The therapeutic effects of glucagon-like peptide-1 receptor agonists and metformin on polycystic ovary syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Obesity and insulin resistance (IR) are common in polycystic ovary syndrome (PCOS), which contribute to reproductive and metabolic abnormalities. Metformin increases insulin sensitivity, but it is associated with unsatisfied benefits of weight loss. Recent studies have reported that glucagon-like peptide 1 (GLP-1) receptor agonists improve IR and reduce weight in women with PCOS. We conducted a systematic review and meta-analysis to compare the effects between GLP-1 receptor agonists and metformin, and between GLP-1 receptor agonist-metformin combination and GLP-1 receptor agonists in overweight/obese women with PCOS on anthropometric, metabolic, reproductive outcomes. METHODS: Databases including PubMed, EMBASE, Web of Science, and Cochrane Library were selected to search for randomized controlled trials (RCTs) published in English up to March 2020. Eligible studies were identified according to the inclusion criteria. The primary outcomes included menstrual frequency, body mass index (BMI), total testosterone, and the homeostatic model assessment of insulin resistance. GRADE criteria were implemented to assess the quality of evidence for primary outcomes. RESULTS: Seven RCTs were selected for analysis, comprising 464 overweight/obese women with PCOS. In the low-quality evidence, a meta-analysis demonstrated that GLP-1 receptor agonists showed better effects relative to metformin on the reduction of body mass index (mean difference - 1.72; 95% confidence interval -2.46 to -0.99, P < .001) and homeostatic model assessment of insulin resistance (standard mean difference -0.37; 95% confidence interval - 0.60,- 0.15, P = .001). Moreover, the combination therapy exhibited similar effects on primary outcomes relative to GLP-1 receptor agonist alone. GLP-1 receptor agonists were also found to be associated with lower abdominal girth compared to metformin. A meta-analysis of gastrointestinal discomfort showed no significant difference between GLP-1 receptor agonist and metformin therapies, and between the combination therapy and GLP-1 receptor agonist alone. CONCLUSIONS: GLP-1 receptor agonists appear to be more beneficial for weight loss and IR improvement compared to metformin for overweight/obese women with PCOS. However, the combination treatment displays comparable effects with GLP-1 receptor agonist alone. The incidence of gastrointestinal discomforts was similar in different groups. However, the quality of the body of evidence is "low." Further prospective RCTs and cost-effectiveness analyses are also warranted to guide GLP-1 receptor agonists to treat women with PCOS.

Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. METHODS: We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). RESULTS: Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I2 = 72%). CONCLUSIONS: Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.

Order of discontinuation of glucose-lowering medications following bariatric surgery.

AIMS: To assess the order of glucose-lowering medication (GLM) discontinuation following bariatric surgery among patients taking ≥2 GLMs. METHODS: Patients with diabetes mellitus taking ≥2 GLM classes who underwent bariatric surgery were identified using health claims data from the United States. The order of discontinuation was assessed in patients taking ≥2 GLM classes by comparing each GLM class to the other classes in aggregate. Descriptive statistics and Poisson regression were used to assess the order of discontinuation and changes in trends in the order of discontinuation. RESULTS: Overall, 12,244 of 26,651 patients with type 2 diabetes who underwent bariatric surgery were taking ≥2 GLM classes. When each GLM class was assessed separately, fewer than 50% of patients had metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, glucosidase inhibitor, or insulin discontinued first when compared to the other classes in aggregate. Between 2008 and 2014, thiazolidinediones were increasingly more likely to be the first GLM discontinued (p = 0.0432). Slightly more than 50% of patients whose GLM regimen included a sulfonylurea discontinued the sulfonylurea first despite clinical recommendations. CONCLUSIONS: From a population level, there was no consistent approach in the order of discontinuation of GLM classes in patients following bariatric surgery.

Pleiotropic effects of anti-diabetic drugs: A comprehensive review.

Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.

Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus: Part 2.

Ideal drugs to improve outcomes in type 2 diabetes mellitus (T2DM) are those with antiglycemic efficacy, as well as cardiovascular safety that has to be determined in appropriately designed cardiovascular outcome trials as mandated by regulatory agencies. The more recent antihyperglycemic medications have shown promise with regards to cardiovascular disease (CVD) risk reduction in T2DM patients at a high cardiovascular risk. Sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists are associated with better cardiovascular outcomes and mortality in T2DM patients than are dipeptidylpeptidase-4 inhibitors, leading to the Food and Drug Administration's approval of empagliflozin to reduce mortality, and of liraglutide to reduce CVD risk in high-risk T2DM patients. For heart failure outcomes, sodium glucose cotransporter-2 inhibitors are beneficial, while glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are neutral. Ongoing and planned randomized controlled trials of these newer drugs should clarify the possibility of class effects and of CVD risk reduction benefits in low-moderate cardiovascular risk patients. While we eagerly await the results on ongoing studies, these medications should be appropriately prescribed in T2DM patients with baseline CVD or those at a high CVD risk after carefully evaluating the elevated risk for adverse events like gastrointestinal disturbances, bladder cancer, genital infections, and amputations. Studies to understand the pleotropic and novel pathophysiological mechanisms demonstrated by the sodium glucose cotransporter-2 inhibitors will shed light on the effects of the modulation of microvascular, inflammatory, and thrombotic milieu for improving the CVD risk in T2DM patients. This is part 2 of the series on noninsulin antihyperglycemic drugs for the treatment of T2DM.

Intensification of medical management in type 2 diabetes: A real-world look at primary care practice.

AIMS: To determine which drugs were selected to be added to metformin for patients on dual anti-diabetic medication in the management of type 2 diabetes and to assess HbA1c and BMI outcomes at 6 and 12 months after the initiation of a second anti-diabetic medication. METHODS: A retrospective chart review of electronic medical record data. Second line anti-diabetic medication added to metformin between 7/1/2012 to 8/31/2017 in the primary care practice in Fairview Health System in Minnesota. RESULTS: 3413 patients met the selection criteria of type 2 diabetes, 18 years and older, dual anti-diabetes therapy with metformin being the first prescribed. The most frequently prescribed medications added to metformin were sulfonylurea and basal insulin accounting for 51% (1724/3413) and 37% (1268/3413) respectively. Mean HbA1c reductions at 6 and 12 months among 2134 patients with baseline and follow-up HbA1c data respectively were: GLP-1 agonist (-1.3, P < 0.001; -1.2, P < 0.001), sulfonylurea (-1.1, P < 0.001; -0.9, P < 0.001), basal insulin (-1.1, P < 0.001; -1.0, P < 0.001), DPP4 inhibitor (-0.7, P = 0.223; -0.8, P = 0.049). Patients prescribed a GLP-1 agonist had a higher mean baseline BMI (BMI =40.3 kg/m2) and this was the only group with a statistically significant BMI reduction from baseline at 6 and 12 months (-1.5, P = 0.049 and -1.8, P = 0.041). CONCLUSION AND RELEVANCE: Type 2 diabetes patients treated with sulfonylurea, basal insulin and GLP-1 agonist as an add on to metformin had significant reductions in HbA1c. Patients prescribed a GLP-1 agonist had a significant BMI reduction.

Polypharmacy and oral antidiabetic treatment for type 2 diabetes characterised by drug class and patient characteristics: A Japanese database analysis.

Polypharmacy (PP) occurs in patients with type 2 diabetes (T2DM) owing to multimorbidity. We evaluated concomitant PP and medication adherence in T2DM 3 years after initiation of administration of a hypoglycaemic agent using a nationwide claim-based database in Japan. Factors associated with medication PP and imperfect adherence were identified using multivariable logistic regression. PP was defined as using ≥6 medications. Patients with proportion of days covered (PDC) of <80% were defined as having poor medication adherence. A total of 884 patients were analysed. Multivariate analysis revealed that age, total number of consultations and body mass index (BMI) are factors that influence PP. Factors associated with PDC < 80% were 2-3, 4-5 and ≥ 6 medications compared with 1 medication, male sex, <17 consultations and age 50-59 and ≥ 60 years compared with <40 years. In conclusion, older age, high total number of consultations and BMI ≥ 25 kg/m2 are risk factors for PP. PP influenced good medication adherence at the end of the observation period.

The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect.

Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially associated with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiology, its treatment is varied and based upon a multitude of pharmacologic agents aiming to tackle the many aspects of the disease pathophysiology (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or "gliptins") represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biological activity of the "incretin" hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiological problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.

Antidiabetic Medications and Mortality Risk in Individuals With Pancreatic Cancer-Related Diabetes and Postpancreatitis Diabetes: A Nationwide Cohort Study.

OBJECTIVE: There are no specific treatment guidelines for diabetes of the exocrine pancreas. High-quality studies are warranted to investigate whether the use of antidiabetic medications has survival benefit in individuals with diabetes of the exocrine pancreas. The objective was to determine the risk of mortality associated with the use of antidiabetic medications in individuals with pancreatic cancer-related diabetes (PCRD) and postpancreatitis diabetes mellitus (PPDM). RESEARCH DESIGN AND METHODS: Nationwide pharmaceutical dispensing data (2006-2015) linked to hospital discharge data were used to identify 1,862 individuals with PCRD or PPDM. Multivariable Cox regression analysis was conducted, and the risk was expressed as hazard ratios and 95% CIs. A 6-month lag was used to minimize reverse causality. RESULTS: In individuals with PCRD, ever users of metformin (adjusted hazard ratio 0.54; 95% CI 0.46-0.63) and ever users of insulin (adjusted hazard ratio 0.46; 95% CI 0.39-0.55) had significantly lower risks of mortality compared with never users of antidiabetic medications. These associations attenuated toward the null with the use of a 6-month lag. In individuals with PPDM, ever users of metformin had a significantly lower risk of mortality (adjusted hazard ratio 0.51; 95% CI 0.36-0.70), whereas ever-users of insulin did not have a significantly changed risk of mortality (adjusted hazard ratio 0.75; 95% CI 0.49-1.14) compared with never users of antidiabetic medications. The former association remained significant with the use of a 6-month lag. CONCLUSIONS: Metformin promotes a survival benefit in individuals with PPDM but not PCRD. Reverse causality may play a role in the association between insulin use and mortality in PCRD.

Diabetes Mellitus and Cardiovascular Disease.

Cardiovascular disease remains a leading cause of morbidity and mortality in people with types 1 or 2 diabetes mellitus. Although beneficial roles for strict control of hyperglycemia have been suggested, such a strategy is not without liabilities. Specifically, the risk of hypoglycemia and its consequences remain an omnipresent threat with such approaches. The advent of the CVOT (Cardiovascular Outcomes Trials) for new antidiabetes mellitus treatments has uncovered unexpected benefits of cardiovascular protection in some of the new classes of agents, such as the GLP-1 RAs (glucagon-like peptide-1 receptor agonists) and the SGLT-2 (sodium-glucose cotransporter-2) inhibitors. Further, state-of-the-art approaches, such as antibodies to PCKSK9 (proprotein convertase subtilisin-kexin type 9); RNA therapeutics; agents targeting distinct components of the immune/inflammatory response; and novel small molecules that block the actions of RAGE (receptor for advanced glycation end products) signaling, also hold potential as new therapies for diabetes mellitus and cardiovascular disease. Finally, interventions such as weight loss, through bariatric surgery, may hold promise for benefit in diabetes and cardiovascular disease. In this Brief Review, some of the novel approaches and emerging targets for the treatment of diabetes mellitus and cardiovascular disease are discussed. Ultimately, identification of the optimal timing and combinations of such interventions, especially in the context of personalized approaches, together with emerging disease-modifying agents, holds great promise to reduce the burden that diabetes poses to the cardiovascular system.

Obesity and type 2 diabetes: Also linked in therapeutic options. / Obesidad y diabetes mellitus tipo 2: también unidas en opciones terapéuticas.

The prevalence of obesity has increased worldwide over the past decades. Obesity is associated with multiple comorbidities, such as type 2 diabetes, that generates a great impact on health and economy. Weight loss in these patients leads to glycemic control so it is a target to achieve. Lifestyle changes are not effective enough and recently other treatments have been developed such as bariatric/metabolic surgery, as well as drugs for type 2 diabetes and antiobesity drugs. The aim of this review is to compare the results in weight reduction and glycemic control of the different kinds of drugs with bariatric / metabolic surgery's results in type 2 diabetes.

Prediabetes.

The burden of diabetes is expected to rise from 415 million individuals in 2015 to 642 million individuals by 2040. Most individuals pass through a phase of prediabetes before developing full-blown diabetes. Insulin resistance, impaired incretin action, and insulin hypersecretion are central to the pathophysiology of prediabetes. Individuals older than 40 years of age and other high-risk individuals should be screened for diabetes with fasting plasma glucose and/or hemoglobin A1c. For those diagnosed with prediabetes, the goal of treatment should be restoring euglycemia, because there are data showing that restoring normoglycemia during prediabetes and early diabetes can produce lasting remission. The preferred approach for this is intensive lifestyle intervention, which besides reducing progression to diabetes, has also been shown to reduce all-cause mortality in a long-term follow-up study. The best evidence for a pharmacological approach is with metformin. Other drugs that have shown efficacy include thiazolidinediones, alpha-glucosidase inhibitors, orlistat, basal insulin, and valsartan. However, except for metformin, none of these drugs are currently recommended for this purpose. Newer agents such as glucagon-like peptide-1 agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors also have considerable promise in this area. Bariatric surgery can be offered to patients with metabolic syndrome and body mass index of 30-35.

Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study.

BACKGROUND: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications. OBJECTIVE: To evaluate the association between diabetes medications other than DPP4i and development of BP. METHODS: We investigated the prevalence of diabetes among patients with BP and the association between the use of diabetes drugs (excluding DPP4i, metformin, and insulin) and BP by analyzing national Finnish registry data for 3397 patients with BP and 12,941 patients with basal cell carcinoma as controls. RESULTS: Our results show that 19.6% of patients with BP have type 2 diabetes. Use of none of the investigated medications was associated with an increased risk of BP. LIMITATIONS: Because this was a registry-based study, it was not possible to verify the accuracy of the diagnoses. The risk of BP in users of glucagon-like peptide 1 receptor agonists could not be analyzed. CONCLUSION: Our study shows that the investigated diabetes drugs are not associated with an increased risk of BP in a Finnish patient database, indicating they can be safely used in this population. Generalization of these results to other populations will require further study.

Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment - a clinical appraisal.

AIM: A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes. METHOD: A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel. RESULTS: Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature. CONCLUSIONS: While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies.

Adenosine monophosphate-activated protein kinase-based classification of diabetes pharmacotherapy.

The current classification of both diabetes and antidiabetes medication is complex, preventing a treating physician from choosing the most appropriate treatment for an individual patient, sometimes resulting in patient-drug mismatch. We propose a novel, simple systematic classification of drugs, based on their effect on adenosine monophosphate-activated protein kinase (AMPK). AMPK is the master regular of energy metabolism, an energy sensor, activated when cellular energy levels are low, resulting in activation of catabolic process, and inactivation of anabolic process, having a beneficial effect on glycemia in diabetes. This listing of drugs makes it easier for students and practitioners to analyze drug profiles and match them with patient requirements. It also facilitates choice of rational combinations, with complementary modes of action. Drugs are classified as stimulators, inhibitors, mixed action, possible action, and no action on AMPK activity. Metformin and glitazones are pure stimulators of AMPK. Incretin-based therapies have a mixed action on AMPK. Sulfonylureas either inhibit AMPK or have no effect on AMPK. Glycemic efficacy of alpha-glucosidase inhibitors, sodium glucose co-transporter-2 inhibitor, colesevelam, and bromocriptine may also involve AMPK activation, which warrants further evaluation. Berberine, salicylates, and resveratrol are newer promising agents in the management of diabetes, having well-documented evidence of AMPK stimulation medicated glycemic efficacy. Hence, AMPK-based classification of antidiabetes medications provides a holistic unifying understanding of pharmacotherapy in diabetes. This classification is flexible with a scope for inclusion of promising agents of future.

Novel approaches to the treatment of hyperglycaemia in type 2 diabetes mellitus.

Control of hyperglycaemia is a fundamental therapeutic goal in patients with type 2 diabetes. The progressive nature of ß-cell dysfunction in type 2 diabetes leads to the need for escalating anti-hyperglycaemic treatment, including insulin, in most patients. Given the prevalence of complications such as weight gain and hypoglycaemia associated with traditional anti-hyperglycaemic agents (AHA), including sulphonylureas and insulin, it is unsurprising that recent years have seen the development of novel agents to treat hyperglycaemia. With increasing evidence supporting the need for a multi-faceted approach to the prevention of adverse cardiovascular events in people with type 2 diabetes, a patient-centred and individualised management strategy addressing lifestyle, cardiovascular risk factor modification and glycaemic control remains critical in improving outcomes in these patients.

Atividade de novos derivados de tiazolidinodionas sobre a diferenciação de pré-osteoblastos e pré-adipócitos / Activity of new derivatives of thiazolidinediones on differentiation of preosteoblasts and preadipocytes

As tiazolidinodionas (TZDs) são sensibilizadores de insulina utilizados no tratamento do diabetes mellitus tipo 2. Contudo, apesar dos efeitos benéficos sobre a glicemia, importantes efeitos adversos incluindo perda óssea e aumento de adiposidade são relatados com o uso clínico das TZDs. Assim, é necessário o desenvolvimento de novos derivados de TZDs com potenciais efeitos benéficos sobre a hiperglicemia e menos efeitos adversos. Neste estudo, investigamos os efeitos de 5 novos derivados de TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) sobre a diferenciação celular de pré-osteoblastos murinos MC3T3-E1, pré-adipócitos murinos 3T3-L1 e pré-adipócitos SGBS de linhagem humana. Seus potenciais efeitos sobre a utilização de glicose, a produção de adipocinas e mediadores pró-inflamatórios também foram avaliados, utilizando linhagens murinas e humanas de adipócitos, e macrófagos THP-1 de linhagem humana. O principal achado de nosso estudo foi que os novos derivados de TZDs estimulam a utilização celular de glicose, porém não alteram o processo de diferenciação celular de pré-osteoblastos e pré-adipócitos, quando comparados com a TZD clássica Rosiglitazona. Conforme esperado, o tratamento com Rosiglitazona na concentração de 5 µM inibiu a osteogênese de pré-osteoblastos murinos MC3T3-E1. No entanto, o tratamento com 2 novos derivados de TZDs (GQ-89 e GQ-177) na mesma concentração não afetou a diferenciação celular, sendo possível observar níveis de mineralização de matriz extracelular similares aos do grupo controle. Além disso, enquanto a GQ-89 estimulou a atividade da fosfatase alcalina, a GQ-177 não modulou sua atividade enzimática e induziu a expressão gênica de osteocalcina. Contudo, ambos inibiram a expressão de Runx2 e colágeno. Por sua vez, quando os efeitos foram avaliados sobre a diferenciação de adipócitos, foi possível observar que ao contrário do efeito pró-adipogênico constatado com a Rosiglitazona na concentração de 1 µM, as TZDs GQ-150, GQ-177, LYSO-7 e SF-3 foram incapazes de induzir o acúmulo lipídico em pré-adipócitos murinos e humanos. Além disso, a GQ-150 inibiu a expressão gênica de C/EBPα, assim como a expressão gênica e os níveis protéicos de CD36, enquanto que a SF-3 estimulou a expressão gênica de C/EBPα e de FABP4 e diminuiu a expressão gênica e os níveis protéicos de CD36, os quais não foram modificados pela LYSO-7 em pré-adipócitos murinos 3T3-L1. No entanto, em pré-adipócitos SGBS de linhagem humana, nenhum efeito sobre os marcadores de fenótipo adipogênico C/EBPα e FABP4 foi observado com os novos derivados de TZDs. Ademais, os novos derivados de TZDs não interferiram na via de sinalização de Wnt, não apresentaram qualquer efeito sobre a expressão de adipocinas (adiponectina, resistina e leptina) e mediadores pró-inflamatórios (IL-6, CCL2/MCP-1, TNF-α e JNK), bem como não ativaram o fator de transcrição PPARγ no ensaio de gene repórter. Por sua vez, a LYSO-7, GQ-150 e SF-3 aumentaram o consumo de glicose em presença de insulina em adipócitos 3T3-L1 e modificaram a atividade de enzimas mitocondriais em adipócitos SGBS e macrófagos THP-1. Entretanto, o efeito sensibilizador de insulina foi confirmado somente com a GQ-177 pelo aumento da captação de glicose e somente a LYSO-7 e a SF-3 foram capazes de inibir o consumo de oxigênio e modificar a taxa de glicólise em macrófagos, sugerindo que também poderiam alterar os níveis de ATP/ADP. Considerando que baixos níveis de ATP estimulam a via de sinalização de AMPK, essa via também foi investigada em nosso estudo. Entretanto, os resultados sobre a ativação de AMPK foram inconclusivos. Desse modo, nossos resultados apontam que os novos derivados de TZDs não atuam como ligantes de PPARγ, apresentam atividade sensibilizadora de insulina in vitro, e que exercem menores efeitos antiosteoblásticos e adipogênicos quando comparados com a Rosiglitazona. Mais estudos são necessários para elucidar os mecanismos responsáveis por esses efeitos, bem como para estabelecer se os novos derivados de TZDs são mais seguros in vivo, com relação ao risco de fraturas ósseas e ganho de massa adiposa

Thiazolidinediones (TZDs) are insulin sensitizers used in the treatment of type 2 diabetes mellitus. However, despite the beneficial effects on blood glucose, significant adverse effects including bone loss and increased adiposity are reported with the clinical use of TZDs. Thus, it is necessary to develop new derivatives of TZDs with potential beneficial effects on hyperglycemia and fewer adverse effects. In this study, we investigated the effects of 5 new derivatives of TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) on cellular differentiation in murine MC3T3-E1 preosteoblasts, murine 3T3-L1 preadipocytes, and SGBS preadipocytes from human lineage. Potential effects on glucose consumption, adipokines, and pro-inflammatory mediators were also assessed using murine and human strains of adipocytes, and macrophages from human THP-1 lineage. The main finding of this study was that new derivatives of TZDs stimulate glucose consumption, but do not change the cell differentiation process of preosteoblasts and preadipocytes compared to classical TZD Rosiglitazone. As expected, the treatmet with Rosiglitazone, at 5µM, inhibited the osteogenesis in murine MC3T3-E1 preosteoblasts. However, the treatment with 2 new derivatives of TZDs (GQ-89 and GQ-177) at the same concentration did not affect cell differentiation, and levels of mineralization of the extracellular matrix similar to the control group were observed. In addition, whereas the GQ-89 stimulated the activity of alkaline phosphatase, GQ-177 does not modulate its enzymatic activity and induced gene expression of osteocalcin. However, both of them inhibit the expression of Runx2 and collagen. In turn, when the effects were assessed on the adipocyte differentiation, unlike the proadipogenic effect observed with Rosiglitazone at a concentration of 1 µM, the new TZDs GQ-150, GQ-177, LYSO-7 and SF-3 were unable to induce lipid accumulation in human and murine preadipocytes. In addition, GQ-150 inhibited the gene expression of C/EBPα , as well as the gene expression and protein levels of CD36, whereas SF-3 stimulated the gene expression of C/EBPα and FABP4 and decreased gene expression and protein levels of CD36, which was not modified by LYSO-7 on murine 3T3- L1 preadipocytes. However, no effect on markers of adipogenic phenotype C/EBPα and FABP4 has been observed with the novel derivatives of TZDs in human SGBS preadipocytes. Furthermore, the new derivatives of TZDs do not interfere with the Wnt signaling pathway, showed no effect on the adipokines expression (adiponectin, resistin and leptin) and proinflammatory mediators (IL-6, CCL2 / MCP-1, TNF α and JNK) and did not activate the transcription factor PPARγ in the gene reporter assay. In turn, LYSO-7, GQ-150, and SF-3 increased glucose consumption in the presence of insulin in 3T3-L1 adipocytes and modified the activity of mitochondrial enzymes in SGBS adipocytes and THP-1 macrophages. However, the effect on insulin sensitization was confirmed only to GQ-177 that increased glucose uptake and just LYSO-7 and SF-3 were able to inhibit oxygen consumption and modify the rate of glycolysis in macrophages, suggesting that they could also alter the levels of ATP/ADP. Since low levels of ATP could stimulate AMPK pathway, this signaling pathway was also investigated in our study. However, the results on the AMPK activation were inconclusive. Thus, our results demonstrate that the new derivatives of TZDs do not act as PPARγ ligands, present insulin sensitizing activity in vitro, and display minor antiosteoblastic and adipogenic effects when compared to Rosiglitazone. More studies are needed to elucidate the exact mechanisms responsible for these effects, as well as to establish whether the safety of the new TZDs with respect to the risk of bone fractures and body mass gain using in vivo models

[New therapies for type 2 diabetes mellitus]. / Nuevos agentes terapéuticos para la diabetes tipo 2.

The increasing prevalence of obesity and type 2 diabetes mellitus (T2DM) has led to a growing interest in the investigation of new therapies. Treatment of T2DM has focused on the insulinopenia and insulin resistance. However, in the last 10 years, new lines of research have emerged for the treatment of T2DM and preclinical studies appear promising. The possibility of using these drugs in combination with other currently available drugs will enhance the antidiabetic effect and promote weight loss with fewer side effects. The data provided by post-marketing monitoring will help us to better understand their safety profile and potential long-term effects on target organs, especially the cardiovascular risk.