Chromium in glucose metabolism

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Chromium is claimed to be an essential element involved in the regulation of blood glucose levels within the body. [1] More recent reviews have questioned this however. [2]

Contents

It is believed to interact with the low-molecular weight chromium (LMWCr) binding substance to amplify the action of insulin. Today, the use of chromium as a dietary supplement for the treatment of diabetes mellitus type 2 is still controversial. This is because most of the clinical studies that have been conducted around chromium have been administered only for short periods of time on small sample populations, and have in turn yielded variable findings. To better understand the potential role chromium may play in the treatment of type II diabetes, long-term trials need to be conducted for the future. [3]

History

The notion of chromium as a potential regulator of glucose metabolism began in the 1950s when Walter Mertz and his co-workers performed a series of experiments controlling the diet of rats. The experimenters subjected the rats to a chromium deficient diet, and witnessed an inability of the organisms to respond effectively to increased levels of glucose within the blood. They then included "acid-hydrolyzed porcine kidney and Brewer's yeast" in the diet of these rats, and found that the rats were now able to effectively metabolize glucose. Both the porcine kidney and Brewer's yeast were rich in chromium, and so it was from these findings that began the study of chromium as a regulator of blood glucose. [4]

The idea of chromium being used for the treatment of type II diabetes was first sparked in the 1970s. A patient receiving total parenteral nutrition (TPN) had developed "severe signs of diabetes", and was administered chromium supplements based on previous studies that proved the effectiveness of this metal in modulating blood glucose levels. The patient was administered chromium for a total of two weeks, and by the end of this time-period, their ability to metabolize glucose had increased significantly; they also now required less insulin ("exogenous insulin requirements decreased from 45 units/day to none"). It was these experiments that were performed in the 1950s and 1970s that paved the foundation for future studies on chromium and diabetes. [3]

In 2005, the U.S. Food and Drug Administration approved a Qualified Health Claim for chromium picolinate with a requirement for very specific label wording: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." [5] In 2010, chromium(III) picolinate was approved by Health Canada to be used in dietary supplements. Approved labeling statements included: "...provides support for healthy glucose metabolism." [6] The European Food Safety Authority (EFSA) approved claims in 2010 that chromium contributed to normal macronutrient metabolism and maintenance of normal blood glucose concentration. [7]

A 2016 review of meta-analyses concluded that whereas there may be modest decreases in fasting plasma glucose or gylcated hemoglobin that achieve statistical significance, the changes were rarely large enough to be expected to be relevant to clinical outcome. [8]

Human studies

Looking at the results from four meta-analyses, one reported a statistically significant decrease in fasting plasma glucose levels (FPG) and a non-significant trend in lower hemoglobin A1C (HbA1C). [9] A second reported the same, [10] a third reported significant decreases for both measures, [11] while a fourth reported no benefit for either. [12] A review published in 2016 listed 53 randomized clinical trials that were included in one or more of six meta-analyses. It concluded that whereas there may be modest decreases in FPG and/or HbA1C that achieve statistical significance in some of these meta-analyses, few of the trials achieved decreases large enough to be expected to be relevant to clinical outcome. [8]

Proposed mechanism of action

The mode of action through which chromium aided in the regulation of blood glucose levels is poorly understood. Recently, it has been suggested that chromium interacts with the low-molecular weight chromium (LMWCr) binding substance to potentiate the action of insulin. [3] LMWCr has a molecular weight of 1500, and is composed solely of the four amino acid residues of glycine, cysteine, aspartic acid and glutamate. [13] It is a naturally occurring oligopeptide that has been purified from many sources: rabbit liver, porcine kidney and kidney powder, bovine liver, colostrum, dog, rat and mouse liver. [14] Widely distributed in mammals, LMWCr is capable of tightly binding four chromic ions. The binding constant of this oligopeptide for chromium ions is very large, (K ≈ 1021 M−4), suggesting it is strong and tightly binding. LMWCr exists in its inactive or apo form within the cytosol and nucleus of insulin-sensitive cells. [13]

When insulin concentrations within the blood rise, insulin binds to the external subunit of the insulin-receptor proteins, and induces a conformational change. This change results in the autophosphorylation of the tyrosine residue located on the internal ß-subunit of the receptor, thereby activating the receptor's kinase activity. [14] An increase in insulin levels also signals for the movement of transferrin receptors from the vesicles of insulin-sensitive cells to the plasma membrane. Transferrin, the protein responsible for the movement of chromium through the body, binds to these receptors, and becomes internalized via the process of endocytosis. The pH of these vesicles containing the transferrin molecules is then decreased (resulting in increased acidity) by the action of ATP-driven proton pumps, and as a consequence, chromium is released from the transferrin. The free chromium within the cell is then sequestered by LMWCr. [3] The binding of LMWCr to chromium converts it into its holo or active form, and once activated, LMWCr binds to the insulin receptors and aids in maintaining and amplifying the tyrosine kinase activity of the insulin receptors. In one experiment that was performed on bovine liver LMWCr, it was determined that LMWCr could amplify the activity of protein kinase receptors by up to seven-fold in the presence of insulin. [13] Furthermore, evidence suggests that the action of LMWCr is most effective when it is bound to four chromic ions. [14]

When the insulin signaling pathway is turned off, the insulin receptors on the plasma membrane relax and become inactivated. The holo-LMWCr is expelled from the cell and ultimately excreted from the body via urine. [13] LMWCr cannot be converted back into its inactive from due to the high binding affinity of this oligopeptide for its chromium ions. As of currently, the mechanism through which apo-LMWCr is replaced within the body is unknown. [14]

See also

Related Research Articles

Insulin Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

Metabolic syndrome

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.

Type 2 diabetes Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Glucagon

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

Metformin Medication

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is not associated with weight gain. It is taken by mouth.

Transferrin Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of Iron (Fe) through blood plasma. It is produced in the liver and contains binding sites for two Fe3+ atoms. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

Hyperinsulinemia Abnormal increase in insulin in the bloodstream relative to glucose

Hyperinsulinemia is a condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose. While it is often mistaken for diabetes or hyperglycaemia, hyperinsulinemia can result from a variety of metabolic diseases and conditions, as well as non-nutritive sugars in the diet. While hyperinsulinemia is often seen in people with early stage type 2 diabetes mellitus, it is not the cause of the condition and is only one symptom of the disease. Type 1 diabetes only occurs when pancreatic beta-cell function is impaired. Hyperinsulinemia can be seen in a variety of conditions including diabetes mellitus type 2, in neonates and in drug-induced hyperinsulinemia. It can also occur in congenital hyperinsulinism, including nesidioblastosis.

Endothelin

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

Chromium(III) picolinate

Chromium(III) picolinate (CrPic3) is a chemical compound sold as a nutritional supplement to treat type 2 diabetes and promote weight loss. This bright-red coordination compound is derived from chromium(III) and picolinic acid. Large quantities of chromium are needed for glucose utilization by insulin in normal health, but deficiency is extremely common and has been observed in people receiving 100% of their nutrient needs intravenously, i.e., total parenteral nutrition diets. Chromium has been identified as regulating insulin by increasing the sensitivity of the insulin receptor. As such, chromium(III) picolinate has been proposed as a treatment for type 2 diabetes, although its effectiveness remains controversial due to conflicting evidence from human trials.

Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the 1990s. Cases of deficiency were described in people who received all of their nutrition intravenously for long periods of time.

Branched-chain amino acid

A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid.

Glucose transporter type 4 (GLUT-4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.

Blood sugar regulation

Blood sugar regulation is the process by which the levels of blood sugar, primarily glucose, are maintained by the body within a narrow range. This tight regulation is referred to as glucose homeostasis. Insulin, which lowers blood sugar, and glucagon, which raises it, are the most well known of the hormones involved, but more recent discoveries of other glucoregulatory hormones have expanded the understanding of this process.The gland called pancreas secrete two hormones and they are primarily responsible to regulate glucose levels in blood.

Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an oligopeptide that seems to transport chromium in the body. It consists of four amino acid residues; aspartate, cysteine, glutamate, and glycine, bonded with four (Cr3+) centers. It interacts with the insulin receptor, by prolonging kinase activity through stimulating the tyrosine kinase pathway, thus leading to improved glucose absorption. and has been confused with glucose tolerance factor.

Phonemic neurological hypochromium therapy (PNHT) is a technique that uses insemination devices to implement chromium (Cr3+) into the hypothalamic regions of the brain. It has been proposed by Dr. Nicole Kim to offset delayed phonemic awareness in children between the ages of 3 and 8. The causes of delayed phonemic awareness have been linked to an inability to break down chromium triastenitephosphate. PNHT has been successfully implemented into in vivo mice with some controversial side effects, including; polydactyly, regurgitation, fatigue, and nausea. While Russia, Poland, and Ukraine have approved this procedure, the United States Food and Drug Administration (USFDA) has not yet granted its approval.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Diabetes Group of metabolic disorders involving long-term high blood sugar

Diabetes mellitus (DM), commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Symptoms often include frequent urination, increased thirst, and increased appetite. If left untreated, diabetes can cause many complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment.

Lobeglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonist for both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.

References

  1. ↑ Guerrero-Romero, F; Rodríguez-Morán, M (2005). "Complementary Therapies for Diabetes: The Case for Chromium, Magnesium, and Antioxidants". Archives of Medical Research. 36 (3): 250–257. doi:10.1016/j.arcmed.2005.01.004. PMID   15925015.
  2. ↑ Lay, Peter A. (2012). "Chromium: Biological Relevance". "Chromium: biological relevance" in "Encyclopedia of Inorganic and Bioinorganic Chemistry. John Wiley & Sons. doi:10.1002/9781119951438.eibc0040. ISBN   9781119951438.
  3. 1 2 3 4 Cefalu, W. T.; Hu, F. B. (2004). "Role of chromium in human health and in diabetes". Diabetes Care. 27 (11): 2741–2751. doi: 10.2337/diacare.27.11.2741 . PMID   15505017.
  4. ↑ Schwarz, K; Mertz, W (1959). "Chromium(III) and the glucose tolerance factor". Archives of Biochemistry and Biophysics. 85: 292–295. doi:10.1016/0003-9861(59)90479-5. PMID   14444068.
  5. ↑ FDA Qualified Health Claims: Letters of Enforcement Discretion, Letters of Denial U.S. Food and Drug Administration, Docket #2004Q-0144 (August 2005).
  6. ↑ "Monograph: Chromium (from Chromium picolinate)". Health Canada. December 9, 2009. Retrieved March 24, 2015.
  7. ↑ "Scientific Opinion on the substantiation of health claims related to chromium and contribution to normal macronutrient metabolism (ID 260, 401, 4665, 4666, 4667), maintenance of normal blood glucose concentrations (ID 262, 4667), contribution to the maintenance or achievement of a normal body weight (ID 339, 4665, 4666), and reduction of tiredness and fatigue (ID 261) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal. 8 (10). October 2010. doi: 10.2903/j.efsa.2010.1732 . ISSN   1831-4732.
  8. 1 2 Costello RB, Dwyer JT, Bailey RL (2016). "Chromium supplements for glycemic control in type 2 diabetes: limited evidence of effectiveness". Nutr. Rev. 74 (7): 455–468. doi:10.1093/nutrit/nuw011. PMC   5009459 . PMID   27261273.
  9. ↑ San Mauro-Martin I, Ruiz-León AM, et al. (2016). "[Chromium supplementation in patients with type 2 diabetes and high risk of type 2 diabetes: a meta-analysis of randomized controlled trials]". Nutr Hosp (in Spanish). 33 (1): 27. doi: 10.20960/nh.27 . PMID   27019254.
  10. ↑ Abdollahi M, Farshchi A, Nikfar S, Seyedifar M (2013). "Effect of chromium on glucose and lipid profiles in patients with type 2 diabetes; a meta-analysis review of randomized trials". J Pharm Pharm Sci. 16 (1): 99–114. doi: 10.18433/J3G022 . PMID   23683609.
  11. ↑ Suksomboon N, Poolsup N, Yuwanakorn A (2014). "Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes". J Clin Pharm Ther. 39 (3): 292–306. doi:10.1111/jcpt.12147. PMID   24635480.
  12. ↑ Bailey CH (January 2014). "Improved meta-analytic methods show no effect of chromium supplements on fasting glucose". Biol Trace Elem Res. 157 (1): 1–8. doi:10.1007/s12011-013-9863-9. PMID   24293356.
  13. 1 2 3 4 Vincent, J. B. (2000). "Elucidating a biological role for chromium at a molecular level". Accounts of Chemical Research. 33 (7): 503–510. doi:10.1021/ar990073r. PMID   10913239.
  14. 1 2 3 4 Vincent, J. B. (2000). "The biochemistry of chromium". The Journal of Nutrition. 130 (4): 715–718. doi: 10.1093/jn/130.4.715 . PMID   10736319.
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