild local reactions (all), tachycardia (n = 4), abdominal cramps (n = 1), thrombophlebitis (n = 4), scotomas (n = 2), and central retinal vein occlusion at T3 (n = 1, resolution at T6). Group 1 had an increase in basal CP (p = 0.018; mean: 40.41+/-40.79 %), without changes in stimulated CP after mixed meal (p = 0.62), from T0 to T6. Basal CP remained stable in groups 2 and 3 (p = 0.58 and p = 0.116, respectively). Group 1 had small insulin requirements (0.31+/- 0.26 UI/kg) without changes at T6 (p = 0.44) and HbA1c decline (p = 0.01). At T6, all patients (100%; n = 7) in group 1 were in honeymoon vs 75% (n = 3/4) and 50% (n = 3/6) in groups 2 and 3, p = 0.01. Conclusions: Allogenic ASC + VIT D without immunosuppression was safe and might have a role in the preservation of β-cells in patients with recent-onset T1D. ClinicalTrials.gov: NCT03920397.

Adipose tissue-derived stromal/stem cells + cholecalciferol: a pilot study in recent-onset type 1 diabetes patients.

OBJECTIVE: Adipose tissue-derived stromal/stem cells (ASCs) and vitamin D have immunomodulatory actions that could be useful for type 1 diabetes (T1D). We aimed in this study to investigate the safety and efficacy of ASCs + daily cholecalciferol (VIT D) for 6 months in patients with recent-onset T1D. METHODS: In this prospective, dual-center, open trial, patients with recent onset T1D received one dose of allogenic ASC (1 × 106 cells/kg) and cholecalciferol 2,000 UI/day for 6 months (group 1). They were compared to patients who received chol-ecalciferol (group 2) and standard treatment (group 3). Adverse events were recorded; C-peptide (CP), insulin dose and HbA1c were measured at baseline (T0), after 3 (T3) and 6 months (T6). RESULTS: In group 1 (n = 7), adverse events included transient headache (all), mild local reactions (all), tachycardia (n = 4), abdominal cramps (n = 1), thrombophlebitis (n = 4), scotomas (n = 2), and central retinal vein occlusion at T3 (n = 1, resolution at T6). Group 1 had an increase in basal CP (p = 0.018; mean: 40.41+/-40.79 %), without changes in stimulated CP after mixed meal (p = 0.62), from T0 to T6. Basal CP remained stable in groups 2 and 3 (p = 0.58 and p = 0.116, respectively). Group 1 had small insulin requirements (0.31+/- 0.26 UI/kg) without changes at T6 (p = 0.44) and HbA1c decline (p = 0.01). At T6, all patients (100%; n = 7) in group 1 were in honeymoon vs 75% (n = 3/4) and 50% (n = 3/6) in groups 2 and 3, p = 0.01. CONCLUSION: Allogenic ASC + VIT D without immunosuppression was safe and might have a role in the preservation of ß-cells in patients with recent-onset T1D. ClinicalTrials.gov: NCT03920397.

Emerging Roles of Dipeptidyl Peptidase-4 Inhibitors in Delaying the Progression of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) results from the immune cell-mediated destruction of functional pancreatic ß-cells. In the presymptomatic period, T1DM is characterized by the presence of two or more autoantibodies against the islet cells in patients without glycemic decompensation. Therapeutic strategies that can modify the autoimmune process could slow the progression of T1DM. Dipeptidyl peptidase-4 (DPP-4) or CD26, a multifunctional serine protease with a dual function (regulatory protease and binding protein), can modulate inflammation and immune cell-mediated ß-cell destruction. CD26 is involved in T-cell co-stimulation, migration, memory development, thymic maturation, and emigration patterns. DPP-4 degrades the peptide hormones GLP-1 and GIP. In addition to regulating glucose metabolism, DPP-4 exerts anti-apoptotic, regenerative, and proliferative effects to promote ß-cell mass expansion. GLP-1 receptor signaling may regulate murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells. In patients with T1DM, the serum DPP-4 activity is upregulated. Several studies have suggested that the upregulated DPP-4 activity is correlated with T1DM pathophysiology. DPP-4, which is preferentially expressed on the Th1 surface, can promote the polarization of Th1 immunity, a prerequisite for T1DM development. CD26 inhibition can suppress T-cell proliferation and Th1 cytokine production and stimulate tumor growth factor beta-1 (TGF-ß1) secretion, which plays an important role in the regulation of autoimmunity in T1DM. Studies on humans or animal models of T1DM have suggested that DPP-4 inhibitors can improve ß-cell function and attenuate autoimmunity in addition to decreasing insulin dependence. This review summarizes the emerging roles of DPP-4 inhibitors in potentially delaying the progression of T1DM.

Lower Insulin-Dose Adjusted A1c (IDAA1c) Is Associated With Less Complications in Individuals With Type 1 Diabetes Treated With Hematopoetic Stem-Cell Transplantation and Conventional Therapy.

Objective: To evaluate the association between insulin-dose adjusted A1C (IDAA1c) and microvascular complications (MC) and hypoglycemia in a representative Brazilian population of Type 1 diabetes mellitus (T1DM) patients. Research Design and Methods: This was a cross-sectional study based on a previous study, "Microvascular Complications in Type 1 Diabetes: a comparative analysis of patients treated with autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST) and conventional medical therapy (CT)". The 168 patients in that study (144 from CT plus 24 from AHST) were re-subdivided into two groups, according to their IDAA1c values (30 patients had IDAA1c ≤ 9; 138 had IDAA1c > 9). Then, the prevalence of MC (diabetic renal disease, neuropathy, and retinopathy), hypoglycemia (blood glucose <60 mg/dL), and severe hypoglycemic (episode of hypoglycemia that required the assistance of another person to treat) events were compared between the groups. The groups were well-matched on these factors: duration of disease, sex, and age at the time of diagnosis of T1DM. Results: After an average of 8 years after diagnosis, only 6.6% (2/30) of the patients from IDAA1c ≤ 9 group developed any MC, whereas 21.0% (29/138) from the IDAA1c > 9 group had at least one complication (p = 0.044). Regarding hypoglycemic events, the proportion of individuals who reported at least 1 episode of hypoglycemia in the last month was 43.3 and 64.7% from the IDAA1c ≤ 9 and IDAA1c > 9 groups, respectively (p = 0.030). Regarding severe hypoglycemia, the proportion of patients presenting at least one episode in the last month and the rate of episode/patient/month were similar between groups (6.7 vs. 13.2%; p = 0.535; and 0.1/patient/month vs. 0.25/patient/month; p = 0.321). Conclusion: In a representative Brazilian population of T1DM patients, those with IDAA1c ≤ 9 presented a lower frequency of MC, as well as fewer episodes of hypoglycemia, in the month prior to the analysis.

DPP-4 Inhibition Leads to Decreased Pancreatic Inflammatory Profile and Increased Frequency of Regulatory T Cells in Experimental Type 1 Diabetes.

Sitagliptin is a dipeptidyl peptidase-4 inhibitor (iDPP-4), which has been used for type 2 diabetes treatment. Recently, iDPP-4 has been described as a promising treatment of type 1 diabetes (T1D) but is still necessary to evaluate immune effects of sitagliptin. C57BL/6 mice were induced by multiple low doses of streptozotocin. Diabetes incidence, insulin, glucagon, glucagon-like peptide-1 (GLP-1) serum levels, and inflammatory cytokine levels were quantified in pancreas homogenate after 30 and 90 days of treatment. In addition, frequencies of inflammatory and regulatory T cell subsets were determined in the spleen and in the pancreatic lymph nodes. iDPP-4 decreased blood glucose level while increased GLP-1 and insulin levels. After long-term treatment, treated diabetic mice presented decreased frequency of CD4+CD26+ T cells and increased percentage of CD4+CD25hiFoxp3+ T cells in the spleen. Besides, pancreatic lymph nodes from diabetic mice treated with iDPP-4 presented lower percentage of CD11b+ cells and decreased levels of inflammatory cytokines in the pancreas. Treatment of type 1 diabetic mice with iDPP-4 improved metabolic control, decreased inflammatory profile in the pancreatic microenvironment, and increased systemic regulatory T cell frequency. Therefore, we suggest the long-term use of sitagliptin as a feasible and effective therapy for T1D.

Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties.

BACKGROUND: Type 1 diabetes mellitus (T1D) is characterized by autoimmune responses resulting in destruction of insulin-producing pancreatic beta cells. Multipotent mesenchymal stromal cells (MSCs) exhibit immunomodulatory potential, migratory capacity to injured areas and may contribute to tissue regeneration by the secretion of bioactive factors. Therefore, MSCs are considered as a promising approach to treat patients with different autoimmune diseases (AID), including T1D patients. Phenotypical and functional alterations have been reported in MSCs derived from patients with different AID. However, little is known about the properties of MSCs derived from patients with T1D. Since autoimmunity and the diabetic microenvironment may affect the biology of MSCs, it becomes important to investigate whether these cells are suitable for autologous transplantation. Thus, the aim of the present study was to evaluate the in vitro properties and the in vivo therapeutic efficacy of MSCs isolated from bone marrow of newly diagnosed T1D patients (T1D-MSCs) and to compare them with MSCs from healthy individuals (C-MSCs). METHODS: T1D-MSCs and C-MSCs were isolated and cultured until third passage. Then, morphology, cell diameter, expression of surface markers, differentiation potential, global microarray analyses and immunosuppressive capacity were in vitro analyzed. T1D-MSCs and C-MSCs therapeutic potential were evaluated using a murine experimental model of streptozotocin (STZ)-induced diabetes. RESULTS: T1D-MSCs and C-MSCs presented similar morphology, immunophenotype, differentiation potential, gene expression of immunomodulatory molecules and in vitro immunosuppressive capacity. When administered into diabetic mice, both T1D-MSCs and C-MSCs were able to reverse hyperglycemia, improve beta cell function and modulate pancreatic cytokine levels. CONCLUSIONS: Thus, bone marrow MSCs isolated from T1D patients recently after diagnosis are not phenotypically or functionally impaired by harmful inflammatory and metabolic diabetic conditions. Our results provide support for the use of autologous MSCs for treatment of newly diagnosed T1D patients.

Risks, benefits, and therapeutic potential of hematopoietic stem cell transplantation for autoimmune diabetes.

Type 1 diabetes mellitus is a chronic disease that results from the autoimmune response against pancreatic insulin producing ß cells. Apart of several insulin regimens, since the decade of 80s various immunomodulatory regimens were tested aiming at blocking some steps of the autoimmune process against ß cell mass and at promoting ß cell preservation. In the last years, some independent research groups tried to cure type 1 diabetes with an "immunologic reset" provided by autologous hematopoietic stem cell transplantation in newly diagnosed patients, and the majority of patients became free form insulin with increasing levels of C-peptide along the time. In this review, we discuss the biology of hematopoietic stem cells and the possible advantages and disadvantages related to the high dose immunosuppression followed by autologous hematopoietic stem cell transplantation.

Stem cell-based therapies and immunomodulatory approaches in newly diagnosed type 1 diabetes.

Type 1 diabetes mellitus is an autoimmune disease against pancreatic ß cells. The autoimmune response begins months or years before the clinical presentation. At the time of hyperglycemic symptoms a small amount of ß cell mass still remains. The main therapeutic option to type 1 diabetes mellitus is daily insulin injections which is shown to promote tighter glucose control and to reduce much of diabetic chronic complications. Subgroup analysis of the Diabetes Control and Complication Trial (DCCT) showed another important aspect related to long term complications of diabetes, ie, patients with initially larger residual ß cell mass suffered less microvascular complications and less hypoglycemic events than those patients with small amounts of ß cells at diagnosis. In face of this, ß cell preservation has become another important target in the management of type 1 diabetes and its related complications. In this review, we summarize various immunomodulatory regimens ever used in humans, including stem cell-based strategies, aiming at blocking autoimmunity against pancreatic ß cells and at promoting ß cell preservation and/or possible ß cell regeneration in recent-onset type 1 diabetes.

Stem cell therapy for type 1 diabetes mellitus: a review of recent clinical trials.

Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases. With regard to type 1 diabetes, studies analyzing the therapeutic effects of stem cells in humans began in 2003 in the Hospital das Clínicas of the Faculty of Medicine of Ribeirão Preto - SP USP, Brazil, and since then other centers in different countries started to randomize patients in their clinical trials. Herein we summarize recent data about beta cell regeneration, different ways of immune intervention and what is being employed in type 1 diabetic patients with regard to stem cell repertoire to promote regeneration and/or preservation of beta cell mass.The Diabetes Control and Complications Trial (DCCT) was a 7-year longitudinal study that demonstrated the importance of the intensive insulin therapy when compared to conventional treatment in the development of chronic complications in patients with type 1 diabetes mellitus (T1DM). This study also demonstrated another important issue: there is a reverse relationship between C-peptide levels (endogenous indicator of insulin secretion) chronic complications - that is, the higher the C-peptide levels, the lower the incidence of nephropathy, retinopathy and hypoglycemia. From such data, beta cell preservation has become an additional target in the management of T1DM 1.

Stem cell transplantation for type 1 diabetes mellitus.

BACKGROUND: The use of stem cells to treat type 1 diabetes mellitus has been proposed for many years, both to downregulate the immune system and to provide beta cell regeneration. CONCLUSION: High dose immunosuppression followed by autologous hematopoietic stem cell transplantation is able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus.

Autologous stem cell transplantation for early type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is the result of the autoimmune response against pancreatic insulin producing beta cells. This autoimmune response begins months or even years before the first presentation of signs and symptoms of hyperglycemia and at the time of clinical diagnosis near 30% of beta-cell mass still remains. In daily clinical practice, the main therapeutic option for T1DM is multiple subcutaneous insulin injections that are shown to promote tight glucose control and reduce much of diabetic chronic complications, especially microvascular complications. Another important aspect related to long-term complications of diabetes is that patients with initially larger beta-cell mass suffer less microvascular complications and less hypoglycemic events than those patients with small beta-cell mass. In face of this, beta-cell preservation is another important target in the management of type 1 diabetes and its related complications. For many years, various immunomodulatory regimens were tested aiming at blocking autoimmunity against beta-cell mass and at promoting beta-cell preservation, mainly in secondary prevention trials. In this review, we summarize some of the most important studies involving beta-cell preservation by immunomodulation and discuss our preliminary data on autologous nonmyeloablative hematopoietic stem cell transplantation in newly-diagnosed T1DM.

Potential role of stem cell therapy in type 1 diabetes mellitus.

Type 1 diabetes mellitus is the result of the autoimmune response against pancreatic beta-cell(s). At the time of clinical diagnosis near 70% of beta-cell mass is been destroyed as a consequence of the auto-destruction that begins months or even years before the clinical diagnosis. Although marked reduction of chronic complications was seen after development and progression of insulin therapy over the years for type 1 diabetic population, associated risks of chronic end-organ damage and hypoglycemia still remain. Besides tight glucose control, beta-cell mass preservation and/or increase are known to be other important targets in management of type 1 diabetes as long as it reduces chronic microvascular complications in the eyes, kidneys and nerves. Moreover, the larger the beta-cell mass, the lower the incidence of hypoglycemic events. In this article, we discuss some insights about beta-cell regeneration, the importance of regulation of the autoimmune process and what is being employed in human type 1 diabetes in regard to stem cell repertoire to promote regeneration and/or preservation of beta-cell mass.

Potencial role of stem cell therapy in type 1 diabetes mellitus: [review]

Type 1 diabetes mellitus is the result of the autoimmune response against pancreatic beta-cell(s). At the time of clinical diagnosis near 70 percent of beta-cell mass is been destroyed as a consequence of the auto-destruction that begins months or even years before the clinical diagnosis. Although marked reduction of chronic complications was seen after development and progression of insulin therapy over the years for type 1 diabetic population, associated risks of chronic end-organ damage and hypoglycemia still remain. Besides tight glucose control, beta-cell mass preservation and/or increase are known to be other important targets in management of type 1 diabetes as long as it reduces chronic microvascular complications in the eyes, kidneys and nerves. Moreover, the larger the beta-cell mass, the lower the incidence of hypoglycemic events. In this article, we discuss some insights about beta-cell regeneration, the importance of regulation of the autoimmune process and what is being employed in human type 1 diabetes in regard to stem cell repertoire to promote regeneration and/or preservation of beta-cell mass.

O diabetes melito tipo 1 (DM1) é o resultado de uma resposta auto-imune contra as células-beta pancreáticas. Por ocasião do diagnóstico clínico do DM1, aproximadamente 70 por cento da massa de células-beta foram destruídas como conseqüência de uma autodestruição que se iniciou há anos ou meses antes dos primeiros sinais da doença. Embora a redução acentuada das complicações crônicas na população com DM1 foi observada após o desenvolvimento e evolução da insulinoterapia, os riscos associados às lesões dos órgãos-alvo e hipoglicemia persistem. Além do controle intensivo da glicemia, a preservação e/ou o aumento da massa de células-beta são reconhecidos como alvos importantes no tratamento do DM1. Isto vem associado à redução das complicações crônicas microvasculares na retina, rins e nervos e a menor incidência de eventos hipoglicêmicos. Neste artigo, discutimos alguns aspectos da regeneração das células-beta pancreáticas, a importância da regulação do processo auto-imune e o que está sendo empregado no DM1 humano com relação ao repertório das células-tronco nesse sentido.

Mönckeberg's sclerosis - is the artery the only target of calcification?

BACKGROUND: Since its first description, Mönckeberg's sclerosis has only been related to arterial media calcification, being listed among the primary diseases of the vessels. CASE PRESENTATION: We report here a clinically and histologically confirmed case of Mönckeberg's sclerosis in which the patient presented with massive areas of soft tissue calcifications in the pharynx and larynx. Polysomnographic parameters showed severe obstructive apnea refractory to nasal continuous positive airway pressure. Clinical and laboratory findings excluded concomitant endocrine or rheumatological diseases. CONCLUSION: Our data provide a new insight about Mönckeberg's sclerosis, i.e., the fact that the etiopathogenic process involved in the phenomenon of calcification may not be restricted only to the arteries, but may occur in the entire organism. Further studies of the etiopathogenesis of this disease are needed.

Mortalidade por doença cerebrovascular em Juiz de Fora, 1979-1995 / Mortality of cerebrovascular disease in Juiz de Fora, Brazil, 1979-1995

Este trabalho analisa a tendência temporal da mortalidade por doença cerebrovascular em Juiz de Fora, Minas Gerais, de 1979 a 1995. Foram calculados os coeficientes padronizados por idade a partir dos dados do Sistema de Informações sobre Mortalidade (SIM) do Ministério da Saúde e dos Censos de 1980 e 1991 do IBGE. Realizou- se a regressão linear simples, sendo a significância estatística testada pelo t de Student. Houve queda significativa nos coeficientes, tanto nos homens (p<0,01), quanto nas mulheres (p<0,01). Vários grupos etários mostraram tendência ao declínio. A queda pode ser relacionada a alteração na história natural da doença, com curso mais benigno devido a alteração na prevalência dos fatores de risco, principalmente hipertensão arterial, e incremento nos cuidados médicos.

This study evaluated the trend of cerebrovascular disease mortality rates in Juiz de Fora (Minas Gerais, Brazil) from 1979 to 1995. Population figures and data on deaths from cerebrovascular disease were used to calculate specific mortality rates by sex and age. The deaths from cerebrovascular disease were taken from the national mortality surveillance system. The population data were taken from the censuses of 1980 and 1991. The linear regression was calculated and analyzed by Student's t test. There was a decrease in cerebrovascular disease mortality rates for men (p <0.01) and women (p <0.01). Many age groups showed a profile of decline, with may be related to changes in natural history of disease with a more benign course due to a decrease in risk factors prevalence, in special systemic hypertension, and improvement of medical care.