Diabetes Studies

The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults

Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], −26, −6) and 17% lower HOMA-IR (95% CI, −27, −6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response.
Elizabeth A. Penner, MD, MPH,a,b Hannah Buettner, BA,c Murray A. Mittleman, MD, DrPHb,c
a University of Nebraska College of Medicine, Omaha; b Department of Epidemiology, Harvard School of Public Health, Boston, Mass; c Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass. The American Journal of Medicine
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Volume 126, Issue 7, Pages 583–589, July 2013 DOI: http://dx.doi.org/10.1016/j.amjmed.2013.03.002
 


Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.
 
J Am Coll Cardiol. 2010 Dec 14 ;56(25):2115-25. doi: 10.1016/j.jacc.2010.07.033.
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.

Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes.

Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase. In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration. Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme-linked immunosorbent assay, immunohistochemistry, and/or Western blot. CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina. Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase.
El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai N-T, Caldwell RB, Liou GI. Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes. The American Journal of Pathology 2006;168(1):235-244. doi:  10.2353/ajpath.2006.050500 

Cannabidiol arrests onset of autoimmune diabetes in NOD mice.

CBD was administered i.p. to 11–14 week old female NOD mice. Treatment was continued for 4 weeks (5 days a week) at a dose of 5 mg/kg/day. Treatment was then withdrawn and the mice were observed until 24 weeks of age. A remarkable reduction of diabetes development was observed in CBD-treated mice, compared with vehicle-treated mice and untreated controls (p<0.001, log rank test). At the end of the 24 weeks, only 8 of 25 (32%) of the CBD-treated mice developed glucosuria, compared with 18 of 21 (86%) vehicle-treated mice and 100% (21 mice) of the untreated controls (Fig 1).
 
Weiss L, Zeira M, Reich S, et al. Cannabidiol Arrests Onset of Autoimmune Diabetes in NOD Mice. Neuropharmacology 2008;54(1):244-249. doi:10.1016/j.neuropharm.2007.06.029.
 


Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation.

The best-known cannabinoids from marijuana are (-)-Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), and (-)-cannabidiol (CBD) (Figure (Figure11)[66]. THC, but not CBN or CBD, is known to exert psychotropic effects[67,68]. Cannabinoids are also known to be therapeutic with properties of anti-inflammation[69,70] and anti-oxidation[71]. Cannabinoids produce their biological effects by acting through at least two receptors. Receptor CB1 (cloned) is responsible for psychoactivity and is expressed in the brain[72] and retinal neurons[73,74]. Receptor CB2 (cloned) is expressed in immune cells[75] and cerebral microglial cells[76], but also in the retina[77]. These receptors are coupled to Gi/o proteins to inhibit adenylyl cyclase activity and immediate early gene signaling pathway(s)[78]. Receptor CB1 is also coupled through Gi/o proteins to inhibit voltage-sensitive calcium channels[79] and activate potassium channels[80].
Liou GI. Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation. World Journal of Diabetes 2010;1(1):12-18. doi:10.4239/wjd.v1.i1.12.

The endocannabinoid system in obesity and type 2 diabetes.

Endocannabinoids (ECs) are defined as endogenous agonists of cannabinoid receptors type 1 and 2 (CB1 and CB2). ECs, EC anabolic and catabolic enzymes and cannabinoid receptors constitute the EC signalling system. This system participates in the control of lipid and glucose metabolism at several levels, with the possible endpoint of the accumulation of energy as fat. Following unbalanced energy intake, however, the EC system becomes dysregulated, and in most cases overactive, in several organs participating in energy homeostasis, particularly, in intra-abdominal adipose tissue. This dysregulation might contribute to excessive visceral fat accumulation and reduced adiponectin release from this tissue, and to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes. This phenomenon might form the basis of the mechanism of action of CB1 antagonists/inverse agonists, recently developed by several pharmaceutical companies as adjuvants to lifestyle modification for weight reduction, glycaemic control and dyslipidaemia in obese and type 2 diabetes patients. It also helps to explain why some of the beneficial actions of these new therapeutics appear to be partly independent from weight loss.
 
The endocannabinoid system in obesity and type 2 diabetes.  Di Marzo V.
Diabetologia. 2008 Aug ;51(8):1356-67. doi: 10.1007/s00125-008-1048-2. Epub 2008 Jun 18 .


The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications.

Endocannabinoids (ECs) are endogenous, bioactive lipid mediators that exert their effects mainly through specific G protein–coupled (primarily Gi/o) receptors: cannabinoid-1 (CB1) receptor and cannabinoid-2 (CB2) receptor. The signaling of these receptors is complex and, depending on the cell type, may involve inhibition (also activation in certain cases) of adenyl cyclase activity, activation of various mitogen-activated protein kinases (MAPKs) (eg, p38- and p44/42-MAPKs, c-Jun N-terminal kinase, and extracellular signal–regulated kinase), protein kinases A and C, and modulation of various Ca2+ and K+ channels.1–3 Previously, it was thought that the CB1 receptor was predominantly expressed in the central nervous system, mediating undesirable psychoactive effects, whereas the CB2 receptor was expressed mainly in immune and hematopoietic cells, modulating immune activities. However, recent studies also have demonstrated the expression of these receptors in various other cell types, both centrally and in the peripheral organs, implicating these receptors in a wide range of physiologic and pathologic functions and activities.1,4,5 In addition to their primary target cannabinoid receptors, ECs and possibly their metabolites may also activate multiple receptor-dependent and -independent mechanisms.3
 
Horváth B, Mukhopadhyay P, Haskó G, Pacher P. The Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes and Diabetic Complications. The American Journal of Pathology 2012;180(2):432-442. doi:10.1016/j.ajpath.2011.11.003.

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain.

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.
 
Toth CC, Jedrzejewski NM, Ellis CL, Frey WH. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Molecular Pain 2010;6:16. doi:10.1186/1744-8069-6-16.

DIABETES​

The impact of marijuana use on glucose, insulin, and insulin resistance among US adults

http://www.amjmed.com/article/S0002-9343%2813%2900200-3/abstract

(American Journal of Medicine)

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy 

http://www.ncbi.nlm.nih.gov/pubmed/21144973

(PubMed)


Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

http://www.ncbi.nlm.nih.gov/pubmed/16698671 

(PubMed)


Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes 

http://www.ncbi.nlm.nih.gov/pubmed/16400026

(PubMed)

 

Cannabidiol arrests onset of autoimmune diabetes in NOD mice

http://www.ncbi.nlm.nih.gov/pubmed/17714746 

(PubMed)


Diabetic retinopathy: Role of inflammation and potential therapies for anti-inflammation

http://www.ncbi.nlm.nih.gov/pubmed/21537423

 (PubMed)


Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes

http://www.ncbi.nlm.nih.gov/pubmed/24120371 

(PubMed)


The endocannabinoid system in obesity and type 2 diabetes

http://www.ncbi.nlm.nih.gov/pubmed/18563385

 (PubMed)


Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes

http://www.ncbi.nlm.nih.gov/pubmed/21484568

 (PubMed)


The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications

http://www.ncbi.nlm.nih.gov/pubmed/22155112

​ (PubMed)

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

http://www.ncbi.nlm.nih.gov/pubmed/20236533

 (PubMed)

Biochemical and immunohistochemical changes in delta-9-tetrahydrocannabinol-treated type 2 diabetic rats

http://www.ncbi.nlm.nih.gov/pubmed/23845579

 (PubMed)

 


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