Edited by: Alberto Battezzati, University of Milan, Italy
Reviewed by: Somasundaram Arumugam, National Institute of Pharmaceutical Education and Research, Kolkata, India; Bharat B. Aggarwal, University of Texas MD Anderson Cancer Center, United States
*Correspondence: Sandra M. Barbalho,
This article was submitted to Translational Endocrinology, a section of the journal Frontiers in Endocrinology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Diabetes mellitus (DM) is an ensemble of metabolic conditions that have reached pandemic proportions worldwide. Pathology’s multifactorial nature makes patient management, including lifelong drug therapy and lifestyle modification, extremely challenging. Currently, there is growing evidence about the effectiveness of using herbal supplements in preventing and controlling DM. Curcumin is a bioactive component found
The International Diabetes Federation has estimated that since 2000, the prevalence of diabetes mellitus (DM), including type 1 (T1DM) and type 2 (T2DM), has increased from 151 million to 463 million in adults aged 20 to 79 years (
The triggering ways of inflammation in T2DM are still not fully elucidated. The inflammatory process likely contributes to the development of T2DM and may cause insulin resistance which is worsened with hyperglycemia (
On the other hand, oxidative stress has a key role in the development of T2DM. Increased oxidative species production and reduced antioxidant capacity have been repeatedly shown in subjects with T2DM (
Owing to the aforementioned detrimental effects of oxidative stress on the development of T2DM and the progression of its vascular complications, antioxidant therapy has been considered a potentially effective approach (
Curcuminoids have been shown to improve insulin resistance, decrease glucose and insulin levels, increase adiponectin release, and reduce the levels of leptin, resistin, interleukin (IL)-6 IL-1β, and tumor necrosis factor-α in patients with T2DM (
This review was built to answer the focused question: What are the effects of
Only studies in English were selected.
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
This review included studies that reported
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.
This search’s search period included the past five years (January 2016 to December 2020). These studies are described in
Descriptive table of the included studies.
Reference | Local | Model and Patients | Intervention | Outcomes | Adverse effects |
---|---|---|---|---|---|
Jiménez-Osorio et al. ( |
Mexico | Randomized double-blind placebo-controlled clinical trial with 101 individuals, 50 with non-diabetic proteinuric CKD and 51 patients with diabetic proteinuric CKD, 61 ♂ and 40 ♀ (20–70 y). | Subjects received either turmeric capsules with curcumin 107 mg in each meal (320 mg/day) or a PL for 8 w. | The intervention with curcumin did not improve proteinuria, estimated glomerular filtration rate, or lipid profile. However, curcumin attenuated lipid peroxidation in individuals with non-diabetic proteinuric CKD. | NR by the authors |
Rahimi et al. ( |
Iran | Randomized double-blind placebo-control clinical trial with 80 patients with T2DM (FBG ≥ 126 mg/dl or 2-h postprandial blood glucose ≥200 mg/dl), ≥18, 31 ♂ and 39 ♀. | Subjects were assigned to nano-curcumin (as nano-micelle 80 mg/day) or PL for 3 m. | A significant decrease was observed for HbA1C, FBG, TG, and BMI after the treatment. Significant differences in HbA1c, eAG, LDL-c, and BMI variables were observed between the treated group and PL | NR by the authors |
Panahi et al. ( |
Iran | Randomized double-blind placebo-controlled trial with 118 patients with T2DM (FPG ≥126 mg/dl, HbA1C ≥6.5%), or the use of standard anti-diabetic treatments, 51 ♂ and 49 ♀ 18–65 y. | Patients were randomized to curcuminoids (1000 mg/d + piperine 10 mg/d) or matching PL for a period of 12 w. | Curcuminoids lead to a significant elevation in serum total antioxidant capacity and SOD activities, while serum MDA levels were significantly reduced compared with the PL. | No severe adverse events |
Panahi et al. ( |
Iran | Randomized double-blind placebo-controlled trial with 118 patients with T2DM (FPG ≥126 mg/dl, HbA1C ≥6.5%), or the use of standard anti-diabetic treatments, 51 ♂ and 49 ♀, 18–65 y. | Patients received curcuminoids (1000 mg/day + piperine 10 mg/day) or placebo/12 w. | Significant reductions in TC, non-HDL-c, and Lp(a); and elevations in serum HDL-c levels, were observed in the treated group. Serum TG and LDL-c did not show significant difference. | No severe adverse events. |
Panahi et al. ( |
Iran | Randomized double-blind placebo-controlled trial with 118 patients with T2DM based (FPG ≥126 mg/dl, HbA1C ≥6.5%) or standard anti-diabetic treatments, 51 ♂ and 49 ♀, 18–65 y. | Patients were allocated to standard-of-care treatment and dietary advice plus either curcuminoids (500 mg/day + piperine 5 mg/d) or placebo for 3 m. | Significant reduction in glycemia and HbA1c were observed after curcuminoids supplementation. Additionally, participants showed lower serum AST and ALT in the treated group. | NR by patients |
Adab et al. ( |
Iran | Randomized double-blind clinical trial included 80 hyperlipidemic T2DM patients (39 ♀ and 36 ♂); 30–70 y. | The patients received 2,100 mg of turmeric powder (capsules after main meals)/d/8 w. | The intervention caused a significant weight reduction, BMI, TG, and LDL-c in the intervention group compared with baseline. The intervention with turmeric powder also prevented the increase of TC. | NR by patients. |
Adibian M. et al. ( |
Iran | Randomized double-blind placebo-controlled trial included 44 diabetic individuals (22 ♂, 22 ♀;40–70 y; BMI 18.5–30 kg/m2, with a duration of T2DM of 1 to 10 years and intake of oral hypoglycemic agents for control. | Participants were divided into curcumin group (n=21; 13 ♂ and 8 ♀) and PL group (n=23; 9 ♂ and 14 ♀). The curcumin group received 1,500 mg curcumin (500 mg capsules 3×/day)/10 w. | The intervention showed a significant decrease in TG, hs-CRP, mean FBG, and a significant increase in serum adiponectin. The curcumin group also had a significant reduction in mean weight compared with the control group. | NR by authors. |
Asadi et al. ( |
Iran | Randomized double-blind parallel placebo-controlled clinical trial with 80 patients with NIDDM and DSPN (70 ♀ and 10 ♂), 30–60 y, BMI 25 to 39.9 kg/m2. | The participants received curcumin (Nano curcumin capsules, 80 mg/d) or PL/8 w. | After 8 w of curcumin intake, subjects showed a significant decrease in WC, FBS, HbA1c, neuropathy score, and total reflex score. | Two cases of stomachache in the first few days of the study. |
Hodaei et al. ( |
Iran | Randomized double-blind placebo-controlled trial that included 53 patients with NIDDM (22 ♂ and 22 ♀; 40–70 y; BMI between 18.5 to 35 kg/m2. | The patients were allocated to curcumin (n=21) or PL (n=23). The intervention group received 500 mg of curcumin after each main meal/10 weeks. | The intervention showed a significant decrease in body weight, BMI, hip circumference, and FBG. | The participants did not report serious side effects. |
Srinivasan et al. ( |
South India | Randomized placebo-controlled clinical trial with 136 T2DM patients (29 ♂ and 85 ♀), 30–65 y, diagnosed within the past 3 months to 10 years, on treatment with metformin for a period of at least past 3 months. | The patients received 400 mg of |
The |
One patient reported increased frequency, and one referred to upper abdominal pain. |
Vanaie et al. ( |
Iran | Randomized double-blind placebo-controlled clinical trial with 60 patients with T2DM on oral anti-diabetic drugs or insulin. Curcumin group consisted of 19 patients ♀ and 27 ♂ (52–71 y). | Patients received 500 mg of curcumin with each meal (3× d after meal) or PL for 16 w. | The intervention with curcumin showed ameliorating macroscopic proteinuria in T2DM patients. | Epigastric pain in one participant. |
Asadi et al. ( |
Iran | Randomized double-blind parallel and a placebo-controlled clinical trial with 80 T2DM patients with DPN, 40 in each group, 35 ♀ and 5 ♂ received nanocurcumin, and 35 ♀and 5 ♂ received PL (30–60 y). | The participants were allocated randomly to receive either 80 mg of nano-curcumin or PL capsules daily for 8 w. | It was seen a significant reduction in the mean score of depression and anxiety in the treated group compared with PL. | Two patients reported stomachache. |
Funamoto et al. ( |
Japan | Randomized double-blind placebo-controlled clinical trial with 52 patients with impaired glucose tolerance or NIDDM, 23 ♂ and 10 ♀ (20–85 y). | Subjects received Theracurmin® capsule (90 mg 2× d) for 6 m or PL. | Curcumin inhibited the increase in oxidized LDL-c. | NR by the authors |
Shafabakhsh et al. ( |
Iran | Randomized double-blind placebo-controlled clinical trial with 60 participants with diabetes on HD (18- 80 y), 32 ♂ and 21 ♀.with 60 subjects. | Subjects were randomly separated into two groups that received 80 mg/day nano-curcumin capsule or PL for 12 w. | Nano-curcumin showed benefits on the metabolic profile in patients with diabetes on HD since it showed a significant decrease in FBG and serum insulin levels compared with PL. Nano-curcumin was also related to a significant decrease in TG, VLDL-c, TC, LDL-c, HDL-c, serum hs-CRP, and plasma MDA. | NR by patients |
Shafabakhsh et al. ( |
Iran | Randomized double-blind placebo-controlled trial with 60 patients with |
Patients received 1000 mg/day curcumin or PL for 12 w. | Curcumin intake showed beneficial effects on PSQI, TAC, GSH, MDA values, and gene expression of PPAR-γ, but did not affect BDI, BAI, and mRNA expression for IL-1, IL-8, TGB-β, and VEGF. | NR by patients |
Mokhtari et al. ( |
Iran | Randomized double-blind placebo-controlled clinical trial with 60 patients with grade 3 DFU; 39 ♂ and 11 ♀ (45–85 y). | Subjects were randomized to receive 80 mg nano-curcumin tablets daily for 12 w or PL. | Nanocurcumin intake resulted in a significant improvement of glycemic control, total- and LDL-cholesterol, TAC, and GSH. | NR by patients |
BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BMI, body mass index; DFU, diabetic foot ulcer; CHD, coronary heart disease; CKD, chronic kidney disease; DBP, diastolic blood pressure; DPN, diabetic peripheral neuropathy; DSPN, diabetic sensorimotor polyneuropathy; eAG, estimated average glucose; FBG, fasting blood glucose; FBS, fasting blood sugar; FPG, fasting plasma glucose; GSH, glutathione; HbA1C, glycated hemoglobin; HD, hemodialysis; HDL-C, high density lipoprotein-cholesterol; hs-CRP, high-sensitivity C-reactive protein; IL-1, interleukin-1; IL-8, interleukin-8; LDL-C, low density lipoprotein-cholesterol; Lp(a), lipoprotein A; MDA, malondialdehyde; mRNA, messenger RNA; NIDDM, non-insulin-dependent diabetes mellitus; non-HDL-C, non high-density lipoprotein cholesterol; NR, not reported; PL, placebo; PPAR-g, peroxisome proliferator-activated receptor gamma; PSQI, Pittsburgh Sleep Quality Index; PWV, pulse wave velocity; RT-PCR, reverse transcription polymerase chain reaction; SBP, systolic blood pressure; SOD, superoxide dismutase; TAC, total antioxidant capacity; TC, total cholesterol; TG, triglyceride; TGF-b, transforming growth factor beta; T2DM, type 2 diabetes mellitus; T2D, type 2 diabetes; VEGF, vascular endothelial growth factor; VLDL-c, very low density lipoprotein-cholesterol; WC, waist circumstance.
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.
From the 16 articles selected (
Flow diagram showing the literature search (based on PRISMA, 2009) (
Nine of them were performed with T2DM patients, one with T2DM and non-diabetic proteinuric Chronic kidney disease (CKD) patients, one with T2DM and Diabetic Sensorimotor Polyneuropathy (DSPN) patients, one with T2DM and Diabetic Peripheral Neuropathy (DPN) patients, one with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) patients, one with DM on Hemodialysis patients, one with T2DM and coronary heart disease, and one diabetic foot ulcer (DFU). Only one study included patients with type 1 and T2DM.
Five studies used curcumin, five used nano-curcumin, one used Theracurmin®, one
The studies showed that the use of
Descriptive table of the biases of the included randomized clinical trials.
Study | Question focus | Appropriate randomization | Allocation blinding | Double-blind | Losses (<20%) | Prognostics or demographic characteristics | Outcomes | Intention to treat analysis | Sample calculation | Adequate follow-up |
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Jiménez-Osorio et al. ( |
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Rahimi et al. ( |
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Panahi et al. ( |
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Panahi et al. ( |
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Panahi et al. ( |
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Adab et al. ( |
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Adibian et al. ( |
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Asadi S et al. ( |
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Hodaei et al. ( |
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Srinivasan et al. ( |
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Vanaie et al. ( |
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Asadi et al. ( |
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Funamoto et al. ( |
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Shafabakhsh et al. ( |
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Shafabakhsh et al. ( |
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Mokhtari et al. ( |
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NR, not reported.
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 (
The chronic hyperglycemic state contributes to oxidative stress by increasing levels of AGEs and ROS (
Arterial hypertension, dyslipidemia, older age, sedentary lifestyle, and abdominal obesity are key risk factors for T2DM (
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 (
Pathophysiology of diabetes mellitus. The hyperglycemic state leads to the increase in ROS and pro-inflammatory biomarkers related to the complications associated with diabetes. ROS, reactive oxygen species; AGEs, advanced glycation end-products; MAPK, mitogen-activated protein kinase; NADPHOX, nicotinamide adenine dinucleotide phosphate oxidase; NFKβ, nuclear factor-kappa β; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; IL-6, interleukin-6; VEGF, vascular endothelial growth factor; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion protein.
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 (
The genus
The main part of the plant is the rhizomes, and the most prevalent active components are the curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) (
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 (
The peculiar characteristics that attract scientists’ attention are the antioxidant and anti-inflammatory activities and the safety of its pharmacological profile (
Effects of curcumin. Curcumin can inhibit hyperglycemia, oxidative stress, and the inflammatory processes caused by Diabetes Mellitus, in addition, and consequently inhibits the systemic complications of this disease, such as hypertension, dyslipidemia, neuropathy, nephropathy, and endothelial dysfunction.
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 (
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 (
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 (
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 (
Several studies have investigated the effects of curcumin on diabetes. These studies are shown in
A Pilot Study performed in Mexico (
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 (
The results of Panahi et al. (
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 (
The trial results performed by Panahi et al. (
Positive effects of curcumin were also found by Adab et al. (
The trial performed by Adibian et al. (
In the trial performed by Asadi et al. (
The randomized, double-blind placebo-controlled trial performed in Iran by Hodaei et al. (
Srinivasan et al. (
In the trial performed by Vanaie et al. (
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 (
Funamoto et al. (
The results of Shafabakhsh et al. (
Another clinical trial developed by Shafabakhsh et al. (
The clinical trial developed by Mokhtari et al. (
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.
T2DM has a multifactorial pathology and affects thousands of people worldwide. Its treatment consists of lifestyle changes, diet, physical activity, and therapies with medications for the rest of life. Curcumin is a natural anti-inflammatory and anti-diabetic agent representing a safe and low-cost alternative for this condition’s therapeutic approach, although it is still necessary to know its effective dose. We suggest that more robust and rigorous randomized controlled clinical trials are carried out to establish the role of curcumin in the therapeutics of T2DM.
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
All the authors contributed equally to the manuscript. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.