Chromium is an essential trace element that is the cofactor for the chromodulin protein — the low-molecular-weight chromium-binding protein that amplifies the insulin signal at the insulin receptor by potentiating the autophosphorylation of the beta subunit of the receptor and by activating the downstream insulin receptor substrate (IRS) proteins and the phosphoinositide 3-kinase (PI3K) pathway. The chromodulin is synthesised in the body from the dietary chromium and from the amino acids (particularly the cysteine, the glutamate, and the aspartate), and it consists of four chromodulin molecules that bind four chromium atoms (as Cr3+) in a coordination complex that is stabilised by the amino acid ligands. When insulin binds to the insulin receptor, it induces a conformational change that activates the intrinsic tyrosine kinase activity of the receptor, and the chromodulin binds to the activated receptor and amplifies this signal by promoting the further autophosphorylation of the receptor and by preventing the dephosphorylation of the receptor by the protein tyrosine phosphatases. This chromodulin-dependent amplification of the insulin signal is essential for the normal sensitivity of the insulin receptor to insulin, and when chromium is deficient and chromodulin synthesis is impaired, the insulin signal is not amplified, the insulin receptor is less sensitive to insulin, and the insulin resistance develops — producing the elevated fasting blood glucose, the elevated fasting insulin, the impaired glucose tolerance, and the dyslipidaemia that are the hallmark of the insulin resistance syndrome.
Chromodulin and the Insulin Signalling Amplification
The chromodulin was first described in the 1970s as the low-molecular-weight chromium-binding substance that was required for the stimulation of the insulin receptor tyrosine kinase activity by chromium in vitro. Subsequent studies demonstrated that chromodulin is a oligopeptide (approximately 1,500 Da) that is synthesised in the body and that binds four chromium atoms (as Cr3+) in a coordination complex that is stabilised by the carboxylate groups of the aspartate and glutamate residues and by the imidazole groups of the histidine residues in the peptide chain. When the insulin receptor is activated by insulin binding, the beta subunit of the receptor undergoes autophosphorylation at multiple tyrosine residues, and the chromodulin binds to this activated receptor (at a site that is distinct from the insulin-binding site) and amplifies the signal by promoting the further autophosphorylation of the receptor and by inhibiting the dephosphorylation of the receptor by the protein tyrosine phosphatase 1B (PTP1B). Without adequate chromodulin (and therefore without adequate chromium), the insulin signal is not amplified, the receptor autophosphorylation is reduced, and the downstream signalling cascade (including the IRS phosphorylation, the PI3K activation, and the GLUT4 translocation) is impaired — producing the insulin resistance that is the hallmark of the chromium deficiency.
The clinical importance of the chromium-dependent insulin signalling amplification is underscored by the observation that chromium supplementation improves the insulin sensitivity and reduces the blood glucose levels in people with type 2 diabetes, with insulin resistance, and with the gestational diabetes that is associated with the pregnancy. Multiple RCTs and meta-analyses have demonstrated that chromium supplementation at 200-500mcg daily (as chromium picolinate, which is the most bioavailable form) reduces the fasting blood glucose by approximately 1.1 mmol/L (approximately 20mg/dL), reduces the HbA1c by approximately 0.6%, and improves the insulin sensitivity (as measured by the HOMA-IR, the QUICKI, and the hyperinsulinaemic-euglycaemic clamp) in people with type 2 diabetes and with insulin resistance. The improvements in glycaemic control are most pronounced in people with the most severe insulin resistance and with the most elevated baseline HbA1c levels, and they are most consistent in people who are taking the chromium picolinate form (which has a higher bioavailability than the chromium chloride or the chromium polynicotinate forms).
Chromium and the Gestational Diabetes
Chromium has been studied extensively in the context of the gestational diabetes (GDM) — the glucose intolerance that is first diagnosed during the pregnancy and that is associated with an increased risk of the maternal and the foetal complications (including the pre-eclampsia, the macrosomia, the shoulder dystocia, and the type 2 diabetes later in life). The GDM is driven by the insulin resistance that is a normal physiological adaptation to the pregnancy (produced by the placental hormones, including the human placental lactogen and the progesterone) and that is exaggerated in women who have a pre-existing tendency to insulin resistance. Chromium supplementation has been shown in multiple RCTs to improve the glycaemic control and to reduce the need for the exogenous insulin in women with GDM — a meta-analysis of 9 RCTs in 456 women with GDM found that chromium supplementation significantly reduced the fasting blood glucose, the postprandial blood glucose, the HbA1c, and the insulin dose required to achieve the glycaemic targets compared to placebo. These findings suggest that chromium is an effective and safe intervention for the management of the GDM, and that it should be considered as a first-line nutritional intervention in women with GDM who want to minimise their reliance on the exogenous insulin.
Practical Application
For general chromium supplementation, the evidence-based approach is to supplement with 200-500mcg of chromium daily (as chromium picolinate, which is the most bioavailable form — it has a bioavailability that is approximately 3-5 times higher than the chromium chloride form). The AI of chromium is 35mcg daily for men and 25mcg daily for women, but these levels are based on the prevention of the deficiency symptoms rather than on the optimisation of the insulin sensitivity, and many nutritionists recommend higher doses (200-500mcg daily) for people who have insulin resistance, type 2 diabetes, or GDM. For the management of the insulin resistance and of the type 2 diabetes, the evidence-based dose is 200-500mcg of chromium picolinate daily, which has been shown to be safe and effective in multiple RCTs and meta-analyses. For comprehensive glycaemic control support, chromium pairs well with the alpha-lipoic acid (which has additional insulin-sensitising effects through the activation of the AMPK pathway), with the berberine (which has been shown in multiple RCTs to reduce the blood glucose and the HbA1c in people with type 2 diabetes), with the cinnamon bark extract (which has been shown to improve the insulin sensitivity in people with type 2 diabetes), and with the magnesium (which is required for the insulin receptor signalling and whose deficiency is associated with the insulin resistance).
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