US Pharm. 2006;31(11)(Diabetes suppl):1-4.
the rising number of patients opting for alternative therapies, it behooves
health care practitioners to learn more about the value of these approaches.
It is increasingly important for physicians, pharmacists, and other providers
to have a working understanding of how essential nutrients promote health and
prevent disease. There is no greater need for such a comprehensive approach
than in metabolic health, given the sharp rise in the past 25 years in the
number of people with diabetes and those at risk.1 The learning
curve starts with an understanding of the basic building blocks that promote
metabolic health, particularly insulin health and glucose metabolism. This
article reviews recent studies on two essential nutrients--chromium and
biotin--and their beneficial effects on glycemic control.
Chromium is an essential trace mineral required by the human body for normal carbohydrate and lipid metabolism.2 The body cannot make chromium; it must be obtained through the diet or by supplementation. The U.S. Department of Agriculture's analysis of food intake data suggests that the average American diet is low in chromium.3 Anderson reported that dietary intake of chromium is suboptimal in the U.S.3 Nutritional chromium is found in minute quantities in foods such as organ meats, oysters, mushrooms, broccoli, and brewers' yeast, and is further compromised by modern food processing and cooking methods. Rising sugar consumption also reduces chromium reserves in the body. Finally, aging is associated with a 25% to 40% drop in tissue chromium and may be implicated in type 2 diabetes mellitus (T2DM).4
Research indicates that diets containing less than 25% of normal chromium levels adversely affect insulin sensitivity in subjects with mildly impaired glucose tolerance. Over time, chromium loss may contribute to insulin resistance or may exacerbate it in people with T2DM.3
Chromium picolinate (CrPic) is an excellent source of chromium, since it is better absorbed and utilized by the body than is chromium chloride or other forms of nutritional chromium. Daily supplementation with 200 to 1,000 mcg of chromium as CrPic has consistently been found to improve insulin sensitivity, glucose tolerance, and circulating insulin levels.2,3 Of 13 human studies investigating CrPic's effectiveness in improving glucose control, 12 have shown significant positive effects in patients with type 1, type 2, and gestational diabetes, as well as in those at risk for diabetes.2,3
Biotin, a member of the B vitamin complex, is necessary for both metabolism and growth in humans, particularly in the production of fatty acids, antibodies, and digestive enzymes and in tissue metabolism.5 Importantly, for patients with diabetes, biotin stimulates liver glucokinase activity, increases insulin production, and enhances glucose uptake in muscle cells.6-8 Food sources of biotin include organ meats, soy, egg yolks, whole grains, and yeast. There is growing evidence of suboptimum biotin intake in the U.S. population.9
The following data are presented to support the beneficial effects of a supplement containing CrPic and biotin.
Increased Glucose Uptake: Researchers from University of Vermont incubated human skeletal muscle cell with CrPic, biotin, or a combination of these. The combination enhanced glucose uptake and increased glycogen synthesis through elevated glycogen synthase levels (Figure 1).8 A deficiency in glycogen synthase may lead to hyperglycemia and may contribute to insulin resistance.
Improved Glucose Metabolism and HDL Cholesterol Levels: JCR:LA-cp rats, a genetically obese, insulin-resistant animal model, were given CrPic and biotin combined or separately. This animal model exhibits many cardiovascular risk factors seen in obese humans. All nutrients, except for the lowest CrPic dose, significantly raised HDL cholesterol (HDL-C) levels. The highest doses of CrPic/biotin worked synergistically to increase HDL-C and improved glucose metabolism beyond that of either nutrient alone (Figure 2 ).10 Researchers hypothesized that the combination might benefit people who are insulin resistant and at risk for cardiovascular disease (CVD).
Importantly, some combinations of CrPic and biotin were more effective than others and were defined in these preclinical studies prior tohuman clinical trials.10
Human Clinical Studies
Improved Glycosylated Hemoglobin Levels: A 447-patient, double-blind, placebo-controlled study was conducted examining the impact of CrPic and biotin on glycemic control and lipid profile in patients with T2DM.11 Subjects had hemoglobin A1C (HbA1c) levels of 7% or higher, were taking stable oral antidiabetic medications for at least 60 days, had a body mass index more than 25 and less than 35 kg/m2, and had at least a one-year history of T2DM. Subjects received CrPic/biotin or placebo for 90 days. They continued therapy with their current oral antidiabetic agent(s) throughout the study.
A total of 369 subjects completed at least one follow-up visit. Of this population, those taking CrPic/biotin showed significant improvements in their levels of HbA1c (P <.01) and total cholesterol (TC) (P <.02) and in their triglycerides (TG)/HDL-C ratio (P <.0001), compared to placebo recipients. The greatest improvement in HbA1c levels occurred in subjects with the highest baseline HbA1c levels. For example, subjects whose baseline HbA1c level was above 10% averaged a 1.78-percentage point decrease, and those whose level was above 11% averaged nearly a 2–percentage point drop. In this high-risk group, the proportion of subjects with a 1–percentage point relative reduction from baseline was significantly higher in the CrPic/biotin group (74%) than in the placebo group (39%). Thus, CrPic/biotin may benefit individuals with T2DM who are hyperglycemic and have dyslipidemia, by reducing risk factors.
As a follow-up to this clinical trial, an open-label study followed 24 subjects taking CrPic/biotin along with their diabetes medications for another nine-month period. The mean HbA1c dropped significantly (-1.07%, P <.0001). Ten of 24 subjects reached the target of 7% established by the American Diabetes Association. This long-term study demonstrated the safety and effectiveness of the combination for the treatment of T2DM.
Improved Postprandial Glucose Levels: In a 30-day, double-blind, placebo-controlled study, 36 subjects with persistent impaired glucose control (two-hour glucose > 200 mg/dL) and HbA1c level at or above 7% and with at least a one-year history of T2DM were randomized to receive CrPic/biotin or placebo.12 Results showed a significant decrease in area under the curve for glucose (two-hour oral glucose tolerance test: P <.03), TG (P<.03), and TG/HDL-C ( P <.05) between groups. A significant correlation was noted between body weight and lipids (P<.05) and in the homeostasis model assessment for insulin resistance (P<.03) in the active group but not in the placebo group. In addition, a highly significant decrease in TC/HDL-C (P <0.03) and LDL-C/HDL-C (P <.05) was observed between groups. Consistent with its impact on impaired glucose control and coronary risk factors, CrPic/biotin improved insulin sensitivity and may therefore be a useful and cost-effective adjuvant therapy to improve impaired glucose tolerance.
Improved Glycemic Control: In an intervention program called the Diachrome Patient Experience Program (PEP), more than 100 participants with T2DM were tested. Patients worked with diabetes educators, received educational literature, were instructed in the use of a home blood glucose monitor, and received supplements containing CrPic/biotin. Participants continued their prescription antidiabetic medications.
The PEP aimed to evaluate whether CrPic/biotin could reduce elevated HbA1c levels when used in a "real life uncontrolled environment" in people with T2DM. Participants received CrPic/biotin for 12 weeks. Overall, the study found significant improvements in fasting and postprandial blood glucose levels, as well as lowered HbA1c levels. The average drop in fasting blood glucose (FBG) levels was from 158 to 137 mg/dL (P <.05), with an average drop of postprandial readings from 191 to 163 mg/dL (P<.01; Figure 3A).13 Significant changes in postprandial levels were seen within the first month, while significant lowering of fasting levels was seen at 90 days.
A separate analysis was performed of subjects (n = 30) whose HbA1c levels were highly elevated (>7%) despite the use of oral hypoglycemic agents. In these subjects, a reduction of 1.1 percentage points in average HbA1c (from 8.5% to 7.4%; P <.005) was seen. Eighteen participants with baseline HbA1c levels above 8% showed an average decrease of 1.8 percentage points (from 9.3% to 7.5%; P<.001) ( Figure 3B). Thus, the greatest improvements were observed in patients with the highest baseline levels (P<.001).13
Improved Lipid and Lipoprotein Levels: In the 90-day, double-blind, placebo-controlled study in people with T2DM referenced above, a subset of patients with high cholesterol levels (>200 mg/dL) taking CrPic/biotin showed improved blood lipid profiles, including reduced LDL (P <.02) and TC levels (P<.02).11,14 In addition, subjects with elevated non–HDL-C levels (>130 mg/dL) taking CrPic/biotin experienced reductions in TG (225 vs. 278 mg/dL), TG/HDL-C (5.4 vs. 6.6), TC/HDL-C (4.5 vs. 5.0), very low-density lipoprotein (VLDL)-C (37 vs. 49 mg/dL), and LDL-C/TG (0.79 vs. 0.66), compared to placebo recipients. The atherogenic index (AI = log[Tg/HDL]), a surrogate marker for CVD risk, was significantly reduced (P <.04) in active subjects, compared to placebo recipients. Thus, diabetic patients with elevated cholesterol can obtain significant improvement in lipid and lipoprotein levels after taking CrPic/biotin.
Another controlled study included subjects with two-hour glucose levels above 200 mg/dL on stable oral antidiabetic medications, HbA1c levels higher than 7%, and at least a one-year history of T2DM. Subjects were placed on CrPic/biotin (n =13) or placebo (n = 11). During a 30-day period, decreases in FBG, lipids, and lipoproteins were observed. Subjects treated with CrPic/biotin experienced significant decreases in TC (-19.1 mg/dL; P <.03), LDL-C (-10.9 mg/dL; P<.01) and apolipoprotein B (-5.3 mg/dL; P<.03) levels, while placebo recipients experienced increases in these measures (Figure 4).12,15
Mounting clinical evidence supports
the efficacy of CrPic/biotin for improving parameters of blood glucose
utilization, insulin sensitivity, and lipid metabolism in patients with
diabetes. Based on clinical results, dosing is recommended in a single daily
capsule containing 600 mcg of chromium (as CrPic) plus 2 mg of biotin, taken
in the morning preferably.
Proposed mechanisms for the nutrient combination suggest an enhancement of glucose disposal, glycogen synthesis, and increased glycogen synthase levels in skeletal muscle, with major implications in insulin resistance.
A 30-day rapid response to this nutrient formulation has been demonstrated in controlled studies measuring FBG and coronary risk factors. Longer-term (90-day) studies have shown additional improvements in HbA1c levels. Improvements in glycemic control, coupled with reductions in coronary risk factors, suggest that this product holds promise for longer-term impact in people with diabetes.
This nutritional adjuvant therapy offers promise for many of today's most critical health concerns linked to insulin resistance, including diabetes, impaired glucose tolerance, and metabolic syndrome. To better manage patients with T2DM, the addition of CrPic/biotin should be considered as part of first-line treatment, in addition to lifestyle modification and longer-term adjuvant therapy.
CrPic/biotin is available as Diachrome from Nutrition 21, Inc.
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12. Singer GM, Geohas J. The effect of chromium picolinate and biotin supplementation on glycemic control in poorly controlled patients with type 2 diabetes mellitus: A placebo-controlled, double blinded, randomized trial. Diab Ther Tech. 2006;(8-6), in press.
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