Precision Medicine in Patients with Differential Diabetic Phenotypes: Novel Opportunities from Network Medicine

Introduction: Diabetes mellitus (DM) comprises differential clinical phenotypes ranging from rare monogenic to common polygenic forms, such as type 1 (T1DM), type 2 (T2DM), and gestational diabetes, which are associated with cardiovascular complications. Also, the high-risk prediabetic state is rising worldwide, suggesting the urgent need for early personalized strategies to prevent and treat a hyperglycemic state. Objective: We aim to discuss the advantages and challenges of Network Medicine approaches in clarifying disease-specific molecular pathways, which may open novel ways for repurposing approved drugs to reach diabetes precision medicine and personalized therapy. Conclusion: The interactome [or protein-protein interactions (PPIs)] is a useful tool to identify subtle molecular differences between precise diabetic phenotypes and predict putative novel drugs. Despite being previously unappreciated as T2DM determinants, the growth factor receptor-bound protein 14 (GRB14), calmodulin 2 (CALM2), and protein kinase C-alpha (PRKCA) might have a relevant role in disease pathogenesis. Besides, in silico platforms have suggested that diflunisal, nabumetone, niflumic acid, and valdecoxib may be suitable for the treatment of T1DM; phenoxybenzamine and idazoxan for the treatment of T2DM by improving insulin secretion; and hydroxychloroquine reduce the risk of coronary heart disease (CHD) by counteracting inflammation. Network medicine has the potential to improve precision medicine in diabetes care and enhance personalized therapy. However, only randomized clinical trials will confirm the clinical utility of network-oriented biomarkers and drugs in the management of DM.

Changes in Cardiac Metabolism in Prediabetes

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

Optimal waist circumference cut-off points and prediabetic state as predictors of metabolic syndrome prevalence among Saudi adults in Jeddah city

With increasing prevalence of metabolic syndrome and absence of local waist circumference cut-off point, it is important to determine the local cut-off point of waist circumference to predict metabolic syndrome. The aim of this study is to estimate the prevalence of metabolic syndrome among Saudi adults who attend primary health care centers (PHC) in Jeddah city in 2017, and to determine the appropriate waist circumference cut-off value for identifying a person at risk for the metabolic syndrome. A cross-sectional analytic study was conducted. Results shows; mean age of participants was 30.94±9.70 and waist circumference was 96.87±17.40 in males and 86.51±15.30 in females. The prevalence (CI: 95%) of pre-diabetes was 16.3% (12.9%; 20.1%), while the prevalence of metabolic syndrome was {(95% CI = 10.6%) (7.80%; 13.8%)}. Abdominal obesity was the most frequent component of MetS, detected in 60.6%, and followed by high blood pressure in 25.0%. In males, a waist circumference≥93.5 cm is likely to indicate MetS with 100% sensitivity and 47.2% specificity; whereas, in females, optimal waist circumference cut-off was determined as ≥83.5 cm, showing 92.3% sensitivity and 46.4% specificity. In multivariate logistic regression, extended waist circumference was the strongest predictor of MetS {OR (95%CI) =3.75 (1.30; 10.81); p=0.014}, followed by the presence pre-diabetes {OR (95%CI) =2.31 (1.06; 5.04); p=0.035}. Further, high educational level was a significant predictor for MetS {OR (95%CI) = 0.34 (0.12; 0.99); p=0.047}; while age and marital status were not significant predictors.

Mobile Health Applications Interventions For Prediabetic State: Protocol of Systematic Review

Background: Individuals with prediabetic state are much more likely to develop Type-2 Diabetes Mellitus (TD2M) 4 times greater than those with normal glucose tolerance. Lifestyle changes such as daily physical activity and healthy diets can decrease the risk of prediabetic state . Mobile applications intervention could be one of the solutions to improve self-management awareness and compliance of prediabetic state intervention. There are no studies in systematic reviews of mobile phone applications intervention to prevent prediabetic state yet. Therefore, the objective of this study was to collect and summarize the evidence from randomized controlled trials (RCTs) exploring the effectiveness of mobile phone applications for intervention in prediabetic state patients.Methods: This protocol was prepared in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) statement. The database that will be used includes PubMed, ProQuest and EBSCO with date restriction between January 2007 and July 2019 in English language only. Identification of articles will be done independently by three reviewers through the title of the articles, reviewing the abstract, and then the full-text-article. Any disagreement will be resolved by consensus. The quality assessment and possible risk of bias will be evaluated using forms adapted from the Jadad score. Extraction and content analysis will be performed systematically. Quantitative data will be presented graphically via forest plot with 95% confidence intervals. Where possible we will explore the heterogeneity and continue to conduct meta-analysis using RevMan software package. Discussion: Changes in lifestyle, such as daily physical activity and a nutritious diet, can help to reduce the risk of prediabetes. Mobile phone applications, including health-related applications, is demonstrated to have a lot of promise in terms of providing tailored medical recommendations. Conclusion: The proposed systematic review and meta-analyses will allow us to obtain the evidence exploring the effectiveness of mobile phone applications for intervention in prediabetic state patients.Systematic review registration: This protocol has been registered in the Prospective Registry of Systematic Review (PROSPERO) database (CRD42021243813).

Modulation and bioinformatics screening of hepatic mRNA-lncRNAs (HML) network associated with insulin resistance in prediabetic and exercised mice

Background Insulin resistance is associated with prediabetes and further progression to type 2 diabetes mellitus (T2DM). This study aims to investigate novel hepatic lncRNAs associated with key genes in insulin resistance in prediabetes. Methods In the bioinformatics phase, we have collected screened a pool of lncRNAs and mRNAs according to their potential association to prediabetic condition. We performed pathway analysis of mRNAs, using DAVID tool based on KEGG repository data. Then, we used Python programming language to get a subset of lncRNAs located in 50 kb proximity with high-fat (HF)-responsive mRNAs. In the experimental phase, prediabetic mice model was established by the treatment of HF diets for 12 weeks. After this treatment, HF-fed animals were divided into two groups of endurance exercised or sedentary, both continuing on the HF diet for 8 weeks. Besides, a group of diabetic mice was treated using a HF diet for 8 weeks followed by injection with STZ solution and then a HF diet for another 4 weeks. Results We found three genes having paired lncRNAs annotated in insulin resistance pathway. Their hepatic expression levels were altered in prediabetic condition as upregulation of Srebf1 was associated with GM38501, upregulation of Pck1 was associated with Ctcflos and GM36691, downregulation of Cpt1b was associated with GM44502. All of these expression patterns were replicated in diabetic mice, correlated positively with their predicted lncRNAs. Interestingly, exercise reversed their expression patterns. Conclusions We suggest that the expression pattern of the hepatic mRNA-lncRNA (HML) network in prediabetic state undergoes similar modification to that of diabetes.

Insulin sensitivity predicts cognitive decline in individuals with prediabetes

IntroductionEpidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).Research design and methodsWe investigated longitudinal data from participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer’s Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1–3: 2.2–4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%–6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.ResultsInsulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.ConclusionsInsulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

Chronic Microvascular Complications in Prediabetic States—An Overview

A prediabetic state is a major risk factor for the development of diabetes, and, because of an identical pathophysiological background of both conditions, their prevalence increases parallelly and equally fast. Long-term hyperglycemia is the main cause inducing chronic complications of diabetes, yet the range of glucose levels at which they start has not been yet unequivocally determined. The current data show that chronic microvascular complications of diabetes can be observed in patients with abnormal glucose metabolism in whom glycaemia is higher than optimal but below diagnostic criteria for diabetes. Prediabetes is a heterogenous nosological unit in which particular types are differently characterized and show different correlations with particular kinds of complications. Analysis of the latest research results shows the need to continue studies in a larger population and can imply the need to verify the currently employed criteria of diagnosing diabetes and chronic complications of diabetes in people with prediabetes.

Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence

Background: Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. Introduction: The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. Methods: Pubmed and Google databases have been thoroughly searched and relevant studies were selected. Results: This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. Conclusion: Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.

Ameliorative Effects of Bredemolic Acid on Markers Associated with Renal Dysfunction in a Diet-Induced Prediabetic Rat Model

Recently, studies have shown that renal dysfunction is associated not only with overt diabetes but also with the preceding stage known as prediabetes. Diet and pharmacological interventions are the therapeutic approaches to managing prediabetes, but the compliance in combining the two interventions is low. Hence, the efficacy of pharmacological intervention is reduced without diet modification. In our previous study, we established that bredemolic acid (BA) ameliorated glucose homeostasis via increased GLUT 4 expression in the skeletal muscle of prediabetic rats in the absence of diet intervention. However, the effects of bredemolic acid on renal function in prediabetic condition are unknown. Therefore, this study was aimed at investigating the ameliorative effects of bredemolic acid on renal dysfunction in a diet-induced prediabetic rat model. Thirty-six Sprague-Dawley male rats (150–180 g) were divided into two groups: the nonprediabetic (n=6) and prediabetic (n=30) groups which were fed normal diet (ND) and high-fat high-carbohydrate (HFHC) diet, respectively, for 20 weeks. After the 20th week, the prediabetic groups were subdivided into prediabetic control (PD) and 4 other prediabetic groups which were treated with either BA (80 mg/kg) or metformin (MET, 500 mg/kg) for further 12 weeks (21st to 32nd). Plasma, urine, and kidney samples were collected for biochemical analysis. The untreated prediabetic (PD) rats presented increased fluid intake and urine output; increased creatinine, urea, and uric acid plasma concentrations; albuminuria; proteinuria; sodium retention; potassium loss; increased aldosterone and kidney injury molecule (KIM-1) concentration; and increased urinary podocin mRNA expression. However, BA administration attenuated the renal markers and oxidative stress and decreased the urinary podocin mRNA expression. In conclusion, BA administration, regardless of diet modification, attenuates renal dysfunction in an experimentally induced prediabetic state.