Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus.
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ABSTRACT:
SUBMITTER: Ferguson D
PROVIDER: S-EPMC8570106 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectivesNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have become public health problems in the pediatric population. However, the relationship between these two conditions is not well understood. The primary objective of this study was to assess whether treatment of hyperglycemia in obese, treatment-naive children with type 2 diabetes (T2DM) was associated with an improvement of surrogate markers of NAFLD.Materials and methodsThis retrospective, longitudinal study included 151 obese children with a diagnosis of T2DM (Age: 14 ± 1 years, 72% female children, BMI: 98.6th percentile, and A1c: 10.3 ± 0.2%). Clinical/demographic information was collected before patients started any diabetes treatment and 1 and 3 years after starting metformin and/or insulin therapy.ResultsForty-eight patients (32%) had abnormal ALT/AST (i.e., >40 U/L), suggestive of NAFLD. After 1 year of therapy, there were no significant differences in plasma ALT among patients started on insulin, metformin, or combination: 5±4 vs. -10 ± 3 vs. -2±2 IU/L, respectively, P = .07. Of note, changes in plasma ALT were small, despite a significant reduction of A1c in patients prescribed insulin (alone or with metformin): -2.8 ± 1.0%, P = .01, and -2.7 ± 0.3%, P < .001, respectively. In line with this, no significant correlations were found between changes in A1c and plasma aminotransferases. In contrast, changes in plasma AST/ALT were more strongly associated with BMI changes (r = 0.32, P < .001, and r = 0.19, P = .04, respectively). Similar results were observed after 3 years of follow-up.ConclusionsNonalcoholic fatty liver disease is highly prevalent in obese children with T2DM. Treatment of hyperglycemia with metformin and/or insulin did not result in any significant improvement in surrogate markers of NAFLD (i.e., plasma aminotransferases). While changes in ALT and/or AST may not perfectly reflect histological changes in NAFLD, our findings suggest that the treatment of hyperglycemia per se may not be associated with NAFLD improvement.
| S-EPMC9152559 | biostudies-literature
Project description:The two main subsets of nonalcoholic fatty liver disease (NAFLD) include: (1) nonalcoholic fatty liver (NAFL), the more common and non-progressive subtype; and (2) nonalcoholic steatohepatitis (NASH), the less common subtype, which has the potential to progress to advanced liver damage. Current treatment strategies have focused on lifestyle management of modifiable risk factors, namely weight, and on the optimization of the management of individual components of metabolic syndrome. Various hypothetical pathogenic mechanisms have been proposed, leading to the development of novel drugs with the potential to effectively treat patients with NASH. Numerous clinical trials are ongoing, utilizing these experimental drugs and molecules targeting specific mechanistic pathway(s) to effectively treat NASH. Some of these mechanistic pathways targeted by experimental pharmacologic agents include chemokine receptor 2 and 5 antagonism, inhibition of galectin-3 protein, antagonism of toll-like receptor 4, variation of fibroblast growth factor 19, agonism of selective thyroid hormone receptor-beta, inhibition of apoptosis signal-regulating kinase 1, inhibition of acetyl-coenzyme A carboxylase, agonism of farnesoid X receptor, antibodies against lysl oxidase-like-2, and inhibition of inflammasomes. Emerging data are promising and further updates from ongoing clinical trials are eagerly awaited.
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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disease of impaired glucose utilization. Uncontrolled high sugar levels lead to advanced glycation end products (AGEs), which affects several metabolic pathways by its receptor of advanced glycation end products (RAGE) and causes diabetic complication. MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis, and target tissues, influencing health and disease processes.AimTo explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.MethodsWe systematically searched the electronic database PubMed using keywords. We included free, full-length research articles that evaluate the role of miRNAs in T2DM and its complications, focusing on genetic and molecular disease mechanisms. After assessing the full-length papers of the shortlisted articles, we included 12 research articles.ResultsSeveral types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications. miR-96-5p, miR-7-5p, miR-132, has_circ_0071106, miR-143, miR-21, miR-145-5p, and more are associated with various aspects of T2DM, including disease risk, diagnostic markers, complications, and gene regulation.ConclusionTargeting the AGE/RAGE axis, with a focus on miRNA regulation, holds promise for managing T2DM and its complications. MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE, potentially reducing inflammation, oxidative stress, and vascular complications. Additionally, miRNAs may serve as early diagnostic biomarkers for T2DM. Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.
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Project description:Elderly patients with type 2 diabetes mellitus (T2DM) are a rapidly emerging population that presents unique clinical challenges. This diverse patient group can differ widely in terms of physical and mental status, which can increase their risk of complications including hypoglycemia, falls, and depression. These factors can negatively impact their glycemic control, safety, and quality of life. The risk of hypoglycemic events is elevated among elderly patients with diabetes. In many cases, these events are related to antidiabetic therapy and the pursuit of strict glycemic control. Fear of a hypoglycemic episode, on the part of the patient and/or healthcare provider, is another major barrier to achieving glycemic control. Hypoglycemic events, even in the absence of awareness of the event (asymptomatic), can have negative consequences. To help manage these risks, several national and international organizations have proposed guidelines to address individualized treatment goals for older adults with diabetes. This article reviews current treatment guidelines for setting glycemic targets in elderly patients with T2DM, and discusses the role of emerging treatment options in this patient population.
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Project description:The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.
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Project description:Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD+) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting novel interventional strategies for metabolic disorders/complications.
| S-EPMC8228721 | biostudies-literature
Project description: Not available
| S-EPMC2494653 | biostudies-literature
Project description:BACKGROUND:Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states. CONTENT:Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates. SUMMARY:The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
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Project description:SGLT2 inhibitors are plausible second-line drugs that provide powerful additional A1c-lowering effects while inducing weight loss without hypoglycemia.
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Project description:It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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