scholarly journals Combinatorial approaches using an AI/ML-driven drug development platform targeting insulin resistance, lipid dysregulation, and inflammation for the amelioration of metabolic syndrome in patients

2021 ◽  
Author(s):  
Maksim Khotimchenko ◽  
Mark S. Hixon ◽  
Nicholas E. Brunk ◽  
Daniel M. Walden ◽  
Hypatia Hou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Chronic Inflammation ◽  
Glucose Control ◽  
Combinatorial Approach ◽  
Development Platform ◽  
Drug Classes ◽  
Treatment Measures ◽  
Clinical Risks

Dysregulations of key signaling pathways leading to metabolic syndrome (MetS) are complex eventually leading to cardiovascular events and type 2 diabetes. Dyslipidemia induces progression of insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, acceleration of lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with MetS. As MetS is considered a multifactorial disorder, the treatment measures cannot be focused on the specific pathway because other metabolic changes keep the pathological processes in progression. In our present research we have modeled an outcomes of metabolic syndrome treatment using two distinct drug classes. Targets were chosen based on the clustered clinical risks in MetS; dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. The AI/ML platform, BIOiSIM, was used in narrowing down two different drug classes with distinct mode of action and modalities. Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Alogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, IL-17A sequestering agent used in treating psoriasis, was selected as a candidate to address inflammatory disorders. Our analysis suggests this novel combinatorial approach has a high likelihood of ameliorating a significant portion of the clustered clinical risk in MetS.

Long-term Effect of Glimepiride and Rosiglitazone on Non-conventional Cardiovascular Risk Factors in Metformin-treated Patients Affected by Metabolic Syndrome: A Randomized, Double-blind Clinical Trial

2005 ◽  
Vol 33 (3) ◽  
pp. 284-294 ◽  
Author(s):  
G Derosa ◽  
AV Gaddi ◽  
L Ciccarelli ◽  
E Fogari ◽  
M Ghelfi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Cardiovascular Risk ◽  
Plasma Glucose ◽  
Double Blind Study ◽  
Model Assessment ◽  
Rapid Improvement ◽  
Double Blind

We evaluated the effect of glimepiride plus metformin and rosiglitazone plus metformin on glucose, and on cardiovascular risk parameters such as lipoprotein(a) (Lp[a]) and homocysteine (HCT) in patients with type 2 diabetes and metabolic syndrome. Ninety-nine patients in the multicentre, randomized, double-blind study took metformin (1500 mg/day) plus glimepiride (2 mg/day) or rosiglitazone (4 mg/day) for 12 months. Changes in body mass index, glycosylated haemoglobin (HbA1c), Lp(a) and HCT were primary efficacy variables. Fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) and homeostasis model assessment index were also used to assess efficacy. On average, HbA1c decreased by 9.1% and 8.1%, FPG decreased by 7.3% and 10.9%, and PPG decreased by 7.6% and 10.5%, respectively, in the glimepiride and rosiglitazone groups after 12 months. Patients receiving rosiglitazone experienced more rapid improvement in glycaemic control than those on glimepiride, and showed a significant improvement in insulin resistance-related parameters. There was a statistically significant decrease in basal homocysteinaemia in glimepiride-treated patients (−27.3%), but not in rosiglitazone-treated patients. Rosiglitazone plus metformin significantly improved long-term control of insulin resistance-related parameters compared with glimepiride plus metformin, although glimepiride treatment was associated with a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients, and with significant improvements in non-traditional risk factors for cardiovascular disease, such as basal homocysteinaemia and plasma Lp(a) levels.

Diabetes

2016 ◽  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Diabetic Retinopathy ◽  
Diabetic Nephropathy ◽  
Diabetic Neuropathy ◽  
Endocrine System ◽  
Basic Training ◽  
Term Management

Chapter 8 covers the basic science and clinical topics relating to the endocrine system which trainees are required to learn as part of their basic training and demonstrate in the MRCP. It covers diabetes mellitus, diabetic emergencies, diabetes-long-term management, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, the diabetic foot, diabetic skin, the diabetic pregnancy, and metabolic syndrome and insulin resistance.

scholarly journals Androgen Deprivation Therapy in Prostate Cancer and Metabolic Risk for Atherosclerosis

2008 ◽  
Vol 93 (6) ◽  
pp. 2042-2049 ◽  
Author(s):  
Sadeka Shahani ◽  
Milena Braga-Basaria ◽  
Shehzad Basaria
Keyword(s):  
Prostate Cancer ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Androgen Deprivation Therapy ◽  
Cardiovascular Mortality ◽  
Prospective Studies ◽  
Androgen Deprivation ◽  
Negative Consequences ◽  
Metabolic Complications

Abstract Context: Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population. Evidence Acquisition: A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant. Evidence Synthesis: Prospective studies evaluating early (3–6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (≥12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality. Conclusion: Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.

Drug therapy and nutritional management of metabolic syndrome associated with hyperadrenocorticism in a dog – case report

2017 ◽  
Vol XXII (131) ◽  
pp. 38-46
Author(s):  
Viviani De Marco ◽  
Elidia Zotelli dos Santos
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Arterial Hypertension ◽  
Systemic Arterial Hypertension ◽  
The Metabolic Syndrome ◽  
Generic Term ◽  
High Concentrations ◽  
Stable Control ◽  
Biochemical Abnormalities

Hyperadrenocorticism (HAC) is a generic term that refers to clinical and biochemical abnormalities resulting from persistently high concentrations of glucocorticoids in the bloodstream, which may occur spontaneously or iatrogenically. Chronic hypercortisolism may promote abdominal obesity, dyslipidemia, systemic arterial hypertension and insulin resistance, abnormalities associated with the metabolic syndrome (MS). The present study aims to report the presence of MS in a dog with spontaneous HAC, and its satisfactory long-term therapeutic resolution. The animal presented marked alterations in addition to the classic symptoms of HAC: discrete hyperglycemia, insulin resistance, hyperlipidemia, arterial hypertension and obesity. Complete resolution of MS and stable control of HAC were observed after five months of treatment.

scholarly journals Luteolin-Enriched Artichoke Leaf Extract Alleviates the Metabolic Syndrome in Mice with High-Fat Diet-Induced Obesity

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 979 ◽  
Author(s):  
Eun-Young Kwon ◽  
So Kim ◽  
Myung-Sook Choi
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome

This current study aimed to elucidate the effects and possible underlying mechanisms of long-term supplementation with dietary luteolin (LU)-enriched artichoke leaf (AR) in high-fat diet (HFD)-induced obesity and its complications (e.g., dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease) in C57BL/6N mice. The mice were fed a normal diet, an HFD, or an HFD plus AR or LU for 16 weeks. In the HFD-fed mice, AR decreased the adiposity and dyslipidemia by decreasing lipogenesis while increasing fatty acid oxidation, which contributed to better hepatic steatosis. LU also prevented adiposity and hepatic steatosis by suppressing lipogenesis while increasing biliary sterol excretion. Moreover, AR and LU prevented insulin sensitivity by decreasing the level of plasma gastric inhibitory polypeptide and activity of hepatic glucogenic enzymes, which may be linked to the lowering of inflammation as evidenced by the reduced plasma interleukin (IL)-6, IL-1β, and plasminogen activator inhibitor-1 levels. Although the anti-metabolic syndrome effects of AR and LU were similar, the anti-adiposity and anti-dyslipidemic effects of AR were more pronounced. These results in mice with diet-induced obesity suggest that long-term supplementation with AR can prevent adiposity and related metabolic disorders such as dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.

scholarly journals Massive Ovarian Growth in a Woman With Severe Insulin-Resistant Polycystic Ovary Syndrome Receiving GnRH Analogue

2019 ◽  
Vol 104 (7) ◽  
pp. 2796-2800 ◽  
Author(s):  
Prapti Singh ◽  
Ariela Agress ◽  
Vanessa Kasarah Madrigal ◽  
Clara Magyar ◽  
Nora Ostrzega ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Polycystic Ovary Syndrome ◽  
Granulosa Cell ◽  
Polycystic Ovary ◽  
Gnrh Analogue ◽  
Ovary Syndrome ◽  
Severe Insulin Resistance ◽  
Antral Follicles

Abstract Context Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis. Case Description A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas. Conclusions In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

Genetic Polymorphisms of β-Cell Differentiation Confer Risk of Alterations of Glucose Metabolism in Survivors of Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1908-1908
Author(s):  
Pacharapan Surapolchai ◽  
Suradej Hongeng ◽  
Pat Mahachoklertwattana ◽  
Samart Pakakasama ◽  
Angkana Winaichatsak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Lymphoblastic Leukemia ◽  
Β Cell ◽  
Childhood All ◽  
Β Cell Function

Abstract Purpose: Long-term survivors of acute lymphoblastic leukemia (ALL) seem to be at risk of insulin resistance, impaired glucose tolerance and may develop typical signs of metabolic syndrome with disturbances in lipid metabolism. The aim of the present study was to study the prevalence of alterations in glucose metabolism and the predisposing factors of these disturbances in survivors of childhood ALL. Furthermore, we intended to identify the role of such genetic polymorphisms affecting β-cell function and glucose metabolism and possibly to develop them as markers for monitoring β-cell dysfunction following treatment for ALL in the future. Patients and methods: In 131 ALL survivors after cessation of therapy, an oral glucose tolerance test was performed to determine β-cell function/insulin sensitivity. Six single-nucleotide polymorphisms of PAX4 and TCF7L2 genes were genotyped in order to evaluate the association between these polymorphisms and β-cell function/insulin sensitivity. Results: Ten out of 131 (7.6%) survivors had impaired glucose tolerance (IGT) while 40 out of 131 (30.5%) had insulin resistance (IR) and demonstrated characteristics of metabolic syndrome (hyperinsulinemia, hypertriglyceridemia, low HDL-C). In the logistic regression analysis, the most important factor predicting IGT and IR was older current age (p= 0.010 and <0.001, respectively) while the PAX4 R192H mutation (rs2233580) was significant associated only to IGT after adjusted for age (p=0.043) (adjusted OR 5.28, 95%CI 1.06–26.40). Conclusion: Our findings suggest that older age of childhood ALL survivors is the most important risk factor of IGT and IR, underlining the need to continue regular and long-term screening till adulthood. Moreover, after adjusted for age, the PAX4 R192H variant (rs2233580) seemed to be associated with IGT. If this association is confirmed, institution of lifestyle and therapeutic measures may be needed to reduce metabolic risk and diabetes.

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