The Effects of Curcumin on Diabetes Mellitus: A Systematic Review

Focused Question

This review was built to answer the focused question: What are the effects of Curcuma longa on T2DM patients?

Language

Only studies in English were selected.

Databases

This study has included studies in MEDLINE–PubMed (National Library of Medicine, National Institutes of Health), EMBASE, and COCHRANE databases. The descriptors used were Hyperglycemia or Diabetes or Insulin resistance and Curcuma Longa or Curcumin or Curcuminoids. The use of these mesh-terms helped identify studies related to curcumin intake and its beneficial role in metabolic status in T2DM patients. The authors have followed PRISMA (Preferred Reporting Items for a Systematic Review and Meta-Analysis) guidelines (27).

Study Selection

This review included studies that reported Curcuma longa or potential curcumin role to patients with T2DM. This study’s inclusion criteria were Randomized Clinical Trials (RCTs), prospective, double-blind, and placebo-controlled studies. Only full texts were included.

The exclusion criteria were studies with animals, reviews, studies not in English, retrospective studies, case reports, poster presentations, and editorials. Reviews were consulted to build the discussion but were not included.

Data Extraction

This search’s search period included the past five years (January 2016 to December 2020). These studies are described in Table 1 .

Quality Assessment

To evaluate the risk of biases in the selection, detection, and reporting bias of each.

RCT, we applied the Cochrane Handbook for Systematic Reviews of Interventions. Other risks of biases in the selection of patients, classification of interventions, missing data, and measurement of outcomes were also evaluated.

Type II Diabetes Mellitus in a Nutshell

T2DM is a prevalent chronic disorder characterized by high blood sugar levels representing 80% of DM patients. This condition has a multifactorial nature, triggered by several genetic and environmental factors, with a critical mechanism of progressive loss of β-cell insulin secretion (42–44). As long as the patient β-cells can compensate for insulin resistance, the normoglycemia is preserved. However, the natural disease progression is hyperglycemia (43, 45).

The chronic hyperglycemic state contributes to oxidative stress by increasing levels of AGEs and ROS (46), increasing the risk of development of microvascular (retinopathy, nephropathy, and neuropathy), and macrovascular complications (congestive heart failure, stroke, coronary heart disease, myocardial infarction, and peripheral vascular disease) (42, 47). These consequences result in a reduction in quality of life and life expectancy by even ten years among diabetic patients (42, 48).

Arterial hypertension, dyslipidemia, older age, sedentary lifestyle, and abdominal obesity are key risk factors for T2DM (43, 48) since the adipose tissue secretes several biomarkers, such as resistin, TNF-α, and IL-6, which can induce a chronic inflammatory state and insulin resistance. Moreover, in obese patients, low adiponectin levels and a leptin-resistance state are commonly seen (42).

The natural progression of DM is hyperglycemia, which contributes to oxidative stress, and pro-inflammatory markers, which lead to lipid peroxidation, increase the oxidative stress scenario, resulting in inflammation and increased VEGF, ICAM-1, VCAM-1, endothelial dysfunction, and apoptosis. These processes increase the risk of micro and macrovascular complications (49–51). Figure 2 summarizes the pathophysiology of DM.

The current DM treatment strategies are based on a multifactorial approach, targeting all risk factors rather than glucose control alone, resulting in a decrease or delay in its progression and improving the overall life quality (42, 48). However, there is no cure for diabetes so far, and none of the large numbers of the drug classes that are used modifies the progressive decline in β-cell function over time (42, 43). Therefore, researchers have been searching for evidence about herbal therapy’s effectiveness in preventing and controlling DM.

Curcuma longa

The genus Curcuma (Zingiberaceae) includes perennial rhizomatous plants native to subtropical to tropical regions. Curcuma cultivation is extensively found in tropical and subtropical regions of Asia, Australia, and South America (52). Since ancient times in India and China, it has been considered to treat illnesses such as dermatologic diseases, infection, stress, and depression (53–55).

The main part of the plant is the rhizomes, and the most prevalent active components are the curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) (53, 56, 57). Curcuminoids are nontoxic polyphenolic that exerts a wide range of biological activities (58, 59), such as the production of significant immunosuppressants that inhibit the production of IL-2 and IL-12. This compound inhibits the expression of iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), lipoxygenase-5, and many other pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8 (60–62).

Curcuminoids can also regulate apoptosis and suppress neurotoxic factors in macrophages and alveolar monocytes stimulated by lipopolysaccharides. Besides, it inhibits phosphorylation and degradation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) and activates the γ receptor mechanism activated by peroxisome proliferator, reducing inflammation pattern induced by NF-κB pathway (62–64).

The peculiar characteristics that attract scientists’ attention are the antioxidant and anti-inflammatory activities and the safety of its pharmacological profile (14, 15, 65, 66). The mechanism of action in several molecular pathways is due to curcumin’s particular chemical structure, capable of having many molecular targets. The biological effects may include the inhibition of reactive oxygen species (ROS) production, playing a fundamental role, particularly for diseases related to oxidative stress and inflammation, such as DM (67, 68). Figure 3 shows some systemic effects of curcumin.

As seen above, curcumin can exhibit a huge range of therapeutic possibilities; however, it presents low solubility and rapid metabolism limiting its absorption in the gastrointestinal tract and resulting in weak bioavailability. The weak bioavailability has been associated to its insolubility in the water and the increased degradation in alkaline solutions or crystallization in acidic environments (69–71). Significant changes occur in its degradation time according to the pH, at pH> 7 if it degrades in about 30 min, already in acidic conditions, the degradation is much slower, with less than 20% of the total curcumin decomposed in 1 h. When ingested orally, the bioavailability of curcumin can be influenced by the food matrix, like lipids and proteins. Most of it is excreted in the feces, and only a small part will be absorbed in the intestine, which still undergoes a fast metabolism in the liver and the plasma. A high conjugation rate via glucuronidation and sulfation is also largely converted to its water-soluble metabolites (sulfates and glucuronides) that are excreted in the urine, explaining its concentration has a very low level in the blood (72–74).

The low bioavailability leads to reduced serum concentrations, reducing the possibilities of producing positive health effects. Due to these reasons, in the last few years, several delivery methods have been developed to improve oral curcumin bioavailability (75, 76). Some pharmaceutical technologies, and combinations with other compounds, such as piperine or lecithin, are being considered as they increase curcumin´s solubility, extend its residence in plasma, and improve the pharmacokinetic profile and cell absorption. Different new delivery systems, such as solid lipid particles, micellar systems, or hydrophilic nanoparticles, can increase curcumin concentration up to 15 to 20 times. Therefore, there is an improved curcumin solubility, bioavailability, transmembrane permeability, prolonged plasma half‐life, long‐term stability, target‐specific delivery, and upgraded therapeutic effects (77, 78).

According to studies that explored the safety of turmeric, standardized powder and extract of turmeric and curcumin are safe for human use, even in high doses of 6 g/day for seven weeks. Moreover, endovenous use of curcumin is safe if used if the dose administered is lower than that used orally. In pregnant animals, curcumin showed to be safe, but further studies are needed to confirm its safety in pregnant women (79, 80). Curcumin is also a nontoxic, non-mutagenic, non-carcinogenic, non-photo toxic agent and considered safe at lower doses than oral doses in intravenous administration in humans.

Nevertheless, some adverse effects are related to its consumption, such as dyspepsia, nausea, flatulence, and diarrhea. It was also demonstrated that turmeric could interact with some medications; it affects cytochromes P450, and the pharmacokinetics of some conventional drugs such as anticoagulants, antibiotics, antidiabetics, cardiovascular drugs, anticancer drugs, and antidepressants are influenced by curcuminoids (52, 80–82).

Effects of Curcuma longa and Curcumin on Type 2 Diabetes Mellitus

Several studies have investigated the effects of curcumin on diabetes. These studies are shown in Table 1 and discussed below.

A Pilot Study performed in Mexico (28) showed evidence that dietary supplementation with curcumin can reduce oxidative stress in patients with non-diabetic or diabetic proteinuric CKD. Curcumin significantly improved the elimination of free radicals activity in individuals with non-diabetic proteinuric CKD and reduced the plasma levels of malondialdehyde (MDA). However, its effects were limited; patients with diabetic proteinuric CKD treated with placebo showed a significant reduction in MDA content after the intervention. Also, no significant differences were observed in glutathione disulfide (GSSG) content or glutathione (GSH)/GSSG ratio between groups or with relation to sampling. Curcumin treatment did not modify the antioxidant activity of glutathione peroxidase, glutathione reductase, erythrocyte superoxide dismutase (SOD), and erythrocyte catalase, or to increase nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation in both patients with non-diabetic and diabetic proteinuric CKD. A study with a higher dose and longer follow-up is necessary to confirm these findings.

Another study, which investigated the effect of nano-curcumin in T2DM individuals, was adequately randomized, with no significant loss of participants, and even with a dose that the authors considered low, the effects of curcumin were positive. The fasting blood glucose (FBG), Hemoglobin A1c (HbA1C), body mass index (BMI), Estimated Average Glucose (eAG), total cholesterol (TC), LDL-c, HDL-c, and triglyceride (TG) were compared between the two groups after the intervention. Curcumin improved FBG, HbA1c, BMI, and eAG, but did not affect LDL-c, HDL-c, TG, and TC (29).

The results of Panahi et al. (20) showed an antioxidant effect of curcuminoid supplementation in patients with T2DM since supplementation promoted a significant increase in total antioxidant capacity and serum SOD activities, while MDA amounts were significantly decreased compared to the placebo group. Future studies may assess the impact of these antioxidant effects on diabetic complications and cardiovascular outcomes.

The treatment of T2DM patients with curcuminoid plus piperine resulted in a reduction in serum Lp (a) and an increase in HDL-c concentrations. These results are important because, until very recently, the possibilities of influencing Lp (a) were extremely limited. Serum concentrations of lipids including TC, LDL-c, HDL-c, TG, lipoprotein (a) (Lp(a)), and non-HDL-c were investigated at the beginning and at the end of the trial and revealed significant reductions in serum TC, non-HDL-c, and Lp (a) levels, and increase in serum HDL-c levels in the curcuminoid group compared to the placebo. Therefore, curcuminoids plus piperine may be a useful supplement in treating dyslipidemia in patients with T2DM (21).

The trial results performed by Panahi et al. (30) also revealed a beneficial effect of curcuminoids plus piperine supplementation on glycemic and hepatic parameters but not on hs-CRP levels in T2DM patients. However, this study has insufficient information regarding standard-of-care treatment that may be involved in the lack of curcuminoid efficacy on some parameters measured, particularly hs-CRP. Second, dietary intake and physical activity were not assessed; nevertheless, by randomization, it is expected that these characteristics were distributed similarly in the study groups minimizing the risk of bias. Finally, the trial duration was short, and it would help assess the efficacy of curcuminoids in long-term trials.

Positive effects of curcumin were also found by Adab et al. (31) in hyperlipidemic T2DM patients who received turmeric powder daily for eight weeks. BMI, TC, TG, LDL-c, HDL-c, insulin, HbA1C, FBG, fasting serum insulin, Apolipoprotein A1 and B were evaluated at the beginning and after the period of intervention. The authors concluded that this intervention could be used as an adjunct therapy to reduce diabetes complications, atherosclerosis, and overweight. The limitations of this trial may include a short intervention duration and low sample size.

The trial performed by Adibian et al. (32) with T2DM patients showed that the intervention with 1,500 mg daily of curcumin for ten weeks might reduce diabetes complications by decreasing indicators of inflammation. However, the authors suggest that higher sample sizes, longer duration, and different curcumin doses could lead to better outcomes.

In the trial performed by Asadi et al. (33), supplementation with nano-curcumin in patients with T2DM improved and reduced the severity of DSPN. The study also showed a reduction in glycemia after 2 h (Bs2hp), weight, and body mass index; however, these modifications were not significant. Meanwhile, the authors recognize some limitations: a short duration of follow-up, a single-dose trial, and low male participation.

The randomized, double-blind placebo-controlled trial performed in Iran by Hodaei et al. (34) indicated that the daily administration of a high dose of curcumin for ten weeks in NIDDM patients had positive effects on inflammatory indicators. However, this intervention had no effects on oxidative stress, serum insulin levels, IR, and HbA1c. The authors recognize that the study had a short duration of intervention and showed significant loss of patients.

Srinivasan et al. (35) showed that intervention with Curcuma longa produced a significant reduction in arterial stiffness in T2DM patients. The carotid-femoral pulse wave velocity (PWV), left brachial-ankle PWV, aortic augmentation pressure, aortic augmentation index, and aortic augmentation index decrease significantly. The authors attributed the lack of statistical reduction in endothelial dysfunction markers as adiponectin, leptin, ICAM, and VCAM due to methodological analysis limitations.

In the trial performed by Vanaie et al. (36), curcumin’s oral administration showed benefit on renal function by significantly decreasing albuminuria, therefore being considered a promising alternative therapy for T2DM patients with a mild decrease in glomerular filtration rate (GFR). The authors recognized some study limitations, such as small sample size and short intervention time.

The treatment of patients with T2DM with nano-curcumin capsules showed a beneficial effect on depression and anxiety. Moreover, curcumin was safe and well-tolerated during the study (37). However, these effects were minor, and no significant effect was observed for stress. The authors considered that the intervention might show better effects in the long term or higher supplementation doses.

Funamoto et al. (38) showed that the oral intervention with Theracurmin^® in patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus could increase adiponectin expression, resulting in antiatherosclerotic action. Besides, the authors noticed that leptin demonstrated a decreasing trend after administration of Theracurmin. However, this trial’s limitations were the small sample size and the short duration of the intervention.

The results of Shafabakhsh et al. (39) revealed that the intervention with nano-curcumin in T2DM significantly decreased fasting plasma glucose and insulin levels and decreased the plasma lipids. Also, nano-curcumin intake upregulated gene expression of PPAR-γ and LDLR in PBMCs and increased total nitrite and total antioxidant capacity (TAC) levels without affecting GSH levels and gene expression of TGF-β. The authors concluded that this supplementation showed anti-inflammatory and antioxidant effects; however, they recognized some limitations in the trial, since they did not check compliance to nano-curcumin intake, and they were also unable to determine the effects of the administration on other biomarkers of oxidative stress and inflammation.

Another clinical trial developed by Shafabakhsh et al. (40) showed that curcumin intake upregulated PPAR-gamma in peripheral blood mononuclear cells of T2DM subjects with coronary heart disease (CHD). Furthermore, it was able to improve Pittsburgh Sleep Quality Index (PSQI) score. The authors considered that this is the first analysis of curcumin’s effects on psychological symptoms, inflammatory factors, oxidative status, and gene expression related to metabolic profiles in patients with T2DM and CHD. These findings suggest that curcumin can improve the psychological status, metabolic disorders, and patients’ quality of life. The study’s limitations include the short period of intervention, small sample size, lack of examinations for other metabolic and genetic biomarkers of inflammation, and oxidative damage.

The clinical trial developed by Mokhtari et al. (41) showed that the oral intervention with nano-curcumin in patients with diabetic foot ulcer (DFU) resulted in a significant improvement of FPG, insulin levels, the homeostasis model of assessment-insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), LDL-c, TAC and total glutathione (GSH) levels, but did not affect ulcer size, HbA1c, lipid profile, markers of inflammation, and oxidative stress. Therefore, the study revealed strengths, such as the first study that evaluated the effects of nano-curcumin on wound healing parameters and metabolic control in DFU patients. As DFU patients are susceptible to insulin resistance and cardiometabolic disorders, there was a good rationale for this project. However, the trial had few limitations, including the small sample size and the short intervention period. Furthermore, the authors could not assess the effects of curcumin supplementation on gene expression related to insulin resistance, lipid homeostasis, and inflammation in patients with DFU.

The trials that met the eligibility criteria for this review showed that curcumin significantly improves insulin resistance, serum glucose levels, HbA1c, lipid profile, and inflammatory biomarkers in patients with T2DM. However, in low doses and a short period of use, it may not interfere with the disease’s symptoms. Despite this, as T2DM remains incurable, understanding the role of curcumin in this pathology may represent a new therapeutic target.