Diabetes and Insulin Resistance Research Papers (original) (raw)

Metadichol® is a Nanoemulsion of long-chain alcohols found in many foods. Metadichol acts as an inverse ag-onist on Nuclear Vitamin D receptors (VDR) that have a ubiquitous presence in cells and acts by modulating the immune system and affects many biological processes to modulate many diseases. We have demonstrated that Metadichol is useful in both type 1 and two diabetes and in modulating insulin levels and reducing sugar levels and thus increasing insulin sensitivity. We had earlier shown that it binds to VDR and thus an effect on glucose homeostasis that is a hallmark of VDR pathways. We now report also that it is an agonist of GPR120 (G protein-coupled receptor 120) which has emerged as a key target for metabolic diseases like obesity and insulin resistance. In the in-vitro assay, Metadichol is comparable to GW9508 the most extensively used standard compound in GPR 120 research.

- by
- •
- Diabetes, Agonism, Diabetes and Insulin Resistance, GPCR

Obesity is a major contributor to the dysfunction of liver, cardiac, pulmonary, en-docrine and reproductive system, as well as a component of metabolic syndrome. Although development of obesity-related disorders is associated with lipid abnormalities , most previous studies dealing with the problem in question were limited to routinely determined parameters, such as serum concentrations of triacylglycer-ols, total cholesterol, low-density and high-density lipoprotein cholesterol. Many authors postulated to extend the scope of analysed lipid compounds and to study obesity-related alterations in other, previously non-examined groups of lipids. Comprehensive quantitative, structural and functional analysis of specific lipid groups may result in identification of new obesity-related alterations. The review summarizes available evidence of obesity-related alterations in various groups of lipids and their impact on health status of obese subjects. Further, the role of diet and endogenous lipid synthesis in the development of serum lipid alterations is discussed, along with potential application of various lipid compounds as risk markers for obesity-related comorbidities.

- by Adriana Mika
- •
- Obesity, Fatty acids, Diabetes and Insulin Resistance, Lipid peroxidation

The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti-inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors.

Dysregulated lipid and cholesterol homeostasis in the body, and particularly in the brain,has been demonstrated in neurodegenerative diseases such as Alzheimer’s disease (AD), as well as Parkinson’s disease (PD) and Huntington’s disease (HD). These changes in
lipidmetabolismmay be a consequence of the disease process, or part of the pathogenic mechanism, or both. More importantly perhaps, with respect to AD, is the mounting evidence that dyslipidaemia helps to drive production or reduce clearance of Aβ, the amyloidogenic peptide believed to be central in AD pathogenesis. Furthermore, other
dyslipidaemia-related conditions have also been linked to AD pathogenesis, including obesity, hypertension, inflammation, insulin resistance, and type 2 diabetes. Apart from advancing age, the carriage of one or two copies of the APOE 𝜀4 alleles is one of the
biggest risk factors for developing late-onset (sporadic) AD. The product of this gene is apoE, a protein involved in the transport of lipids. Possession of APOE 𝜀4 alleles also predisposes individuals to a higher risk of cardiovascular disease. Here we discuss lipid
and cholesterol metabolism, and we give an overview of the various lipid and cholesterol metabolic pathways and changes that have been linked toAD, particularly the influence of the different forms of apoE on lipid, cholesterol, and Aβ metabolism.

- by Ian J Martins
- •
- Alzheimer's Disease, Fat Studies, Neurodegenerative Diseases, Cholesterol

During the last years, the list of resveratrol effects has grown in parallel with the number of other members of the polyphenol family described to modulate glucose or lipid handling. In the same time, more than ten human studies on the influence of resveratrol supplementation on two related metabolic diseases, obesity and diabetes, have indicated that impressive beneficial effects co-exist with lack of demonstration of clinical relevance, irrespective of the daily dose ingested (0.075 to 1.5 g per capita) or the number of studied patients. Such contrasting observations have been proposed to depend on the degree of insulin resistance of the patients incorporated in the study. To date, no definitive conclusion can be drawn on the antidiabetic or antiobesity benefits of resveratrol. On the opposite, studies on animal models of diabesity consistently indicated that resveratrol impairs diverse insulin actions in adipocytes, blunting glucose transport, lipogenesis and adipogenesis. Since resveratrol also favours lipolysis and limits the production of proinflammatory adipokines, its administration in rodents results in limitation of fat deposition, activation of hexose uptake into muscle, improvement of insulin sensitivity, and facilitation of glucose disposal. Facing to a somewhat disappointing extrapolation to man of these promising antidiabetic and antiobesity properties, attention must be paid to re-examine resveratrol targets, especially those attainable after polyphenol ingestion and to re-define the responses to low doses. In this context, human adipocytes are proposed as a convenient model for the screening of "novel" polyphenols that can reproduce, outclass, or reinforce resveratrol metabolic actions, Moreover, the use of combination of polyphenols is proposed to treat diabesity complications in view of recently reported synergisms. Lastly, multidisciplinar approaches are recommended for future investigations, considering the wide range of polyphenol actions that induce body fat reduction, liver disease mitigation, muscle function improvement, cardiovascular and renal protection.

World-wide epidemic, diabetes has ben found to be increased 100% in a decade according
to the results of Turkish Diabetes Epidemiology Study (TURDEP I and II). Southeastern
Anatolia Diabetes Project (GAPDIAB) even though may help raise the awareness and increase the
standarts of healthcare for those who are in need of, efforts still remain way behind the targets.
Majority of people with type 2 diabetes have insülin resistance. Even in case of lack of diabetes, insülin
resistance lead to cardiovascular problems. The treatment modality of diabetes should be chosen
from anti-glycaemic agents which are effective for insülin resistance, and anti-hypertensive
medications which are at least metabolically neutral or non-diabetogen blood pressure lowering
drugs. Elegant agents are angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor-
1 blockers (ARB), indapamide and spironolactone from diuretics, carvedilol, nebivolol, bisoprolol
from beta-blockers. Use of the

Aim: To investigate the changes of insulin resistance (IR), parameters of arterial stiffness, concentrations of Nterminal pro-brain natriuretic peptide (NT-proBNP), and echocardiographic parameters in patients with cardiac autonomic neuropathy (CAN) and type 2 diabetes mellitus (T2D). Methods: This study recruited 44 patients with T2D (19 patients without CAN and 25 patients with CAN) and 15 healthy volunteers. Arterial stiffness, immunoreactive insulin, homeostasis model assessment IR, NT-proBNP parameters, and echocardiographic examination were assessed. Results: Development of CAN is associated with increase in NT-proBNP levels, IR parameters, and arterial stiffening. Among patients with CAN, arterial stiffness parameters were considered as high. We found out that among patients of this group, the value of brachial augmentation index was normal in 52%, elevated in 40%, and pathological in 8%; pulse wave velocity was normal in 16%, elevated in 52%, and pathological in 32% of cases. Obtained results showed that development of CAN is accompanied by more pronounced left ventricular diastolic dysfunction and by formation of left ventricular hypertrophy (LVH), mostly by concentric type. Among patients of this group concentric LVH was diagnosed among 76 % and eccentric LVH among 16% of persons. Multiple mass index, showed an independent association of heart rate response to deep breathing with pulse wave velocity (P < 0.001). Conclusion: Development of CAN is associated with increased IR parameters, increased levels of NT-proBNP, arterial stiffening, left ventricular diastolic dysfunction, and formation of LVH, mostly by concentric type.

- by Vessel Plus and +1
- •
- Neuroscience, Echocardiography, Insulin Resistance, Diabetes and Insulin Resistance

The Valpolicella Heart Diabetes Study W e read with interest the recent article by van Hecke et al. (1) showing that diabetic retinopathy is associated with an increased risk of mortality and cardiovascular disease (CVD) incidence among... more

- by Eugenia Vlachou
- •
- Diabetes and Insulin Resistance

Aim: To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents.
Methods: A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed.
Results: A total of 70 lean [body mass index (BMI) < 25 kg/m2] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m2) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions.
Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences.

- by Hepatoma Research and +1
- •
- Epidemiology, Type 2 Diabetes, Metabolic syndrome, Liver diseases

Over the past eight years, the genetics of complex traits have benefited from an unprecedented advancement in the identification of common variant loci for diseases such as type 2 diabetes (T2D). The ability to undertake genome wide association studies in large population-based samples for quantitative glycaemic traits has permitted us to explore the hypothesis that models arising from studies in non-diabetic individuals may reflect mechanisms involved in the pathogenesis of diabetes. Amongst 88 T2D risk and 72 glycaemic trait loci only 29 are shared, and show disproportionate magnitudes of phenotypic effects. Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through elucidation of their contribution to glycaemic trait variability. Further investigation is warranted to define causal variants within these loci, including functional characterisation of associated variants, to dissect their role in disease mechanisms and to enable clinical translation.

- by Inga Prokopenko and +1
- •
- Type 2 Diabetes, Insulin Resistance, Insulin, Diabetes and Insulin Resistance

Background: The year 2020 witnessed a largely unprecedented pandemic of coronavirus disease (COVID-19), caused by SARS COV-2. Many people with COVID-19 have comorbidities, including diabetes, hypertension and cardiovascular diseases, which are significantly associated with worse outcomes. Moreover, COVID-19 itself is allied with deteriorating hyperglycemia. Therefore, Bangladesh Endocrine Society has formulated some practical recommendations for management of diabetes and other endocrine diseases in patients with COVID-19 for use in both primary and specialist care settings. Objective: The objective of the article is to develop a guideline to protect the vulnerable group with utmost preference-the elderly and those with comorbid conditions. Therefore, to ensure the adequate protective measures and timely treatment for COVID-19 patients with diabetes, other endocrine diseases or any other comorbidities. Considering and Monitoring Issues: • The risk of a fatal outcome from COVID-19 may be up to 50% higher in patients with diabetes than in non-diabetics. • Patients with diabetes and COVID had CFR 7.3-9.2%, compared with 0.9-1.4% in patients without comorbidities. • Diabetic ketoacidosis may be one of the causes of mortality in COVID-19. • There is wide fluctuation of blood glucose in these patients, probably due to irregular diet, reduced exercise, increased glucocorticoids secretion, and use of glucocorticoids. • HbA1c should be <7.0% for the majority of the patients, this target may be relaxed in appropriate clinical settings. • More emphasis should be given on day-today blood glucose levels. Hypoglycemia (<3.9 mmol/l) must be avoided. • Frequent monitoring of blood glucose is needed in critically ill patients. Conclusion: The fight against COVID-19 has been proven to be a challenging one. Therefore, all healthcare personnel should make the best use of updated knowledge and skills to ensure adequate protective measures and timely treatment for COVID-19 patients with diabetes, other endocrine diseases or any other comorbidities.

- by Shahjada Selim
- •
- Diabetes and Insulin Resistance, Type 2 Diabetes Mellitus, Diabesity

Background: this study set out to examine the effects of the treatment with 1,25dihydroxyvitamin D 3 (1,25D 3 ) [150 IU/Kg (3.75 μg/Kg) one a day, for 15 days] to non-diabetic rats and in rats rendered diabetic by a single injection of... more

- by Consuelo Calle
- •
- Genomics, Diabetes, Vitamin D, Gene expression

The diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) isolated from the leaves of
Calophyllum inophyllum was investigated for the metabolic effect on glucose transport in skeletal muscle
cells. In L6 myotubes, F015 dose-dependently stimulated glucose uptake by increasing translocation of
glucose transporter4 (GLUT4) to plasma membrane without affecting their gene expression. The effects
on glucose uptake were additive to insulin. Inhibitors analyses revealed that F015-induced glucose
uptake was dependent on the activation of phosphatidylinositol-3-kinase (PI-3-K) and extracellular signal-
regulated kinases 1 and 2 (ERK1/2), while independent to the activation of 50AMP-activated kinase
(AMPK). F015 significantly increased the phosphorylation of AKT, AS160 and ERK1/2, account for the augmented
glucose transport capacity in L6 myotubes. Furthermore, F015 improved glucose tolerance and
enhanced insulin sensitivity in skeletal muscle of dexamethasone-induced insulin resistant mice. Our
findings demonstrate that F015 activates glucose uptake in skeletal muscle cells through PI-3-K- and
EKR1/2-dependent mechanisms and can be a potential lead for the management of diabetes and obesity.

Diethyl hexyl phthalate (DEHP) is a plasticizer, commonly used in a variety of products, including lubricants, perfumes, hairsprays and cosmetics, construction materials, wood finishers, adhesives, floorings and paints. DEHP is an endocrine disruptor and it has a continuum of influence on various organ systems in human beings and experimental animals. However, specific effects of DEHP on insulin signaling in adipose tissue are not known. Adult male albino rats of Wistar strain were divided into four groups. Control, DEHP treated (dissolved in olive oil at a dose of 10, and 100 mg/kg body weight, respectively, once daily through gastric intubations for 30 days) and DEHP þ vitamin E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubations for 30 days. After the completion of treatment, adipose tissue was dissected out to assess various parameters. DEHP treatment escalated H 2 O 2 and hydroxyl radical levels as well as lipid peroxidation in the adipose tissue. DEHP impaired the expression of insulin signaling molecules and their phosphorelay pathways leading to diminish plasma membrane GLUT4 level and thus decreased glucose uptake and oxidation. Blood glucose level was elevated as a result of these changes. Supplementation of vitamins (C & E) prevented the DEHPinduced changes. It is concluded that DEHP-induced ROS and lipid peroxidation disrupts the insulin signal transduction in adipose tissue and favors glucose intolerance. Antioxidant vitamins have a protective role against the adverse effect of DEHP.

- by Rajesh Parsanathan
- •
- Environmental Toxicology, Toxicology, Cell Signaling, Insulin Resistance
- by Samuel Acquah
- •
- Metabolic syndrome, Insulin Resistance, Diabetes research, Malaria Research

The study aimed at investigating the effects of adult uncomplicated malaria on insulin resistance. Fasting levels of blood glucose (FBG), glycosylated hemoglobin (HbA1c), and serum insulin were measured in 100 diabetics and 100 age-matched controls before and during Plasmodium falciparum malaria. Insulin resistance and beta cell function were computed by homeostatic models assessment of insulin resistance (HOMAIR) and beta cell function (HOMAB) formulae, respectively. Body mass index (BMI) was computed. At baseline, diabetics had significantly (í µí± < 0.05) higher levels of BMI, FBG, HbA1c, and HOMAIR but lower level of HOMAB than controls. Baseline insulin levels were comparable (í µí± > 0.05) between the two study groups. During malaria, diabetics maintained significantly (í µí± < 0.05) higher levels of BMI, FBG, and HbA1c but lower levels of insulin and HOMAB than controls. Malaria-induced HOMAIR levels were comparable (í µí± > 0.05) between the two study groups but higher than baseline levels. Apart from BMI and HOMAB, mean levels of all the remaining parameters increased in malaria-infected controls. In malaria-infected diabetics, significant (í µí± < 0.05) increase was only observed for insulin and HOMAIR but not the other measured parameters. Uncomplicated malaria increased insulin resistance in diabetics and controls independent of BMI. This finding may have implications for the evolution of T2DM in malaria-endemic regions.

Aberrant Wnt signaling appears to play an important role
in the onset of diabetes. Moreover, the insulin signaling
pathway is defective in the nucleus tractus solitarii (NTS)
of spontaneously hypertensive rats (SHRs) and fructosefed
rats. Nevertheless, the relationships between Wnt
signaling and the insulin pathway and the related modulation
of blood pressure (BP) in the central nervous system
have yet to be established. The aim of this study
was to investigate the potential signaling pathways
involved in Wnt-mediated BP regulation in the NTS. Pretreatment
with the LDL receptor–related protein (LRP) antagonist
Dickkopf-1 (DKK1) significantly attenuated the
Wnt3a-induced depressor effect and nitric oxide production.
Additionally, the inhibition of LRP6 activity using DKK1
significantly abolished Wnt3a-induced glycogen synthase
kinase 3b (GSK-3b)S9, extracellular signal–regulated
kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363,
and AktS473 phosphorylation; and increased insulin receptor
substrate 1 (IRS1)S332 phosphorylation. GSK-3b was
also found to bind directly to IRS1 and to induce the phosphorylation
of IRS1 at serine 332 in the NTS. By contrast,
administration of the GSK-3b inhibitor TWS119 into the
brain decreased the BP of hypertensive rats by enhancing
IRS1 activity. Taken together, these results suggest that
the GSK-3b-IRS1 pathway may play a significant role in
Wnt-mediated central BP regulation.

- by Wen-Han Cheng
- •
- Hypertension, Wnt Signaling, Diabetes and Insulin Resistance

Abstract:
During the last years, the list of resveratrol effects has grown in parallel with the number of other members of the polyphenol family described to modulate glucose or lipid handling. In the same time, more than ten human studies on the influence of resveratrol supplementation on two related metabolic diseases, obesity and diabetes, have indicated that impressive beneficial effects co-exist with lack of demonstration of clinical relevance, irrespective of the daily dose ingested (0.075 to 1.5 g per capita) or the number of studied patients. Such contrasting observations have been proposed to depend on the degree of insulin resistance of the patients incorporated in the study. To date, no definitive conclusion can be drawn on the antidiabetic or antiobesity benefits of resveratrol. On the opposite, studies on animal models of diabesity consistently indicated that resveratrol impairs diverse insulin actions in adipocytes, blunting glucose transport, lipogenesis and adipogenesis. Since resveratrol also favours lipolysis and limits the production of proinflammatory adipokines, its administration in rodents results in limitation of fat deposition, activation of hexose uptake into muscle, improvement of insulin sensitivity, and facilitation of glucose disposal. Facing to a somewhat disappointing extrapolation to man of these promising antidiabetic and antiobesity properties, attention must be paid to re-examine resveratrol targets, especially those attainable after polyphenol ingestion and to re-define the responses to low doses. In this context, human adipocytes are proposed as a convenient model for the screening of "novel" polyphenols that can reproduce, outclass, or reinforce resveratrol metabolic actions, Moreover, the use of combination of polyphenols is proposed to treat diabesity complications in view of recently reported synergisms. Lastly, multidisciplinar approaches are recommended for future investigations, considering the wide range of polyphenol actions that induce body fat reduction, liver disease mitigation, muscle function improvement, cardiovascular and renal protection.

World-wide epidemic, diabetes has ben found to be increased 100% in a decade according to the results of Turkish Diabetes Epidemiology Study (TURDEP I and II). Southeastern Anatolia Diabetes Project (GAPDIAB) even though may help raise the awareness and increase the standarts of healthcare for those who are in need of, efforts still remain way behind the targets. Majority of people with type 2 diabetes have insülin resistance. Even in case of lack of diabetes, insülin resistance lead to cardiovascular problems. The treatment modality of diabetes should be chosen from anti-glycaemic agents which are effective for insülin resistance, and anti-hypertensive medications which are at least metabolically neutral or non-diabetogen blood pressure lowering drugs. Elegant agents are angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor- 1 blockers (ARB), indapamide and spironolactone from diuretics, carvedilol, nebivolol, bisoprolol from beta-blockers. Use of the non-dihyd...

Diabetes is a condition in which blood glucose (sugar) levels are abnormally high. It is caused by the glucose's inability to enter your cells. As a result, your cells are in need of nourishment (glucose).
It would be like a famished person being surrounded by tables of delicious food but unable to eat because their mouth has been stitched shut. Diabetes was once considered a rare disease in both developed and developing countries. Today's narrative is a little different.
It is estimated that about 150 million people are impacted by the condition worldwide. This number is steadily rising; by 2025, more than 250 million individuals will have diabetes if current trends continue.

Diabetes mellitus is a metabolic disorder with a source of associated microvascular and macrovascular complications with it. Globally, 463 million people are living with diabetes, out of that 88 million people are from Southeast Asian regions. Diabetes also affects nearly 8.9% adult population in India. As insulin resistance is a feature of type-2 diabetes mellitus, hence, the present study was undertaken to identify the markers of insulin resistance among type 2 diabetes mellitus north Indian patients. Data were collected from 120 participants from the period of November, 2019 to March 2020 at a tertiary care teaching hospital. Inclusion criteria were patients aged 18-60 years and diagnosed with T2 DM on insulin therapy. Tools used for the data collection were subject datasheets that included demographic variables and clinical variables, biophysiological measures, Pittsburgh Sleep Quality Index (PSQI), and Patient health questionnaire-9 (PHQ-9). Results shows that 72 (60%) patients were male and 66 (55%) patients were from an urban background with a mean age of 46.8± 9 yrs. Body mass index (p-value 0.00), Body fat % (p-value 0.00) Fasting C-peptide (p value 0.00), followed by duration of diabetes (p value 0.03), systolic blood pressure (p value 0.019), cholesterol (p value 0.031) and diastolic blood pressure (p value 0.044) had significant association with insulin resistance among T2DM patients. Depression (p value 0.04) and sleep quality (p value 0.02) also had significant association with insulin resistance among T2DM patients. In resource-limited countries, body mass index and body fat% can be utilized as predictable non-invasive markers of insulin resistance.

- by Rajesh Kumar
- •
- Diabetes and Insulin Resistance

A B S T R A C T High calorie diet promotes oxidative stress and chronic low grade inflammation that predispose to brain dysfunction and neurodegeneration. Hippocampus region of the brain has been shown to be particularly sensitive to high calorie diet. We hypothesize that apigenin (API), a flavonoid could attenuate hippocampal derangements induced by high fat-high fructose diet (HFFD). In this study, we investigated the effects of API on oxidative stress and inflammation in the hippocampus, and compared with those of sitagliptin (STG), a standard drug with neuroprotective properties. The markers of oxidative stress and inflammation were examined using biochemical assays, western blotting and immunohistochemistry techniques. HFFD-fed rats showed severe pathological alterations and API treatment rescued the hippocampus from the derangements. API significantly improved the antioxidant machinery, reduced ROS levels and prevented the activation of the stress kinases, inhibitor of kappa B kinase beta (IKKb) and c-Jun NH2 terminal kinase (JNK), and the nuclear translocation and activation of nuclear factor kappa B (NF-kB). The plasma levels of inflammatory cytokines were also reduced. Our findings suggest that hippocampal derangements triggered by HFFD feeding were effectively curtailed by API. Suppression of oxidative stress, NF-kB activation and JNK phosphorylation in the hippocampus are the mechanisms by which API offers neuroprotection in this model.

- by Jagan Kalivarathan
- •
- Neuroscience, Nutrition and Dietetics, Neuropharmacology, Inflammation

A un anno dalla scomparsa, Maria Paola piange e ricorda la sua dolcissima, adorata, impareggiabile mamma Wanda Muciaccia Zanoboni (28 maggio 1938-31 agosto 2018), endocrinologa e pediatra, distintasi a livello internazionale, insieme a papà Alberto Zanoboni (10 ottobre 1924-23 febbraio 1993), per gli studi pionieristici sull'epifisi, sull'ormone della crescita, sulla sulpiride, sulla prolattina, sull' L-Dopa, sull'insulina e sul diabete, sulla relazione tra cirrosi e cancro.Le loro ricerche vennero riconosciute a livello internazionale con la borsa di studio e l'esperienza di lavoro a Cleveland [Ohio] (1964/65), e a Losanna (1968), dal congresso di Melbourne (febbraio 1980), oltre che da numerosissimi altri simposi nazionali e internazionali. Le pubblicazioni dei loro studi basati su centinaia di esperienze di laboratorio, apparsi su Lancet, Journal Clinical Endocrinology, Acta Endocrinologica, Acta Diabetologica Latina (e molte altre), tra la seconda metà degli anni '60 e la fine degli anni '80, sono ancora di fondamentale importanza per chi si occuapa di endocrinologia e di diabetologia Gli elenchi e gli abstracts di numerose tra le loro pubblicazioni sono rintracciabili ai siti: https://www.researchgate.net/scientific-contributions/38611776_W_Zanoboni-Muciaccia

- by maria paola zanoboni
- •
- Pharmacology, Endocrinology, Neuropsychology, Diabetology

Inflammation triggers cellular stress which induces secretion of inflammatory mediators.Mechanisms of cellular stress triggers cellular senescence that suppresses physiological funcitons of cells. A type of antagonism occurs among tumor suppressor genes and oncogenes.Tumor supressor genes related factors, suppress oncogenes related factors in generally. Increased cell stress causes stimulation of tumor suppressor factors by inflammatory cytokines and reactive oxygene species(ROS).In chronic inflammatory environment, stimulation by excessive cytokines lead to cellular senescence. Tissue disfunctions which are triggered by cellular senescence, cause suppression of metabolic pathways for some glucose and lipid derived metabolites. Accumulated metabolites in extracellular matrix or plasma, oxidized metabolites stimulate several types of Toll Like Receptors(TLRs) which stimulate NfkB dependent cellular stress this causes more accelarated cellular senescence.This physiopathology may trigger Insulin resistance,diabetes and atherosclerosis, and other senescence related diseases like osteoarthrits. Sirtuin(SIRT) agonists can suppress NfkB dependent cellular stress. Suppressing of NfkB by SIRT may decrease inflammatory cytokine production which leads to decreasing of cellular senescence.Thus,SIRT agonists may help protection of tissue and organ functions. SIRT agonists maybe a new therapeautic target for combined therapy of Insulin resistance-Type 2 diabetes mellitus and atherosclerosis.

The physical, chemical, conformational, and energetic properties of amino acid residues in turn alter the physiological properties of the activating protein molecules. The sequence comparison of insulin chain A and chain B of Camelus dromedaries was compared to Homo sapiens. Although the sequences differed only in four amino acids but their physico-chemical properties stretched apart. Camel milk insulin had large mutable affinity for alanine which in turn is responsible for –i. High thermo-stability ii. High aliphatic index and iii. High hydropathicity. Due to this altered behavior of insulin molecule in camel, it does not forms coagulum and is resistant to proteolysis during digestion. In gut part this indigestible insulin peptide enters circulatory system and regulates glycemic loads in diabetic patients.

- by asha arora and +1
- •
- Molecular Biology, Camel Milk, Diabetes and Insulin Resistance

Citation: Ginneken V, Verheij E, de Vries E, et al. The discovery of two novel biomarkers in a high-fat diet C56bl6 obese model for non-adipose tissue: A comprehensive lcms study at hind limb, heart, carcass muscle, liver, brain, blood plasma and food composition following a lipidomics lcms-based approach. Cell Mol Med 2016, 2:3. Abstract Aim/Objective: This study was designed to find via a high-fat (HF) diet induced insulin resistant (IR) and/or type-2 diabetes (T2DM) C57Bl/6 mouse model potential novel biomarkers. Major aiming is to find following this lipidomics based approach novel safe biomarkers applicable for humans with IR/T2DM that can be used in the assessment of diagnosis, intensive treatment, clinical use and new drug development. In addition, the biomarker has to be found in blood-plasma simultaneously while is not a component of the HF-diet. Methods: Reversed phase liquid chromatography coupled to mass spectrometry (LC-MS) were used to quantify and qualify the rearrangement and repartitioning of fat stores in the heart-, hind limb-, carcass-muscle, liver, brain, and blood plasma of this mice model following a systems biology lipidomics based approach. Results: Two potential biomarkers were found for this HF-diet mouse model. The first biomarker was a 20:3 cholesteryl-ester (20:3-ChE) which significantly increased (P ≤ 0.016) in the fatty heart with 1317% while it rose very significantly (P ≤ 0.00001) in blood plasma with 1013% in the HF diet group in comparison to the control-group. (Co). The second biomarker was a 36:1 phosphatidylcholine (36:1-PC), which rose significantly (P ≤ 0.025) mainly in heart muscle with 400% while concentrations increased significantly strongly (P ≤ 0.002) in blood plasma with 1493% in the high-fat diet vs. Co. As an earlier defined prerequisite, both compounds were not found in the food. Conclusion: The 20:3-ChE biomarker (dihomo-γ-linolenic; 20:3 n-6) has been classified as a potential type 2 diabetes biomarker (T2DM) biomarker in a human cohort of the uppsala longitudinal study of adult men (ULSAM). In addition, we give a biochemical explanation for the 36:1-PC as hypoxic biomarker for cardiovascular diseases (CVD) diagnosis and therapy. Both biomarkers are interesting candidates for further validation in human cohorts.

- by Vincent van Ginneken
- •
- Obesity, Systems Biology, Metabolomics, Cardiovascular disease

This study was designed to explore the possible existence and location of estrogen response elements (EREs) in the human insulin receptor (hIR) gene promoter. Transfections of U-937 cells with the reported plasmids phIR(−1819)-GL2, phIR(−1473)-GL2, and phIR(−876)-GL2, that contain the −1819 to −271 bp fragment of the hIR promoter (wild-type promoter) and progressive 5 deletions of this promoter, revealed that while the activity of the wild-type promoter, was repressed 36% by treatment with 17␤-estradiol (E 2 ), the activities of progressive 5 deletions of this promoter were reduced by 26% and by 0%, by this hormone. This suggests that E 2 needs the wild-type promoter for full transcriptional repression of this gene and it also suggests the presence of putative EREs in the region between −1819/−877 bp of this promoter. To identify these EREs we performed a computer search, using the SEQFIND programme developed in our laboratory, by homology with the consensus vit-ERE (5 GGTCAnnnTGACC3 ) of the Xenopus vitellogenin A 2 gene promoter. The results of our search indicated no sequence identical to this consensus ERE, and neither was any sequence found to show 9 or 8 of the 10 bases of this consensus in this promoter. Nevertheless, a putative hIR ERE1 (5 AGTGAaacTGGCC3 ) showing 7 bases of the consensus vit-ERE, and 10 bases of the optimal binding sequence ERE (5 CA/GGGTCAnnnTGACCT/CG3 ), was identified between −1430/−1418 bp of the hIR promoter. An AP-1-like site was covering the 3 half-element of this ERE; another AP-1-like site was overlapping the first AP-1-like site, and finally a third AP-1-like site was located beside to the 5 half-element. In addition, another putative hIR ERE2 (5 GCTCCtagCAAAC3 ) showing 5 bases of the consensus vit-ERE, and 9 bases of the optimal binding sequence ERE, was located upstream of the hIR promoter, between −1567/−1555 bp. An AP-1-like site was located downstream of the 3 half-element of this ERE, and another AP-1-like site was beside the 5 half-element. EMSA analysis using nuclear extracts of E 2 -treated cells and natural sequences, including these putative EREs, indicated that ER␤ -the only isoform expressed in U-937 cells -specifically recognized both EREs because ER␤-DNA complexes were efficiently competed by the corresponding unlabelled probe and supershifted by the anti-human ER␤ (L-20) antibody. These data provide the first identification of EREs complexed with AP-1-like sites in the hIR promoter, which account for the transcriptional repression of the hIR gene mediated by ER␤ in U-937 cells.

- by Consuelo Calle
- •
- Diabetes, Transcription Regulation, Estrogen Receptor, Insulin Resistance

Diabetic peripheral neuropathy is the most common complica¬tion of long-standing diabetes mellitus. The objective of this study was to investigate the fatty acids composition abnormalities of sciatic nerve in streptozotocin (STZ)-induced diabetic neuropathy (DNP) in male rats. Six groups of 20 rats were studied. Group I (control group): received no drugs, Group II (diabetic group) A single dose of streptozotocin (STZ) (50mg/kg i.p.) was used for the induction of diabetes in rats, Group III (normal α-Lipoic acid-treated group), Group IV (diabetic alpha-Lipoic acid -treated group), Group V (diabetic insulin- treated group), Group VI (diabetic alpha-Lipoic acid and insulin-treated group). Eight weeks after diabetes induction therapeutic treatment with alpha-lipoic acid (54 mg/kg body weight i.p daily) and insulin (2U s.c daily) were given either alone or in combination and continued for six weeks. Equivalent volumes of saline were given subcutaneously to the rats in the other diabetic and non diabetic control groups. Blood samples and sciatic nerve tissues were collected from all animal groups two times at 4 and 6 weeks from the onset of treatment which begin after eight weeks of diabetic neuropathy (DNP) induction for determination of serum glucose and sciatic nerve triacylglycerols, non esterified fatty acids (NEFA) and membrane fatty acids composition of sciatic nerve. The obtained results revealed that, a significant increase in serum glucose and sciatic nerve NEFA concentrations with marked decrease in triacylglycerols and fatty acids composition percentage including palmitic acid, palmitoleic acid, oleic acid and arachidic acid were observed in sciatic nerve of STZ-induced DNP in rats. Administration of α -lipoic acid with insulin significantly lowered serum glucose and sciatic nerve NEFA concentrations as well as several fatty acids contents including myristic, palmitic, palmitoleic, oleic, cis-vaccenic, linoleic, alpha linolenic, arachidic, and godoleic acid with increase in margaric, stearic, and eicosadienoic acid percentage in addition to triacylglycerols level in sciatic nerve. The results suggest that, treatment with α-lipoic acid combined with insulin administrations could ameliorate the altered myelin of sciatic nerve lipids induced by diabetes and attenuate the changed fatty acid composition membrane in sciatic nerve and improved the metabolic control of diabetic neuropathy. The results indicated that the beneficial effect of α- lipoic acid treatment in diabetic neuropathy.

Objective:The objective of the present study was to investigate the
insulin sensitizing effect of Scoparia dulcis(L) leave extract (SDE)
against free fatty acid (FFA) induced insulin resistance in an in vitro
L6 myotubes.
Materials and Methods: The rat L6 skeletal muscle cells were
differentiated to myotubes by treating it with DMEMcontaining 2%
horse serum for 12h. For generating an in vitro cellular model of
insulin resistant condition, L6 myotubes were treated with FFA
(palmitate) for 4h. Insulin resistant L6 myotubes were either pre- or
post treated for 1h with SDE and its insulin sensitivity activity was
assessed by measuring cellular glucose uptake and the activation
status of insulin signalling pathway molecules.
Results: SDE significantly stimulated glucose uptake in L6
myotubes in a dose-dependent manner with maximal effect at
50µg/ml. To investigate the underlying mechanism ofeffect SDE, we
examined the expression and activity of insulin signalling pathway
molecules. We found that the SDE treatment notably increased
insulin signalling pathway by inducing activatory phosphorylation
status of IRS-1 and Akt without altering expression levels of these
proteins. The comparative analysis revealed that SDE is more potent
than known insulin sensitizer, pioglitazone.
Conclusion:These results suggest that induction of insulin signalling
pathway and increased glucose uptake activity of SDE will aid in the
treatment of insulin resistance and type 2 diabetes. Future studies on
the isolation of bioactive components and a detailed investigation in
the animal model of insulin resistance may be promising to find out a
novel type 2 diabetes drug.

Intraeellular triglyceride (TG) is an important energy source for skeletal muscle. However, recent evidence suggests that if muscle contains abnormally high TG stores its sensitivity to insulin may be reduced, and this Could predispose to type II diabetes. To test this hypothesis, we measured muscle lipid content in 27 women aged 47 to 55 years (mean, 52) and related it to thei r glucose tolerance, insulin resistance, and muscle insulin sensitivity as measured by insulin activation of glycogen synthase, an insulin-regulated enzyme that is rate-limiting for insulin action in muscle. Both muscle TG content and intracellular lipid determined by Oil red O staining of muscle fibers were negatively associated with glycogen synthase activation (r = .43, P = .03 and r = -.47, P = .02, respectively). In addition, intracellular lipid correlated with features of the insulin resistance syndrome, including an increaSed waist to hip ratio (r = .47, P = .01) and fasting nonesterified fatty acids ([NEFA] r = .44, P = .04). These data demonstrate that increased muscle TG stores are associated with decreased insulin-stimulated glycogen synthase activity. Intracellular fat may underlie a major part of the insulin resistance in normal subjects, as well as type II diabetics.

- by Andy Borthwick
- •
- Diabetes and Insulin Resistance