Category Archives: Diabetes

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study.

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 molecules-logo“Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32138197

https://www.mdpi.com/1420-3049/25/5/1119

Cannabidiol protects against high glucose-induced oxidative stress and cytotoxicity in cardiac voltage-gated sodium channels.

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Publication cover image“Cardiovascular complications are the major cause of mortality in diabetic patients. However, the molecular mechanisms underlying diabetes-associated arrhythmias are unclear.

We hypothesized that high glucose, could adversely affect Nav1.5, the major cardiac sodium channel isoform of the heart, at least partially via oxidative stress.

We further hypothesized that cannabidiol (CBD), one of the main constituents of Cannabis sativa, through its effects on Nav1.5, could protect against high glucose elicited oxidative stress and cytotoxicity.

KEY RESULTS:

High glucose evoked cell death associated with elevation in reactive oxygen species, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. CBD mitigated all the deleterious effects provoked by high glucose. Perfusion with Lidocaine (a well-known sodium channels inhibitor with anti-oxidant effects), or co-incubation of Tempol (a well-known anti-oxidant) elicited protection, comparable to CBD, against the deleterious effects of high glucose.

CONCLUSIONS AND IMPLICATIONS:

These findings suggest that, through its favourable anti-oxidant and sodium channel inhibitory effects, CBD may protect against high-glucose induced arrhythmia and cytotoxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/32077098

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15020

Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

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Biochemical Pharmacology“The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes.

In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on the viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes.

We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in their combination promote their maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs.

Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy.”

https://www.ncbi.nlm.nih.gov/pubmed/32061773

“The promiscuous pharmacology of phytocannabinoids makes them viable candidates for new medicines for the treatment of metabolic syndromes through the simultaneous resolution of collective complications due to impaired development, maintenance, activity and function of the adipose tissue. Furthermore, phytocannabinoids are generally well tolerated in comparison to potent synthetic PPAR agonists, and combination treatments may further improve their efficacy at lower doses.”

https://www.sciencedirect.com/science/article/pii/S0006295220300873?via%3Dihub

Insulinotropic and antidiabetic effects of β-caryophyllene with l-arginine in type 2 diabetic rats.

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Journal of Food Biochemistry banner“Beta-caryophyllene (BCP) is a flavoring agent, whereas l-arginine (LA) is used as a food supplement.

They possess insulinotropic and β cell regeneration activities, respectively.

We assessed the antidiabetic potential of BCP, LA, and its combination in RIN-5F cell lines and diabetic rats.

The results indicated that the combination of BCP with LA showed a significant decrease in glucose absorption and an increase in its uptake in tissues and also an increase in insulin secretion in RIN-5F cells. The combination treatment of BCP with LA showed a significant reduction in glucose, lipid levels, and oxidative stress in pancreatic tissue when compared with the diabetic group. Furthermore, the combination of BCP with LA normalized glucose tolerance and pancreatic cell damage in diabetic rats.

In conclusion, the combinational treatment showed significant potentials in the treatment of type 2 diabetes mellitus.

PRACTICAL APPLICATIONS:

Type 2 diabetes mellitus is the most prevalent chronic metabolic disorder affecting a large population.

Beta-caryophyllene is a CB2 receptor agonist shown to have insulinotropic activity.

l-Arginine is a food supplement that possesses beta-cell regeneration property.

The combination of BCP with LA could work as a potential therapeutic intervention, considering the individual pharmacological activities of each.

We evaluated the antidiabetic activity of the combination of BCP with LA in diabetic rats using ex vivo and in vitro experimentations.

Results from the study revealed that the combination of BCP with LA showed a significant (p < .001) reduction in glucose and lipid levels as compared to individual treatment. In vitro study also supports the diabetic potential of the combination of BCP with LA in the glucose-induced insulin secretion in RIN-5F cell lines.

The study indicates a therapeutic approach to treat T2DM by BCP and LA combination as food and dietary supplement.”

https://www.ncbi.nlm.nih.gov/pubmed/31997410

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.13156

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Involvement of endocannabinoid system, inflammation and apoptosis in diabetes induced liver injury: Role of 5-HT3 receptor antagonist.

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International Immunopharmacology“Confident relationships between diabetes and liver damage have previously been established.

This study was designed to evaluate hepaticinflammation, apoptosis, and endocannabinoid system alterations in diabetes with or without tropisetron treatment.

These findings strongly support the idea that diabetes-induced liver abnormality is mediated by inflammatory reactions, apoptosis, and endocannabinoid system, and that these effects can be alleviated by using tropisetron as an antioxidant and anti-inflammatory agent.”

https://www.ncbi.nlm.nih.gov/pubmed/31926479

https://www.sciencedirect.com/science/article/pii/S1567576919322684?via%3Dihub

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases.

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 ijms-logo“Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/31771129

https://www.mdpi.com/1422-0067/20/23/5875

The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus.

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 “The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease.

RECENT FINDINGS:

As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.”

https://www.ncbi.nlm.nih.gov/pubmed/31686231

https://link.springer.com/article/10.1007%2Fs11892-019-1248-9

Cannabidiol improves metabolic dysfunction in middle-aged diabetic rats submitted to a chronic cerebral hypoperfusion.

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Chemico-Biological Interactions“Cannabidiol (CBD), a compound obtained from Cannabis sativa, has wide range of therapeutic properties, including mitigation of diabetes and neurodegeneration.

Cerebral ischemia and consequent learning disabilities are aggravated in elderly diabetic subjects. However, there are no studies showing the effect of CBD treatment in elderly diabetes patients suffering cerebral ischemia.

The present work tested the hypothesis that CBD treatment improves metabolic dysfunctions in middle-aged diabetic rats submitted to chronic cerebral hypoperfusion.

CBD may be used as therapeutic tool to protect metabolism against injuries from diabetes aggravated by cerebral ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/31499052

“CBD reduced hyperglycemia of middle-aged diabetic rats with CCH. CBD increased insulin secretion and decreased AGEs levels. CBD reduced fructosamine, LDL, HDL, triglycerides and total cholesterol levels. CBD presented hepatoprotective effect. CBD could mitigate neurodegeneration caused by DM associated to cerebral ischemia.”

https://www.sciencedirect.com/science/article/abs/pii/S000927971930701X?via%3Dihub

Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications.

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European Journal of Pharmacology“The biological effects of endocannabinoid system are mediated by two types of receptors, cannabinoid 1 (CB1) and cannabinoid 2 receptor (CB2). They play a pivotal role in the management of pain, inflammation, cancer, obesity and diabetes mellitus.

CB2 receptor activity downregulation is hallmark of inflammation and oxidative stress. Strong evidence display the relation between activation of CB2 receptors with decrease in the pro-inflammatory cytokines and pro-apoptotic factors. Numerous in vitro and in vivo studies have been validated to confirm the role of CB2 receptor in the management of obesity, hyperlipidemia and diabetes mellitus by regulating glucose and lipid metabolism.

Activation of CB2 receptor has led to reduction of inflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6), Nuclear factor kappa beta (NF-κβ) and also amelioration of reactive oxygen species and reactive nitrogen species playing role in apoptosis. Many studies confirmed the role of CB2 receptors in the insulin secretion via facilitating calcium entry into the pancreatic β-cells. CB2 receptors also displayed improvement in the neuronal and renal functions by decreasing the oxidative stress and downregulating inflammatory cascade.

The present review addresses, potential role of CB2 receptor activation in management of diabetes and its complications. It also includes the role of CB2 receptors as an anti-oxidant, anti-apoptotic and anti-inflammatory for the treatment of DM and its complications. Also, an informative summary of CB2 receptor agonist drugs is provided with their potential role in the reduction of glucose levels, increment in the insulin levels, decrease in the hyperglycaemic oxidative stress and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31461639

https://www.sciencedirect.com/science/article/pii/S0014299919305801?via%3Dihub

Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults.

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Journal of Diabetes banner“Obese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuanause with markers of IR have yielded mixed results.

The aim of this study was to examine the association of marijuana use with IR in US adults with different body mass index (BMI) status.

RESULTS:

Of all 129 509 adults aged 18 to 59 years, 50.3% were women. In current obese marijuana consumers, mean FINS in those with less than four uses per month was 52% (95% confidence interval [CI] 19%-71%) lower than in never users. In former obese consumers with eight or more uses per month and who stopped marijuana use <12 months ago, mean FINS was 47% (95% CI 18%-66%) lower than in never users. Mean FINS in those who quit marijuana 12 to 119 and 120 months and more prior the survey was 36% (95% CI 7%-57%) and 36% (95% CI 10%-54%) lower, respectively.

CONCLUSIONS:

Marijuana use is associated with lower FINS and HOMA-IR in obese but not non-obese adults, even at low frequency of less than four uses per month. Former marijuana consumers with high lifetime use had significantly lower FINS levels that persisted, independent of the duration of time since last use.”

https://www.ncbi.nlm.nih.gov/pubmed/31152633

https://onlinelibrary.wiley.com/doi/abs/10.1111/1753-0407.12958

“Cannabis linked to lower insulin levels in adults at risk of type 2 diabetes”   https://www.diabetes.co.uk/News/2019/Jul/cannabis-linked-to-lower-insulin-levels-in-adults-at-risk-of-type-2-diabetes-99514193.html