Glycogen synthase kinase-3 (GSK-3) a magic enzyme: it’s role in diabetes mellitus and glucose homeostasis, interactions with fluroquionlones. A mini-review

Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer’s disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients

Background and AimsChronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies.MethodsWe screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients’ baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment.ResultsHigh IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039).ConclusionsThere were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.

Identification of a regulatory pathway inhibiting adipogenesis via RSPO2

Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142+ cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.

Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells

Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with β2-adrenergic receptor agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several newly developed mutant mouse strains with clenbuterol, a selective β2-adrenergic receptor agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of β-cell dysfunction and insulin resistance. Studies with skeletal muscle-specific mutant mice demonstrated that these metabolic improvements required activation of skeletal muscle β2-adrenergic receptors and the stimulatory G protein, Gs. Unbiased transcriptomic and metabolomic analyses showed that chronic β2-adrenergic receptor stimulation caused metabolic reprogramming of skeletal muscle characterized by enhanced glucose utilization. These findings strongly suggest that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.

Dynamic of Glucose Homeostasis in Virtual Patients: A Comparison between Different Behaviors

This work presents a mathematical model of homeostasis dynamics in healthy individuals, focusing on the generation of conductive data on glucose homeostasis throughout the day under dietary and physical activity factors. Two case studies on glucose dynamics for populations under conditions of physical activity and sedentary lifestyle were developed. For this purpose, two types of virtual populations were generated, the first population was developed according to the data of a total of 89 physical persons between 20 and 75 years old and the second was developed using the Monte Carlo approach, obtaining a total of 200 virtual patients. In both populations, each participant was classified as an active or sedentary person depending on the physical activity performed. The results obtained demonstrate the capacity of virtual populations in the generation of in-silico approximations similar to those obtained from in-vivo studies. Obtaining information that is only achievable through specific in-vivo experiments. Being a tool that generates information for the approach of alternatives in the prevention of the development of type 2 Diabetes.

Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Modelling for Clinical and Psysiological Evaluation of Diabetes and Glucose Homeostasis

There is a long history of arithmetic simulations in the domain of gluconeogenesis. There are various reasons why frameworks are used. Paradigms have been employed to calculate physiologically relevant parameters from intermediate experimental evidence, to offer a clear quantitative description of pathophysiology processes, and to identify clinical relevance indicators from basic empirical procedures. The creation and application of frameworks in this field has expanded in response to the rising social effect of type 2 diabetes that entails a disruption of the glycemic homeostasis system. The frameworks' emphasis has ranged from depictions of entire body functions to lymphocytes (form “in Vivo” to “in Vitro”) study, following the methodologies of physiologic and medicinal exploration. Framework-based techniques to connecting in vivo and in vitro research, and also multi-resolution systems that combine the two domains, have been presented. The arithmetic and psychological domains have had varying levels of effectiveness and influence.

The effect of visfatin genotype on insulin pump therapy on quality of life in patients with type I diabetes

Diabetes is associated with an increase in other chronic diseases and an increase in mortality. The individual differences influence the treatment of this disease in pharmacokinetics and clinical responses. One of the important factors related to individual differences includes genetic factors in transmission, metabolism, and drug function. On the other hand, this disease has a significant impact on the patients’ quality of life and their family. Therefore, this study aimed to investigate the role of single nucleotide polymorphism (rs2110385) of the visfatin gene on insulin required to maintain glucose homeostasis and to evaluate the effect of insulin pump therapy on the quality of life in type 1 diabetic patients. In this regard, this study was performed on 47 patients with type 1 diabetes. The short form of the Diabetes Quality of Life Questionnaire (DQOL) was used to record information. Laboratory tests also included FBS, HbA1C, G2h, serum levels of visfatin, insulin, and adiponectin. Insulin resistance (HOMA) and insulin sensitivity (QUICKI) indices were calculated. The polymorphism of the studied genotype was performed by the PCR-RFLP method. The results showed that the scores of both dimensions of quality of life, including patient care behaviors and satisfaction with the disease control after the intervention increased significantly (P <0.001). There was a significant and direct relationship between the patient's age and the duration of the disease with the score of increasing patients' quality of life. No significant differences were found between HbA1C, G2h, FBS levels, fasting insulin concentration, HOMA, and QUICKI indices. The insulin dose used to maintain glucose homeostasis at the same levels was significantly lower in the GG genotype than in other genotypes. In general, the present study results showed that insulin pump therapy and its dimensions could improve the life quality of patients with type 1 diabetes. Also, genetic evaluation of individuals helps to provide the correct and accurate dose of insulin with the help of the insulin pump for these patients to increase their quality of life as much as possible.

Endocrine Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Endocrine dysfunction is common in critically ill children and is manifested by abnormalities in glucose, thyroid hormone, and cortisol metabolism. OBJECTIVE To develop consensus criteria for endocrine dysfunction in critically ill children by assessing the association of various biomarkers with clinical and functional outcomes. DATA SOURCES PubMed and Embase were searched from January 1992 to January 2020. STUDY SELECTION We included studies in which researchers evaluated critically ill children with abnormalities in glucose homeostasis, thyroid function and adrenal function, performance characteristics of assessment and/or scoring tools to screen for endocrine dysfunction, and outcomes related to mortality, organ-specific status, and patient-centered outcomes. Studies of adults, premature infants or animals, reviews and/or commentaries, case series with sample size ≤10, and non–English-language studies were excluded. DATA EXTRACTION Data extraction and risk-of-bias assessment for each eligible study were performed by 2 independent reviewers. RESULTS The systematic review supports the following criteria for abnormal glucose homeostasis (blood glucose [BG] concentrations &gt;150 mg/dL [&gt;8.3 mmol/L] and BG concentrations &lt;50 mg/dL [&lt;2.8 mmol/L]), abnormal thyroid function (serum total thyroxine [T4] &lt;4.2 μg/dL [&lt;54 nmol/L]), and abnormal adrenal function (peak serum cortisol concentration &lt;18 μg/dL [500 nmol/L]) and/or an increment in serum cortisol concentration of &lt;9 μg/dL (250 nmol/L) after adrenocorticotropic hormone stimulation. LIMITATIONS These included variable sampling for BG measurements, limited reporting of free T4 levels, and inconsistent interpretation of adrenal axis testing. CONCLUSIONS We present consensus criteria for endocrine dysfunction in critically ill children that include specific measures of BG, T4, and adrenal axis testing.