Category Archives: Diabetes

Cannabidiol selectively attenuates lipotoxic immunometabolic inflammation in human macrophages

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“The role of saturated fatty acid-induced immunometabolic stress in macrophage dysfunction during metabolic disease remains incompletely understood, particularly the interplay between inflammatory signaling and intracellular lipid handling.

We employed a tightly controlled palmitic acid (PA)-based lipotoxicity model in PMA-differentiated U937-derived human macrophage-like cells to investigate how lipid excess reshapes inflammatory responses and to evaluate the modulatory effects of cannabidiol (CBD).

PA exposure induced a metabolically stressed yet viable macrophage phenotype, characterized by a broad cytokine remodeling profile. This included induction of classical proinflammatory cytokines such as interleukin (IL)-6, together with activation of inflammasome-associated cytokines IL-1β and IL-18 and additional immunoregulatory mediators, while tumor necrosis factor alpha (TNF-α) contributed to the overall inflammatory profile in a multivariate analysis. These changes were accompanied by a significant, time-dependent storage of intracellular triglycerides (TG) consistent with lipid overload and altered lipid handling.

CBD co-treatment did not compromise cell viability but selectively attenuated PA-induced inflammatory response in a cytokine-dependent manner, with the most significant reduction observed at higher concentrations. In parallel, CBD significantly reduced intracellular TG accumulation under lipotoxic conditions.

Collectively, these findings define a lipotoxicity-associated macrophage phenotype driven by saturated fatty acids and identify CBD as a context-dependent modulator of immunometabolic inflammation.

This work provides a controlled experimental framework to study lipid-driven inflammatory dysfunction and supports the potential of CBD as a targeted strategy to modulate metabolic inflammation without broadly suppressing immune function.”

https://pubmed.ncbi.nlm.nih.gov/42534637

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential regulator of inflammatory and metabolic processes. Unlike traditional anti-inflammatory drugs, CBD exerts context-dependent immunomodulatory effects across multiple experimental systems, encompassing both immune and metabolic cells.”

“Overall, this work supports CBD as a context-dependent modulator of immunometabolism response in PMA-differentiated U937-derived macrophages and provides a controlled experimental framework for studying lipid-driven inflammatory dysfunction in U937-derived macrophages.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1873494/full

Δ9 Tetrahydrocannabinol and cannabis extracts differentially improve adipoinsular dysfunction in diet-induced obesity

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“Diet-induced obesity (DIO) is associated with dysregulated adipoinsular axis and endocannabinoid system (eCBS) function. Acute cannabis consumption stimulates appetite; however, chronic consumption is paradoxically associated with lower prevalence of human obesity and type 2 diabetes.

We investigated the impact of chronic exposure to Δ9 tetrahydrocannabinol (THC) and cannabis extracts on DIO and glucose homeostasis in mice.

Male mice were fed a high-fat/sucrose diet or a low-fat/no-sucrose diet for 60 days. At day 30, mice were administered THC (5 mg/kg) or cannabis extracts matched for THC content daily for 30 days. We assessed adipocyte biology, glucose tolerance, insulin sensitivity, eCBS expression, body weight, food intake and motor activity. Roles for the eCBS in cannabis-induced changes in metabolic processes, including cellular bioenergetics, were analysed in 3T3-L1 adipocytes.

THC and extracts reduced body weight and fat mass in DIO mice, and reversed DIO-associated changes in expression of adipokines that regulate the adipoinsular axis. Extracts normalized expression of adipokines more effectively than THC. Notably, extracts – but not THC – normalized glucose clearance in DIO mice to levels found in lean mice. In addition, THC and extracts promoted anti-adipogenic effects and changes in energy metabolism in 3T3-L1 cells in a concentration-dependent manner.

These studies suggest that chronic cannabinoid exposure improves metabolic function and dysregulated glucose homeostasis in DIO by a mechanism that includes restoring impaired adipoinsular axis function.

KEY POINTS: Δ9 Tetrahydrocannabinol (Δ9THC) and cannabis extracts reduce body weight and fat mass in obese mice. Cannabis extracts, but not Δ9THC alone, improve glucose homeostasis in obese mice. Extracts more effectively normalize expression of components of the adipoinsular axis in obese mice. Δ9THC and extracts promote anti-adipogenic effects in 3T3-L1 cells. Δ9THC and extracts alter cellular bioenergetics in 3T3-L1 cells.”

https://pubmed.ncbi.nlm.nih.gov/42113966

“In conclusion, this study demonstrates that chronic cannabinoid exposure, particularly with cannabis extract, reduces body weight, improves glucose homeostasis and normalizes adipose tissue function in a mouse model of DIO. Our findings highlight the potential therapeutic value of cannabinoids in managing obesity and related metabolic disorders, though further research is needed to fully understand the underlying mechanisms and translate these findings into clinical applications.”

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP290431

Cannabisin A and B from hemp seed hulls improve glucose homeostasis by re-engaging insulin, leptin, and AMPK pathways via selective PTP1B inhibition

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“Background: Protein-tyrosine phosphatase 1B (PTP1B) is a master negative regulator of insulin and leptin receptor tyrosine kinase (RTK) signaling, and its chronic overactivation is strongly implicated in metabolic dysfunction. However, natural compounds capable of simultaneously inhibiting PTP1B and stimulating AMPK-the two major metabolic control nodes-remain scarce.

Methods: Two phenylpropionamide lignanamides, Cannabisin A (CA) and Cannabisin B (CB), were isolated from hemp seed hulls and their functions were evaluated using a multimodal workflow integrating molecular docking (AutoDock 4.2), mixed-type Lineweaver-Burk kinetic modeling, and 100 ns molecular dynamics simulations (CHARMM36/TIP3P). Functional assays included in vitro models such as enzyme inhibition, insulin- and leptin-stimulated glucose uptake assays in C2C12 myotubes and hepatocytes (Hepa1C1C7 and primary hepatocytes from high-fat diet mice), and in vivo models such as a multiple low-dose streptozotocin (MLD-STZ)-induced diabetic mouse model (C57BL/6J). In silico analyses of human transcriptomic and GWAS data (GEO, HuGeAMP) were conducted to assess translational relevance. BioTransformer-based metabolic predictions were used to explore absorption feasibility.

Results: CA and CB inhibited PTP1B with IC₅₀ values of 0.37 and 0.84 μM, respectively. Kinetic analysis demonstrated competitive-dominant (CA) and mixed-type (CB) inhibition, while MD simulations confirmed stable binding via catalytic-site residues (Asp48, Asp181, Arg221, Phe182). In PA-challenged C2C12 cells, both compounds restored glucose uptake and reactivated p-IRS-1, p-AKT, p-AMPK, and p-JAK2/STAT3. Similar recovery was observed in hepatocyte models, including suppression of SREBP-1c and enhancement of GLUT2 in primary HFD hepatocytes. In vivo, oral administration of CA/CB (1.5 and 3 mg/kg) in MLD-STZ diabetic mice improved fasting glucose in a dose-dependent manner, restored OGTT and ITT responses, and reactivated IRS-1/AKT/JAK2 signaling in skeletal muscle and AMPK/AKT/GLUT2 signaling in liver. Human transcriptome data and BioTransformer PK modeling showed that orally administered CA and CB can acquire sufficient polarity through O-demethylation and hydroxylation to exert PTP1B inhibitory effects in obesity and type 2 diabetes.

Conclusion: CA and CB are natural dual-target antidiabetic agents that inhibit PTP1B while activating AMPK, enabling coordinated re-engagement of insulin, leptin, and metabolic signaling. Their multi-tissue efficacy in vitro, ex vivo, and in vivo, combined with human-dataset alignment, highlights their translational potential as first-in-class insulin/leptin sensitizers derived from hemp seed hulls.”

https://pubmed.ncbi.nlm.nih.gov/41831381

“Cannabis sativa L. (Cannabaceae) has long been cultivated for fiber, seed oil, and medicinal uses.”

“In this study, we identified two phenylpropionamides—Cannabisin A (CA) and Cannabisin B (CB)—from hemp seed hulls as first-in-class dual-node metabolic regulators.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326002904?via%3Dihub

Cannabidiol and diabetic heart disease: Mechanistic evidence and translational challenges

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“Diabetic heart disease (DHD) is a major contributor to global cardiovascular morbidity, driven by a complex interplay of metabolic, inflammatory, oxidative, and fibrotic mechanisms. These interconnected pathways are not fully addressed by current cardiometabolic therapies, highlighting the need for novel multi-target interventions.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential modulator of several key processes implicated in DHD pathogenesis.

Preclinical evidence demonstrates that CBD attenuates oxidative stress by reducing reactive oxygen species (ROS) production, suppresses nuclear factor-κB (NF-κB)-mediated inflammatory signaling, preserves endothelial function by improving nitric oxide (NO) bioavailability, and inhibits transforming growth factor-β (TGF-β)-driven fibrotic remodeling.

These effects have been observed across in vitro and in vivo models of diabetic cardiomyopathy, where CBD improves both myocardial and vascular function. Mechanistically, CBD exerts its actions through negative allosteric modulation of CB₁ receptors and interaction with non-cannabinoid targets, including transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled receptor 55 (GPR55).

Despite this robust preclinical foundation, clinical evidence supporting the efficacy of CBD in DHD remains limited. Existing human studies are largely restricted to non-diabetic populations or short-term metabolic and hemodynamic outcomes, and do not address disease-specific cardiac endpoints. Furthermore, translational challenges, including variability in dosing, product standardization, and potential drug-drug interactions, remain significant barriers to clinical implementation.

Collectively, CBD represents a promising investigational candidate with multi-target potential to modulate the core pathophysiology of DHD. However, well-designed, disease-specific clinical trials are required to establish its therapeutic relevance and safety in diabetic populations.”

https://pubmed.ncbi.nlm.nih.gov/41966803

“Diabetic heart disease involves oxidative, inflammatory, and fibrotic pathways.”

“Cannabidiol (CBD) targets multiple pathological processes implicated in diabetic heart disease, including oxidative stress, inflammation, endothelial dysfunction, and fibrotic remodeling.”

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing interest due to its pleiotropic pharmacological actions across multiple molecular targets.”

https://www.sciencedirect.com/science/article/pii/S0753332226003872?via%3Dihub

Cannabinol derivatives, a new series of α-glucosidase inhibitors: synthesis, structure-activity relationship, and kinetic study

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“A new series of cannabinol derivatives was synthesised and assessed for their inhibitory effects against α-glucosidase. Of nineteen derivatives evaluated, the brominated analogues (3a and 3b) demonstrated the most potent inhibition against rat intestinal α-glucosidase. Structure-activity relationship analysis suggested that the phenolic hydroxy group and the introduced bromine atoms play crucial roles in enhancing inhibitory potency. Enzyme kinetic studies further revealed that 3a and 3b retarded both maltase and sucrase via a non-competitive mechanism.”

https://pubmed.ncbi.nlm.nih.gov/41785417

https://www.tandfonline.com/doi/full/10.1080/14786419.2026.2638950

“Three new α-glucosidase inhibitors from aqueous extract of Cannabis sativa leaves: isolation, characterisation, and kinetic study”

https://pubmed.ncbi.nlm.nih.gov/39756038

“Alpha-glucosidase inhibitors are oral antidiabetic medications used to treat type 2 diabetes”

Medical Cannabis for the Treatment of Peripheral Neuropathy due to Diabetes: A Systematic Review

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“Introduction: This systematic review evaluated randomized controlled trials (RCTs) conducted specifically in participants with diabetes and painful peripheral neuropathy to assess the effectiveness and safety of medical cannabis, isolated cannabinoids, or nationally approved cannabis-based medicines as adjuvant treatment, compared with placebo or baseline.

Materials and methods: Controlled clinical studies and RCTs in adults with diabetic peripheral neuropathy were eligible. Animal and in vitro studies were excluded. We searched PubMed, Google Scholar, Cochrane Library, and Scopus and screened 15,377 records; 35 full-text articles were assessed for eligibility, and 4 RCTs were included in the qualitative synthesis.

Results: Three of four studies reported statistically significant reductions in neuropathic pain with cannabinoid-based interventions compared with placebo, whereas one trial did not demonstrate superiority. In two trials using vaporized or sublingual Δ9-tetrahydrocannabinol (THC), doses in the range of approximately 16-18 mg were associated with clinically meaningful pain relief in participants. Adverse effects, including dizziness and cognitive symptoms, were common but generally mild-to-moderate, and discontinuations due to adverse effects varied across studies.

Discussion/conclusion: Evidence from four small, heterogeneous RCTs suggests that cannabinoid-based therapies may reduce pain in some patients with diabetic peripheral neuropathy; however, the limited number of studies, variability in formulations and comparators, and risk of bias preclude firm conclusions regarding efficacy. Observed THC doses around 16-18 mg/day delivered via vaporized or sublingual routes should be viewed as preliminary, hypothesis-generating ranges rather than definitive recommendations. Larger, contemporary RCTs with rigorous risk-of-bias control, standardized outcomes, and detailed safety reporting are needed.”

https://pubmed.ncbi.nlm.nih.gov/41714301

“three of four identified studies demonstrated statistically significant reductions in pain compared with placebo or baseline, suggesting that cannabinoid-based interventions may offer analgesic benefit for some patients with diabetic peripheral neuropathy.”

https://journals.sagepub.com/doi/10.1177/25785125261425444

Bioactive metabolites and antidiabetic activity of Cannabis sativa-derived endophytic fungi

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“Cannabis sativa L. (Cannabaceae) has long been valued in traditional medicine, including Ayurveda, for managing disorders such as diabetes, cancer, and kidney diseases.

Although the plant itself is known to influence glucose metabolism, the therapeutic potential of its associated endophytic fungi remains underexplored. In this study, 56 fungal isolates were obtained from different tissues of C. sativa and evaluated for antidiabetic activity.

Two isolates, identified by ITS1/4 rDNA sequencing as Aspergillus micronesiensis and Nodulisporium verrucosum, exhibited strong inhibitory effects on α-amylase, α-glucosidase, DPP-IV, and lipase (IC₅₀ < 100 µg/mL). Their ethyl acetate extracts demonstrated low cytotoxicity, enhanced cell viability, and significantly promoted insulin secretion in MIN6 pancreatic β-cells. GC-MS analysis revealed bioactive metabolites, including 1-butyl-4-tert-butylbenzene, 7,9-di-tert-butyl-1-oxaspiro (4,5) deca-6,9-diene-2,8-dione, 2-methylcinnamic acid, and tetraneurin-A, which are reported to possess antidiabetic potential. FTIR further confirmed the presence of functional groups corresponding to these compounds.

Together, these findings highlight C. sativa-derived endophytic fungi as promising sources of novel antidiabetic agents, bridging traditional knowledge with modern drug discovery.”

https://pubmed.ncbi.nlm.nih.gov/41249583

https://link.springer.com/article/10.1007/s00203-025-04539-1

“The term “endophytic fungi” refers to fungi that live in plant tissues throughout the entire or partial life cycle by establishing a mutually beneficial symbiotic relationship with its host plant without causing any adverse effect or disease.” https://pmc.ncbi.nlm.nih.gov/articles/PMC8877053/


Protective Effects of Hemp (Cannabis sativa) Root Extracts against Insulin-Deficient Diabetes Mellitus In Mice

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“The pharmacological potential of industrial hemp (Cannabis sativa) has been widely studied. However, the majority of studies have focused on cannabidiol, isolated from the inflorescence and leaf of the plant.

In the present study, we evaluated the anti-diabetic potential of hemp root water (HWE) and ethanol extracts (HEE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice.

The administration of HWE and HEE ameliorated hyperglycemia and improved glucose homeostasis and islet function in STZ-treated mice (p < 0.05). HWE and HEE suppressed β-cell apoptosis and cytokine-induced inflammatory signaling in the pancreas (p < 0.05). Moreover, HWE and HEE normalized insulin-signaling defects in skeletal muscles and apoptotic response in the liver and kidney induced by STZ (p < 0.05).

Gas chromatography-mass spectrometry analysis of HWE and HEE showed possible active compounds which might be responsible for the observed anti-diabetic potential.

These findings indicate the possible mechanisms by which hemp root extracts protect mice against insulin-deficient diabetes, and support the need for further studies geared towards the application of hemp root as a novel bioactive material.”

https://pubmed.ncbi.nlm.nih.gov/37175224/

“In conclusion, the present study demonstrated that HWE and HEE counteracted STZ-induced hyperglycemia and islet dysfunction via the inhibition of β-cell apoptosis in mice. The inhibition of β-cell apoptosis by HWE and HEE was associated with the suppression of cytokine-induced inflammatory signaling. In addition, HWE and HEE attenuated apoptosis in the liver and kidney and improved insulin signaling in skeletal muscle. These findings provide novel scientific evidence for the pharmaceutical application of hemp root, which has been considered a minor part of the plant in Cannabis-based medicinal and functional food studies.”

https://www.mdpi.com/1420-3049/28/9/3814

Long-Term Efficacy and Safety of Inhaled Cannabis Therapy for Painful Diabetic Neuropathy: A 5-Year Longitudinal Observational Study

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“Background/Objectives: Diabetic neuropathy (DN) is a prevalent complication of diabetes mellitus, affecting up to 50% of long-term patients and causing significant pain, reduced quality of life, and healthcare burden. Conventional treatments, including anticonvulsants, antidepressants, and opioids, offer limited efficacy and are associated with adverse effects. Emerging evidence suggests that cannabis, acting via the endocannabinoid system, may provide analgesic and neuroprotective benefits. This study evaluates the long-term effects of inhaled cannabis as adjunctive therapy for refractory painful DN. Inhaled cannabis exhibits rapid onset pharmacokinetics (within minutes, lasting 2-4 h) due to pulmonary absorption, targeting CB1 and CB2 receptors to modulate pain and inflammation. 

Methods: In this prospective, observational study, 52 patients with confirmed painful DN, unresponsive to at least three prior analgesics plus non-pharmacological interventions, were recruited from a single clinic. Following a 1-month washout, patients initiated inhaled medical-grade cannabis (20% THC, <1% CBD), titrated individually. Assessments occurred at baseline and annually for 5 years, including the Brief Pain Inventory (BPI) for pain severity and interference; the degree of pain relief; Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score; HbA1c; and medication usage. Statistical analyses used repeated-measures ANOVA, Kruskal-Wallis tests, Welch’s t-tests, and Pearson’s correlations via Analyze-it for Excel. 

Results: Of 52 patients (mean age 45.3 ± 17.8 years; 71.2% male; diabetes duration 23.3 ± 17.8 years), 50 completed follow-up visits. Significant reductions occurred in BPI pain severity (9.0 ± 0.8 to 2.0 ± 0.7, p < 0.001), interference (7.5 ± 1.7 to 2.2 ± 0.9, p < 0.001), LANSS score (19.4 ± 3.8 to 10.2 ± 6.4, p < 0.001), and HbA1c (9.77% ± 1.50 to 7.79% ± 1.51, p < 0.001). Analgesic use decreased markedly (e.g., morphine equivalents: 66.8 ± 49.2 mg to 4.5 ± 9.6 mg). Cannabis dose correlated positively with pain relief (r = 0.74, p < 0.001) and negatively with narcotic use (r = -0.43, p < 0.001) and pain interference (r = -0.43, p < 0.001). No serious adverse events were reported; mild side effects (e.g., dry mouth or euphoria) occurred in 15.4% of patients. 

Conclusions: Inhaled cannabis showed sustained pain relief, improved glycemic control, and opioid-sparing effects in refractory DN over 5 years, with a favorable safety profile. These findings are associative due to the observational design, and randomized controlled trials (RCTs) are needed to confirm efficacy and determine optimal usage, addressing limitations such as single-center bias and small sample size (n = 52). Future studies incorporating biomarker analysis (e.g., endocannabinoid levels) could elucidate mechanisms and enhance precision in cannabis therapy.”

https://pubmed.ncbi.nlm.nih.gov/41153689/

“Inhaled cannabis add-on therapy mitigated symptoms of diabetic neuropathy over the course of a five-year observation period. Some reduction in glycosylated hemoglobin is observed as well as major reduction in the need for other prescription medications, including opiates and opioids. It is possible to state the following: (1). Inhaled cannabis significantly reduced pain and neuropathic symptoms over 5 years. (2). It decreased opioid use, supporting an opioid-sparing effect. (3). HbA1c improvements suggest a metabolic benefit, though causality is unproven. (4). No serious adverse events occurred, with mild effects in 15.4% of patients. (5). RCTs are needed to confirm efficacy and address accessibility barriers. Integration of objective pain assessment tools, such as salivary biomarker devices, could enhance the precision and reproducibility of cannabis therapy outcomes in DN.”

https://www.mdpi.com/2227-9059/13/10/2406

Anti-inflammatory effects of cannabidiol in the treatment of type 1 diabetes: A mini review

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“This study reviews the anti-inflammatory potential of cannabidiol (CBD) in the management of type 1 diabetes (T1D).

A comprehensive search was conducted across PubMed, Scopus, and ScienceDirect databases using the terms “type 1 diabetes”, “cannabidiol”, “anti-inflammatory effect”, and “CBD”. Articles published between 2005 and 2025 were screened, and studies involving animal models that examined CBD as a therapeutic intervention for T1D and reported on its anti-inflammatory effects were included. Of the 62 retrieved articles, only 6 met the predefined inclusion criteria.

Although limited in number, the available studies show promising outcomes. CBD demonstrates potential as an adjuvant therapy for T1D due to its immunomodulatory and anti-inflammatory actions. Nonetheless, further research is required to establish safe and effective clinical application protocols.”

https://pubmed.ncbi.nlm.nih.gov/41113484/

https://doi.org/10.4239/wjd.v16.i10.110041