3.1. Flowchart and studies selection
From a total of 1.129 publications that were obtained by the combined searches on databases Pubmed, Scopus, ScienceDirect, Cochrane, and other additional sources like Google Scholar and Academic databases, 346 were removed because they were duplicates publications and 783 were evaluated by title and whole abstract. After reading title and abstracts, 731 were excluded because they were unrelated to the topics- they were not randomized clinical studies, but they were observational studies, epidemiological studies, animal studies, review studies, previous systematics reviews and metanalysis. Other studies evaluated patients without type 2 diabetes mellitus but related diseases or they evaluated other substances on food or other dietary supplementation without chromium. When full-text version of remaining 52 articles were read, 37 studies did not fulfill the inclusion criteria. Finally, 15 RCTs were included in the systematic review (Fig1., Table 1-2), and they were evaluated (Table 3) with Cochrane assessment tool of quality.
3.2. Main characteristics of selected studies
The included RCT studies which were published between 2002-2023, included a total of 1.223 participants and were conducted in 11 different countries. The studies provided evidence for a potential link between chromium (picolinate, chloride, yeast, nicotinate) exposure through dietary supplementation and affection of type 2 diabetes mellitus (Table 1). Previous several studies had identified significant associations between chromium supplementation and inadequate glucose regulation or insulin resistance, indicating that chromium supplementation may benefit glucose metabolism in type 2 diabetes.
The design of the included trials was either a double-blind randomized placebo-controlled study, or single-blind randomized placebo-controlled study, and a parallel or crossover study. The mean age of the participants ranged from 30 to 70 years. All studies were done on both genders except for two trials that did not report the distinction of the genders of participants. Participants in all studies were patients with type 2 diabetes mellitus. In each study there were specific criteria for the patient-participants in the research. Most studies excluded diabetic patients with preexisting chronic conditions or a family history of cardiovascular disease, a history of liver or kidney disease, sickle cell anemia, or metabolic disorders, including uncontrolled hypertension, hypothyroidism, or hyperthyroidism. Patients also with a gastrointestinal disorder, peptic ulcer, severe constipation, or diarrhea requiring long-term medication, lactose intolerance, pregnant and lactating women, patients who have recently undergone surgery or had an acute infection, renal dysfunction with serum creatinine 1.5 mg /dl or greater, increased liver enzymes aspartate aminotransferase and aminotransferase (AST) (ALT) more than 2.5 times. People who used drugs or consumed alcohol daily were also excluded from the studies (Table 2).
3.3. Assessment of studies methodological quality
Eleven researches indicated an unclear possibility of bias, whereas four studies revealed a random assignment of participants. Five trials with allocation concealment were reported, and the remaining trials had an unclear risk of bias. Bias in participants, individuals, and evaluation of outcomes blinding was minor throughout the most of trials. Based on incomplete outcome data and selective reporting, six studies reported a low probability of bias. For further biased sources, ten studies indicated a low risk of bias (Table 3). Overall, based on Cochrane tool scores, 7 studies were classified as good-quality (score > 3), 6 studies were fair-quality (score = 3), and 2 study were weak-quality (score < 2). More details of the risk of bias assessment are described in Table 2 and illustrated in Fig2..
Table 1. Main characteristics of studies selected.
Author/Publication
|
Study's Country
|
Study Design
|
Type of patient
|
Total Sample size
|
Male/Female (Sex)
|
M. Age (yo)
|
Duration of trial (months)
|
Intervention
|
Experimental Group
|
Dose of Chromium
|
Control Group
|
Final Sample Size
|
Ghosh et al., 2002
|
India
|
DBRP-CCS
|
T2DM
|
100
|
50M:50F
|
53-63
|
3
|
CrPic
|
400 μg
|
placebo
|
50EG:50CG
|
Vrtovec et al., 2005
|
Slovenia
|
DBRP-CCS
|
T2DM
|
60
|
NR
|
NR
|
3
|
CrPic
|
1000 μg
|
placebo
|
30EG:30CG
|
Racek et al., 2006
|
Denmark
|
RP-CPS
|
T2DM
|
36
|
9M:27F
|
60-70
|
4
|
CY
|
400 μg
|
placebo
|
19EG:17CG
|
Kleefstra et al., 2006
|
Netherlands
|
DBRP-CS
|
T2DM
|
46
|
19M:27F
|
60-62
|
6
|
CrPic
|
500 μg & 1000 μg
|
placebo
|
29EG:17CG
|
Lai, 2008
|
Taiwan
|
RP-CPS
|
T2DM
|
20
|
9M:11F
|
50-53
|
5
|
CY
|
1000 μg
|
placebo
|
10EG:10CG
|
Sharma et al., 2011
|
India
|
RP-CPS
|
T2DM
|
40
|
NR
|
35-67
|
3
|
CY
|
378 μg
|
placebo
|
20EG:20CG
|
Chen et al, 2013
|
Taiwan
|
DBRP-CS
|
T2DM
|
66
|
43M:23F
|
30–75
|
4
|
CrCl3
|
200 lg/tablet
|
placebo
|
38EG:28CG
|
Rocha et al., 2014
|
Brazil
|
CRCT
|
T2DM
|
17
|
2M:15F
|
59
|
3
|
CrPic
|
100 μg BID
|
placebo
|
6EG:6CG
|
Paiva et al., 2015
|
Brazil
|
SBRP-CS
|
T2DM
|
71
|
25M:46F
|
30-70
|
4
|
CrPic
|
600 μg/day
|
placebo
|
32EG:39CG
|
Guimaraes et al., 2016
|
Brazil
|
DBRP-CS
|
T2DM
|
56
|
12M:30F
|
30-60
|
3
|
CrN
|
50 μg & 200 μg
|
placebo
|
28EG:28CG
|
Karim et al., 2018
|
Pakistan
|
DBRP-CS
|
T2DM
|
400
|
200M:200F
|
30-60
|
6
|
CrPic
|
200 μg/day
|
sitagliptin
|
200EG:200CG
|
Derosa et al., 2019
|
Italy
|
DBRP-CS
|
T2DM
|
164
|
38M:43F
|
62-63
|
6
|
CrPic
|
1/day
|
placebo
|
89EG:86CG
|
Imanparas et al.. 2020
|
Iran
|
RP-CS
|
T2DM
|
46
|
23M:23F
|
35-70
|
4
|
CrPic
|
500 μg
|
placebo
|
23EG:23CG
|
Talab et al., 2020
|
Iran
|
DBRP-CS
|
T2DM
|
41
|
7M:34F
|
50-51
|
2
|
CrPic
|
400 μg
|
placebo
|
22EG:19CG
|
Alkhalidi , 2023
|
Iraq
|
SBRP-CS
|
T2DM
|
60
|
28M:32F
|
40-60
|
3
|
CrPic
|
200 μg
|
placebo
|
30EG:30CG
|
Abbreviations: DBRP-CCS: Double-blind randomized placebo-controlled crossover study; RP-CS: Randomized placebo-controlled study; RP-CPS: Randomized placebo-controlled study; CRCT: Crossover randomised controlled trial; DBRP-CS: Double-blind randomized placebo-controlled study; SBRP-CS: Single-blind randomized placebo-controlled study; T2DM: Type 2 diabetes mellitus; M: Male; F: Female; yo: years old; CP: Chromium picolinate; EG: Experimental group; CG: Control group; FPG: Fasting plasma glucose; HbA1c: hemoglobin A1c; BMI: Body Mass Index; CHD: Coronary heart disease; BID: twice daily; NR: No Reply or Response; CrPic: Chromium picolinate; CrCl3: Chromium chloride; CrN: Chromium nicotinate; CY: Chromium yeast
|
Table 2. Eligibility criteria of selected studies
Author
|
Eligibility Criteria
|
Ghosh et al., 2002
|
Patients with diet alone for T2DM or diet and oral hypoglycaemic agents with reasonably stable (not optimum in all cases) glycemic control.
|
Vrtovec et al., 2005
|
No patients were using medications that could affect glucose homeostasis or QTc interval duration (thiazides, corticosteroids, phenothiazines, estrogens, sympathomimetics, type I and type II antiarrhythmic agents).
|
Racek et al., 2006
|
Patients with clinically diagnosed type 2 diabetes mellitus.
|
Kleefstra et al., 2006
|
1. A1C: 8%, daily use of insulin 50 units. 2. Creatinine: 150 mol/l for men and 120 mol/l for women. 3. Creatinine clearance: 50 ml/min. 4. Alanine aminotransferase: 90 units/l.
|
Lai, 2008
|
1. Patients who had been diagnosed with diabetes at least 5 years previously (fasting glucose >8.5 mmol/L and HbA1c >8.5%).
2. No trace element and vitamin supplementation in the preceding 3 months, and ongoing gastric or diuretic treatment.
|
Sharma et al., 2011
|
New-onset patients with type 2 diabetes.
|
Chen et al, 2013
|
1. FPG: 140 - 250 mg/dl & HbA1c: 7.5–12 % & BMI: 20 - 35 kg/m2. 2. No patients who received an insulin injection in the last three months. 3. No patients with other diseases.
|
Rocha et al., 2014
|
1. No patients who received an insulin therapy. 2. No patients with schemic heart disease.
|
Paiva et al., 2015
|
1. HbA1c ≥7% 2. 2. No patients who characterized with poorly controlled diabetes. 3. No patients with use of chromium supplements within the 4 months prior to the study.
|
Guimaraes et al., 2016
|
1. BMI: > 25 Kg/m2 & increased waist circumference (men ≥ 102 cm and women ≥ 88 cm). 2. No patients with insulin therapy & with chronic complications of diabetes.
|
Karim et al., 2018
|
1. HbAlc >8% & Hb >12-14. 2. No patients with kidney disease. 3. Last 2 months, the patient did not take vitamins or minerals.
|
Derosa et al., 2019
|
1. Patients needed to take different anti-diabetic treatments at a stable dose form at least 3 months. 2. HbA1c >6.5%, & BMI ≥25 and <30 Kg/m2. 3. No previous ketoacidosis or unstable or rapidly progressive diabetic retinopathy, nephropathy, or neuropathy.
|
Imanparas et al.. 2020
|
1. BMI <35 kg/m2. 2. Patients not to change their diabetes drugs or diet.
|
Talab et al., 2020
|
1. No patients with background of thyroid, liver, and any chronic diseases or under medical therapy for hyperlipidemia. 2. No consumption of any other supplements (antioxidants, minerals or vitamins, omega 3, and carnitine) or herbal medicines.
|
Alkhalidi , 2023
|
Uncontrolled type two diabetes mellitus.
|
Abbreviations: T2DM: Type 2 diabetes mellitus; FPG: Fasting plasma glucose; HbA1c: hemoglobin A1c; BMI: Body Mass Index; CHD: Coronary heart disease; BID: twice daily; NR: No Reply or response
|
Table 3. Reporting the quality/risk of bias with Cochrane quality assessment tool (Higgins et al., 2011).
3.4.Trivalent chromium and its types
Chromium is an essential nutrient, with a particularly significant function in carbohydrate and lipid metabolism (Abdollahi et al., 2013). The problem with chromium is that it has a generally low bioavailability, causing the question of which form of supplemental chromium has the best bioavailability essential. In the systematic review, in terms of supplement type, 10 studies chromium picolinate, 3 studies chromium yeast, 1 study chromium chloride, and 1 study chromium nicotinate. The dosage of chromium was between 50 and 1000 μg/day and it was consumed from 2 to 6 months.
Trivalent chromium is available on the market as a dietary supplement in various forms, with chromium picolinate, chromium chloride, and chromium yeast being the dominant forms. Chromium chloride is the naturally occurring trivalent variety of chromium found in common food sources such as whole grains, broccoli, mushrooms, and green beans. Cr picolinate, a trivalent variety of chromium, is the synthetic salt form of Cr chloride. Chromium yeast is a nutritional supplement that is used in the food industry to fortify diets with trivalent chromium. To increase the nutritional content of processed goods like bread, cereals, and pasta, chromium yeast is commonly added. Furthermore, it has the potential to decrease the sugar and fat content of some foods, which will enhance their nutritional value.
These forms of chromium are provided either as stand-alone supplements or in combination products with other minerals or vitamins, such as nicotinic chromium. Chromium nicotinate is a chromium complex combining chromium, and niacin - a B vitamin (B3). Previous studies support the effectiveness of nicotinic chromium in regulating glycemic control in type 2 diabetes, balancing blood sugar levels, reducing relative weight, and lowering cholesterol levels.
3.5. Relationship between chromium and type 2 diabetes mellitus
The results highlight the potential role of trivalent chromium as an adjunctive pharmaceutical supplement in the management of T2DM, emphasizing the importance of nutritional interventions for the greater well-being of diabetic patients. Several studies investigated the impact of trivalent chromium supplementation, as chromium picolinate, on glycemic control (GC), on insulin sensitivity (ISF), on insulin resistance (HOMA-IR), on glycated hemoglobin levels (HbA1c), fasting blood sugar (FBS or fasting plasma glucose-FPG)), on postprandial glucose (PPG), on waist circumference (WC), on electrocardiographic interval (QTc) and on related parameters in patients with type 2 diabetes mellitus (T2DM). The potential positive effect of chromium chloride, chromium nicotine and chromium yeast has been investigated to a lesser extent. These types of trivalent chromium, emphasize on reduced insulin sensitivity (SI), on β-cell function, on low-grade inflammatory state, on insulin sensitivity (ISF), on markers of oxidative stress (glutathione peroxidase, reduced glutathione) and on other related parameters in patients with type 2 diabetes mellitus (T2DM).
Ghosh et al. (2002) found that by administering chromium picolinate (200 µg BID), there was significantly increased serum chromium levels, improving glycemic control (GC) and insulin sensitivity (ISF) in T2DM patients. In contrast, other parameters such as cardiovascular potential and lipid profile changes had no significant change. Kleefstra et al., 2006 evaluated the effect of chromium picolinate treatment on glycemic control (GC) in an obese Western population of insulin-dependent patients with poorly controlled type 2 diabetes. Daily administration of chromium picolinate resulted in its change. Other parameters such as lipid profile, BMI, blood pressure and insulin requirements had no significant differences.
In another RCT study with 600 diabetic patients, the combination of low-dose niacin and chromium picolinate with sitagliptin proved highly effective in their fasting blood sugar values (FBS), as well as in glycated hemoglobin levels (HbA1c), positioning it as a viable therapeutic option for diabetes management (Karim et. al, 2008). A similar study, (Rocha et al., 2014) investigated the effect of twice-daily chromium picolinate supplementation (100 μg) in T2DM patients. Although, there was no significant changes in anthropometric measures, there was a significant reduction in HbA1c, indicating improved glycemic control.
Another study (Paiva et al., 2015) highlighted chromium picolinate's role as an adjunctive therapy for glycemic control (GC) in patients with uncontrolled T2DM, showing reductions in fasting and postprandial glucose concentrations and greater reductions in glycated hemoglobin (HbA1c). However, lipid profile changes were not significant, except for a decrease in serum ferritin. Only one study investigated the effect of chromium picolinate supplementation on the duration of the electrocardiographic interval (QTc) in patients with type 2 diabetes (Vrtovec et al. 2015). They observed a significant reduction in QTc duration after three months with chromium picolinate administration, particularly in patients with higher BMI, suggesting potential benefits in obese patients with significant insulin resistance (HOMA-IR). Derosa et al. (2019) evaluated a dietary combination of polyphenolic extracts and chromium picolinate as an additional supplement to the existing antidiabetic treatment in T2DM patients. The group consuming the supplement showed significant reductions in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG) and waist circumference (WC) compared to baseline and placebo. The combination's inhibitory effects on enzyme activities contributed to glucose reduction, highlighting its effectiveness as an adjunct to antidiabetic therapy. Polyunsaturated fatty acids (PUFAs) and chromium in the nutrient mixture further improved glycometabolic parameters.
Talab et al. (2020) reported modest beneficial effects of chromium picolinate on insulin resistance (HOMA-IR) and lipid profile in T2DM patients. Specifically, no significant changes were observed in body weight, body mass index and fasting blood glucose (FBG), but significant differences in total cholesterol, low-density lipoprotein cholesterol and on insulin resistance (HOMA-IR). Imanparast et al. (2020) conducted a randomized trial with vitamin D3 and chromium picolinate supplementation, showing a synergistic effect in controlling insulin and insulin resistance (HOMA-IR), with a decrease in tumor necrosis factor-α (TNF-α). In a similar study by Alkhalidi (2023), chromium supplementation significantly reduced glycated hemoglobin levels (HbA1c) and approached normal fasting blood sugar levels (FBS) in T2DM patients. Serum cholesterol decreased, and high-density lipoprotein (HDL) increased, aligning with previous studies emphasizing chromium's positive effects on blood sugar and lipid levels, indicative of its role in insulin sensitivity and glucose regulation. Chen et al., 2014, investigated the effects of chromium chloride on insulin sensitivity (SI), β-cell function, and inflammatory markers in type 2 diabetes mellitus. Chromium chloride supplementation significantly improved insulin sensitivity (SI), while an increased static insulin response index (US) and a decrease in interleukin-6 (IL-6) were observed. However, no significant correlation was observed between changes in IL-6 and SI or Us. Consequently, there was a significant improvement in the second phase of insulin and IL-6 response, with positive implications for the management of type 2 diabetes mellitus. Other study focused on nicotinic chromium supplementation at two doses of 50 μg and 200 μg in T2DM patients. The patients who receiving nicotinic chromium 50 μg had a moderate to significant reduction in body weight, without significant changes in body composition or insulin sensitivity (ISF) (Guimaraes et al., 2016).
The study by Racek et al., 2006 evaluated the effect of chromium-enriched yeast on blood glucose, insulin variables, blood lipids, and markers of oxidative stress in people with type 2 diabetes mellitus. The study showed a significant increase in serum chromium levels and a reduction in fasting serum glucose. Oxidative stress markers (glutathione peroxidase, reduced glutathione) remained stable, and glycated hemoglobin levels (HbA1c) tended to increase in the placebo group. HbA1c and fructosamine were essentially unchanged in the the patients who consumed chromium yeast. In contrast, HbA1c tended to increase on placebo. Serum chromium levels were significantly increased in both patients and controls, possibly influenced by dietary variations. Serum chromium measurements reflected good compliance and absorption in the patients who consumed chromium yeast. Lai (2008) explored yeast chromium supplementation independently and in combination with vitamins C and E in patients with type 2 diabetes mellitus, with glycosylated hemoglobin (HbA1c) >8.5%. The findings indicated significant reductions in thiobarbituric acid active substances (TBARS) and improvements in fasting glucose (FPG), HbA1c, and insulin resistance (ISF). This suggests the efficacy of chromium supplementation, alone or combined with vitamins C and E, in minimizing oxidative stress and improving glucose metabolism in T2DM. In a similar study, patients newly diagnosed as type 2 diabetics showed a significant reduction in fasting blood glucose levels, improved glycemic control with reduced HbA1C values, and positive changes in lipid variables. In addition, total cholesterol, triglyceride, and LDL levels were significantly reduced. This suggests a positive effect of yeast chromium supplementation on glycemic control and lipid variables in patients with newly diagnosed type 2 diabetes (Sharma et al., 2011).