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Metabolic effects of chromium—Potential molecular mechanisms
CHAPTER
Metabolic effects of chromium—Potential molecular mechanisms
5 Sreejayan Nair
University of Wyoming, School of Pharmacy, College of Health Sciences, Laramie, WY, United States
INTRODUCTION Diabetes is a chronic metabolic disease in which the body does not produce or adequately use the hormone insulin leading to a dysregulation of glucose. Despite the discovery and characterization of new chemical entities that work by novel mechanisms, the number of people with diabetes has doubled over the past three decades. The Center for Disease Control estimates that the prevalence of diabetes will rise sharply over the next 40 years with as many as 1 in 3 Americans afflicted by this condition by the year 2050 (1). As per the National Diabetes Statistics Report of 2014, 29.1 million people or 9.3% of the US population have diabetes of which 21.0 million people are diagnosed and a whopping 8.2 million people (which represents 27.8% of the people with diabetes) remain undiagnosed (2). According to the World Health Organization, the number of people with diabetes globally as of 2014 is 422 million, with a prevalence of 8.5% (3). Diabetes and uncontrolled blood glucose have been attributed to 1.5 and 2 million deaths, respectively, in the year 2012 (4). In addition to treating diabetes, the costs of treating the complication of diabetes add to the economic burden of this disease. The total costs of treating diabetes and its complications are an estimated $174 billion annually, including $116 billion in direct medical costs (5,6). Type 1 diabetes, which accounts for 5%–10% of the total cases of diabetes worldwide and is most common form of diabetes in childhood, is a condition characterized by autoimmune destruction of the insulin-producing beta cells (7,8). Consequently, this condition requires exogenous administration of insulin for the lifetime of the afflicted individual (9). Type 2 diabetes, on the other hand, affects about 90%–95% of diabetics and results when the body becomes resistant to the effects of insulin and/or does not produce sufficient insulin (10–12). The etiology of type 2 diabetes is multifactorial with the risk factors including environmental or genetic factors and a combination of both (13). A major contributor to increasing prevalence of diabetes is the epidemic of obesity. Two-thirds of the adult population in the United States are currently overweight or obese. Per the recent CDC estimate, the prevalence of obesity The Nutritional Biochemistry of Chromium(III). https://doi.org/10.1016/B978-0-444-64121-2.00005-2 © 2019 Elsevier B.V. All rights reserved.
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among children in the United States has been on the rise. In the years 2011–14, 17% of US children and adolescent (2–19 years) population were obese, which amounts to a staggering 12.7 million. Prediabetes is a condition that is observed long before the appearance of fullblown diabetes. Subjects with prediabetes are at higher risk for developing type 2 diabetes. Prediabetes is characterized by insulin resistance (impaired body’s ability to respond to insulin and is associated with elevated blood glucose levels, but not high enough to be diagnosed as overt diabetes) (14). In addition to insulin resistance, individuals with prediabetes may exhibit cardiometabolic anomalies (such as hypertension, dyslipidemia) and central obesity, and this symptom has also been collectively referred to as metabolic syndrome. A recent study indicates that more the half of American adults had either diabetes or prediabetes in the year 2012 (15–17). As alluded to earlier, poorly controlled diabetes can lead to a number of microvascular and macrovascular complications including atherosclerosis, retinopathy, nephropathy, and neuropathy (18,19). Atherosclerosis, the major macrovascular complication of diabetes, can lead to heart disease, circulatory disorders, and stroke, which is the major cause of morbidity and mortality in the developed world. Diabetic retinopathy, which affects about 28.5% of diabetic individuals 40 years and above, is also the most frequent cause of blindness (20–22). Diabetes is also the major risk factor for nephropathy and end-stage renal disease, which accounts for 44% of a newly diagnosed kidney failure (23–25). Uncontrolled diabetes is also a predisposing factor for vasculopathy, impaired wound healing, and neuropathy, which accounts for over 60% of nontraumatic lower limb amputations (26–28). Identifying and characterizing novel strategies to counter diabetes, is therefore, an important unmet challenge. Despite the availability of several pharmacological agents that are used to control diabetes and its complications, a large number of individuals use nutraceuticals and dietary supplements to complement conventional therapies (29–32). Unfortunately, most of the claims made by nutraceuticals have not been validated by controlled clinical studies. In contrast, however, several preclinical and clinical studies have been performed with chromium; and despite the existing controversies, taken together these studies tend to support the notation that chromium may have beneficial cardiometabolic effects.
CHROMIUM AND DIABETES Although the role of chromium in regulating blood glucose level was identified by Mertz and Schwarz in 1959 (33), the ‘essentiality’ of chromium in human nutrition was suggested about when Freund and coworkers demonstrated the need for chromium supplementation of the total parenteral nutrition in patients undergoing total parenteral nutrition after complete bowel resection for maintaining normal glucose tolerance (34). Five months of total parenteral nutrition without chromium supplementation in these patients lead to severe glucose intolerance, weight loss, and a metabolic encephalopathy-like confusional state. Quite dramatically, supplementation
Chromium and diabetes
of 150 micrograms of chromium per day reversed the glucose intolerance, reduced insulin requirements, and resulted in weight gain and the disappearance of encephalopathy. Since this time chromium has been added as a supplemental micronutrient in total parenteral nutrition (35). This also led to the belief that chromium is an ‘essential’ micronutrient for carbohydrate metabolism, although the notion of ‘essentiality’ has been recently questioned because of the ubiquitous nature of chromium and its low dietary requirement (36). Nevertheless, several preclinical and clinical studies have demonstrated the benefits of chromium in improving carbohydrate and lipid metabolism and chromium features as a micronutrient in multivitamin tablets and energy drinks (37–41). Despite these proposed benefits of chromium, several recent meta-analyses has indicated that the benefits of chromium in glycemic control may only be marginal, especially given the fact that not all studies with chromium are well controlled for chromium intake (42,43). Also randomized, placebo-controlled studies did not find any reductions in hemoglobin A1c following chromium supplementation (44,45). Subsequent meta-analyses also indicate that chromium may not have a beneficial effect in blood glucose regulation (46,47). Cefalu and coworkers, who have extensively studied chromium for its beneficial effects under hyperglycemic condition, argue that the discrepancies in the literature are attributable to the phenotype of the subjects that receive chromium (48). Whereas some patients with diabetes show improved response to chromium others may not, which may be based on the extent of insulin resistance, alterations in the rate of chromium excretion, and their genetic makeup. Vincent (the editor of this volume), who has done seminal studies on the molecular biochemistry of chromium over the last three decades, suggests the importance of delineating the physiological effects of chromium from its pharmacological effects seen with higher doses of chromium (49–51). Mclver and coworkers examined the publically available NHANES database for years 1999–2010 and the study cohort included 28,539 subjects based on their glycated hemoglobin levels (≥6.5%) or reported to having been diagnosed with diabetes and using chromium supplements (52). Data were obtained on all consumed dietary supplements and was analyzed with the odds ratio of having diabetes as the main outcome of interest based on chromium supplement use. The odds of having type 2 diabetes were lower in the subjects who consumed chromium supplements within the past 30 days as compared to those who did not consume chromium supplements (52). Furthermore, this study found that 28.8% of the adult population of US consumed a dietary supplement containing some form of chromium. However, these authors did not observe a dose–response relationship between chromium supplementation and diabetes. A recently published case–control study involving 1471 patients with newly diagnosed type 2 diabetes mellitus, 682 individuals with newly diagnosed prediabetic, and 2290 individuals with normal glucose tolerance extending from 2009 to 2014 showed that plasma chromium levels were lower in the type 2 diabetic and prediabetic groups compared to the control groups. This led to the suggestion that plasma chromium concentrations are inversely associated with diabetic and prediabetic
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subjects (53). Another recently published meta-analysis by Huang and coworkers which included 28 studies showed that chromium supplementation reduced levels of fasting plasma glucose, hemoglobin A1c, and triglycerides while increasing highdensity lipoprotein (54). Collectively, these large studies give credence to the argument that supplemental chromium may have beneficial effects in diabetic subjects.
LOW-MOLECULAR WEIGHT ORGANIC CHROMIUM COMPLEXES Trivalent chromium is potentially the biologically active form of chromium. Inorganic chromium is poorly (0.4%–2.8%) bioavailable (55), which has led to the synthesis and characterization of organic chromium complexes. Chromium picolinate is the most popular chromium supplement available in the market. Several chromium complexes of amino acids, nicotinic acid, and glutamic acids have been designed and tested based on the fact that the naturally occurring chromium in Brewer’s yeast (originally identified as the glucose tolerance factor) is in the form of complexes with these organic molecules. The potential genomic toxicities attributed to the picolinate ligand (56) encouraged the Nair group to synthesize and test a number of low-molecular-weight organic chromium complexes with amino acids and nicotinic acid as ligands (41). Among these compounds, we found that chromium dinicotinocysteinate was most potent in augmenting insulin signaling (unpublished data). Subsequent clinical studies showed the benefits of this molecule in reducing hemoglobin A1c and oxidative stress in diabetic subjects. This molecule is currently being marketed as Zychrome® (Interhealth) (57–60). Chromium in the body is transferred as a complex with transferrin. Endogenous chromium has been postulated to be bound to an oligopeptide low-molecular-weight chromium-binding substance, named chromodulin (akin to calmodulin) (61). Vincent and coworkers have proposed a model whereby the chromodulin–chromium complex activates the tyrosine kinase activity of insulin receptors, hence its activity (61,62). Recent work from Vincent and coworkers has characterized an endogenous low- molecular weight chromium-binding peptide as a heptapeptide containing the amino acid sequence Glu-Glu-Glu-Glu-Gly-Asp-Asp (EEEEGDD) (63). The Nair group subsequent studies in collaboration with Dr. Vincent’s laboratory demonstrated that the heptapeptide when administered intravenously to mice decreased the glucose area under the curve in an intravenous glucose tolerance test and restored insulin-stimulated glucose uptake in cultured myotubes that were rendered insulin resistant in the presence of highglucose conditions (64). However, the instability of the peptide in the systemic circulation is a major limitation in developing it as an agent to improve insulin sensitivity.
CHROMIUM AND INSULIN SIGNALING Studies from the Nair lab have consistently shown that chromium potentiates insulin signaling (57,65–71). Insulin mediates its metabolic effects by binding to the
Chromium and insulin signaling
extracellular alpha subunit of the cell surface insulin receptor (72). Binding of insulin to the alpha subunit results in the tyrosine phosphorylation of beta subunit of the insulin receptor, leading to the activation of the endogenous tyrosine kinase activity of the receptor. The activated insulin receptor subsequently phosphorylates insulin-receptor substrate-1, which when phosphorylated functions as a docking protein via its Src homology 2 domain to phosphatidylinositol 2-kinase, resulting in the recruitment of the kinase to the plasma membrane and resulting in the conversion of phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-triphosphate, which phosphorylates AKT of protein kinase B at threonine (308) and serine (473) residues, mediated by PI3-dependent kinases. Activated AKT phosphorylates a number of downstream effector including Rab-GTPase, which leads to the membrane translocation of GLUT-4 vesicles, which in turn causes glucose uptake. AKT also phosphorylates glycogen synthase kinase-3 to stimulate glycogen formation from glucose. Studies from the Nair lab and those from that of others have shown that chromium interferes with many processes in the insulin-signaling cascade. The first studies to show the effect of chromium on insulin signaling were reported by Yamamoto and coworkers, who identified that the low-molecular-mass chromium-binding oligopeptide isolated from the liver of mice injected with potassium chromate augmented insulin-mediated glucose metabolism in rat epididymal adipocytes (73). Vincent and colleagues who have worked on chromium and its biological activity for decades (39) showed that a low-molecular-weight oligopeptide chromium complex exhibited a 3–8 fold stimulation of insulin-dependent tryosine kinase activity in rat adipocytes in a chromium-dependent manner (74). Wang and coworkers used CHO-IR cells to demonstrate that chromium picolinate enhances the tyrosine phosphorylation of insulin receptors and enhances its kinase activity (75). In accordance to these studies, studies from the Nair lab demonstrated that a novel low-molecular-weight chromium complex of D-phenylalanine augmented the phosphorylation of insulin receptor substrate-1, AKT, and enhanced insulin-stimulated glucose uptake in cultured adipocytes and liver cells (71). Furthermore, this compound reduced the total area under the glucose curve following glucose challenge in leptin-deficient (ob/ob) mice, improved lipid abnormalities and insulin signaling in the liver and muscle (68,71,76). Using obese, insulin-resistant JCR:LA-cp rats Wang and coworkers showed that supplementation with chromium picolinate enhances skeletal muscle insulin signaling as evidenced by an increase in insulin-stimulated tyrosine phosphorylation of IRS-1 and PI-3-kinase activity, without altering the total protein levels of any of these molecules (77). In addition to the genetic model, the Nair group has also studied the efficacy of chromium in nutritional models involving a high sucrose diet or a high-fat diet and found that chromium improved AKT phosphorylation and PI3 kinase activity in these models (65,67). We also found that chromium supplementation improved membrane-associated GLUT-4 levels in a nutritional rodent model of diabetes (67). Similar effects were observed by Cefalu and coworkers (78) in the skeletal muscle of diabetic rats treated with chromium picolinate and by other investigators in myocardial and liver tissues (79–81). Similarly, Elmendorf and coworkers showed that
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chromium picolinate mediates GLUT-4 translocation to plasma membrane using cultured adipocytes (82). These authors argue that the GLUT-4 translocation is insulin independent and can be explained by the increase in the fluidity of the cellular membrane by a chromium-mediated decrease in the membrane cholesterol levels (82). Chromium treatment also caused a reciprocal decrease in cholesterol efflux protein ABCA1 leading to the suggestion that chromium plays a critical role in regulating cholesterol levels which may, in turn, affect glucose regulation (83,84). In addition to augmenting insulin signal transduction via a possible effect on insulin receptor phosphorylation and the phosphorylation of downstream effectors of the pathway, Nair group studies have demonstrated that chromium can blunt the negative regulators of insulin signaling. As indicated previously, while tyrosine phosphorylation of insulin receptor substrate-1 propagates insulin signaling, serine phosphorylation of the same protein prevents its association with the tyrosine-binding domain of insulin receptor abrogating insulin signaling (85). Furthermore, serine phosphorylation of insulin receptor substrate accelerates degradation of this protein via ubiquitination (86). The phosphorylation of insulin receptor substrate at the serine residue is catalyzed by Jun NH(2)-terminal kinase (JNK) (87). We have found that chromium supplementation of obese, insulin-resistant mice increased the insulin receptor tyrosine phosphorylation levels and caused a reciprocal reduction in cJun and IRS-serine phosphorylation levels (68). Similar observations were made by Chen and coworkers using skeletal muscles of KK/HIH mice, which were genetically obese and insulin resistant (88). Wang and coworkers demonstrated similar effects in 3 T3-L1 adipocytes with hyperinsulinemic and hyperglycemic conditions (89).
CHROMIUM AND PROTEIN TYROSINE PHOSPHATASE Protein tyrosine phosphates dephosphorylate phosphorylated tyrosine residues. Protein tyrosine phosphatase 1B (PTP1B) has been shown to be a major tyrosine phosphatase that dephosphorylates the insulin receptor and thereby functioning as a negative regulator of insulin signaling (90,91). Binding of insulin to its cognate receptors results in the transient release of hydrogen peroxide. This hydrogen peroxide reversibly oxidizes a critical cysteine residue in the catalytic domain of PTP1B, rendering it inactive, and therefore aiding in the insulin signal transduction (92,93). This has led to the search for agents that can oxidize the critical cysteine on the PTP1B molecule (94). McGuire and coworkers measured PTP1B activity in muscle tissue from obese insulin-resistant and nondiabetic patients and lean insulin-sensitive controls and found that PTP activity was 33% lesser in control subjects suggesting that an increased PTP1B activity may contribute to insulin resistance (95). The insulin mimetic activity of vanadium compounds has been attributed to its oxidation of this critical cysteine on PTP1B (96,97). Consequently, a number of vanadate derivatives have been tested for its insulin-sensitizing actions (98). Vincent and coworkers found that low-molecular-weight chromium enhanced protein tyrosine phosphatase activity in adipocytes (99). However, in in the Nair model,
Chromium and AMP-activated protein kinase signaling
we were unable to detect any changes in PTP1B (Yang and Nair, unpublished studies). Similarly, Wang and coworkers reported that chromium did not inhibit recombinant human PTP1B nor alter redox regulation of the phosphatase (75). In a r ecent study, Lipko and Debski evaluated the effects of chromium on insulin-stimulated glucose uptake in C2C12 myotubes. These authors found that both chromium and insulin elevated the formation of reactive oxygen species and promoted cellular glucose uptake (100). Interestingly, the addition of antioxidants to this system abrogated insulin and chromium-induced glucose uptake, and these authors found that chromium treatment augmented the activity of membrane phosphatases (100).
HROMIUM AND AMP-ACTIVATED PROTEIN KINASE C SIGNALING AMP-activated protein kinase (AMPK) functions as a molecular switch regulating insulin-independent glucose uptake in skeletal muscle and is responsible for c ellular energy homeostasis (101,102). Nair group studies have demonstrated that chromium can cause the phosphorylation and activation of the alpha-catalytic subunit of AMPK in cardiomyocytes (103). Furthermore, mice treated with chromium D–phenylalanine complex exhibited increased AMPK phosphorylation in the heart. In accordance with our results, studies by Penumathsa and coworkers reported that a niacin-bound chromium improvers ischemia/reperfusion by increasing the phosphorylation of AMPK (79). A recent study showed that chromium-loaded chitosan nanoparticles increased the mRNA of AMPK subunit gamma-3 and the protein of AMPK-alpha1 in the skeletal muscle of pigs (104). Using normal and insulin-resistant 3T3-L1 adipocytes, Wang and coworkers examined the effects of chromium picolinate on the gene transcription and secretion of adiponectin, resistin, and AMPK. Adiponectin is an adipocyte-derived protein which has antidiabetic properties (105–107). Adiponectin has been shown to cause body mass loss, reduction in plasma glucose, and modulation of hepatic gluconeogenesis and lipogenesis in obese rats (108). The adipokine resistin, on the other hand, has been shown to be implicated in insulin resistance and diabetes, as this adipokine is elevated in obese and diabetic patients (109,110), and has been demonstrated to inhibit insulin-induced glucose uptake in adipocyte and muscle cells (111,112). Furthermore, an antiresistin antibody treatment has been shown to decrease blood glucose level and improve insulin sensitivity in obese mice (113). While chromium picolinate failed to modulate the expression of adiponectin and resistin, it significantly inhibited the secretion of resistin by 3T3-L1 adipocytes in vitro. More importantly, chromium picolinate caused a marked elevation in the phosphorylation of AMPK and acetyl CoA carboxylase in 3 T3-L1 adipocytes. These effects on AMPK phosphorylation and resistin secretion were abrogated by pretreatment of the cells with compound C (114). Collectively, the studies by Wang and coworkers suggest that AMPK activation induced by chromium picolinate reduces resistin secretion, which may be yet another molecular explanation for the beneficial metabolic
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effects of chromium. Activation of AMPK by chromium has also been reported by Elmendorf and coworkers, who show that chromium picolinate increases AMPK signaling and siRNA-mediated depletion of AMPK abolishes the protective effects of chromium picolinate against GLUT4 and glucose transport dysregulation in L6 myotubes (115).
CHROMIUM AND ENDOPLASMIC RETICULUM STRESS Endoplasmic reticulum stress, which results in the formation of misfolded proteins, has been recognized as a common downstream pathway in the development of insulin resistance (116,117). Pharmacological agents that reduce endoplasmic reticulum stress or function as endoplasmic reticulum chaperons have been shown to have beneficial effects in insulin resistance (118–120). Nair group studies have demonstrated that chromium treatment attenuates endoplasmic stress both in vivo and in diabetic mice (68). Like endoplasmic reticulum stress, oxidative stress has been well documented as a key pathological event in the development of diabetes. Studies show that chromium dinicotinocysteinate treatment of diabetic subjects significantly reduced protein carbonyl levels which is a marker of oxidative stress (59,60). Chromium has also been shown to attenuate oxidative stress in cultured monocytes and isolated human mononuclear cells exposed to high-glucose conditions (121,122).
CHROMIUM AND GENE REGULATION Because of the strong genetic component of diabetes, a few studies have evaluated the effects of chromium on the regulation of genes relating to diabetes. Rink and coworkers used microarray studies to assess the gene expression pattern associated with leptin Db obese mice subjected to chromium treatment (38,123). The DNA microarray data was further validated by real-time PCR analysis of the candidate genes. Interestingly, of the over 45,000 genes evaluated in this genome-wide analysis, the expression of only a few genes was altered by chromium supplementation, suggesting a rather specific role of chromium in modulating gene expression. Chromium treatment resulted in upregulation of genes encoding proteins involved in glycolysis, muscle contraction, muscle metabolism, and muscle development. Chromium upregulated the myogenic genes including the calsequestrin, a calcium mediator for muscle contraction, tropomyosin-1, a myosin regulator, and key enzymes necessary for glycolysis such as enolase and glucose phosphate isomerase-1. Calsequestrin is an abundant calcium-binding protein found in the sarcoplasmic reticulum of skeletal and cardiac muscle. In addition, chromium suppressed genes included in celldeath-induced DNA fragmentation factor (CIDEA), thermogenic uncoupled protein 1 (UCP1), and tocopherol transfer protein (TPP). CIDEA is abundantly expressed in the brown adipose tissue, which is a major site for thermogenesis (124). UPC1, on
References
the other hand, is expressed in brown adipose tissue and has been shown to mediate thermogenic activity (125). TTP helps in the transport and storage of tocopherol, which is a lipophilic chain-breaking antioxidant. A recent study showed that restriction of chromium in the mother induces insulin resistance and impaired glucose tolerance in the offspring in WNIN rats suggesting epigenetic programming (126). Zhang and coworkers found that restricting dietary chromium in pregnant mice changes the methylation status of hepatic genes involved in insulin signaling in the offspring (127). These authors find hypermethylation of several genes involved in the insulin signaling pathway including Akt1, Kras, Hras1, and Rims2 and genes involved in hepatic gluconeogenesis G6pc and Pepck. In addition to gene regulation, treatment with chromium has also been shown to alter a variety of microRNAs (128). MicroRNAs are small noncoding RNAs that bind to complementary 3’UTR regions of target mRNAs leading to the degradation of mRNA and repression of transcription of the targeted genes. miR-375 and miR30d, both of which have been shown to play a critical role in stimulating insulin secretion from the islet (129,130) and have been shown to be upregulated by chromium picolinate (128). In another recent study, Zhang and coworkers assessed liver microRNA levels and metabolic parameters in mice offsprings weaned from mothers that were subjected to low-chromium diet (131). They found that maternal low-chromium diet increased fasting serum glucose, insulin, homeostasis model of insulin resistance, and area under the glucose curve following oral glucose tolerance. In addition, miR-327, miR 466f-3p, and miR-223-3p were differentially expressed in the maternal chromium restriction group. Interestingly, miR-327, miR466gp, and miR-223-3p have been shown to downregulate key effectors in the insulin-signaling pathway viz. Glut4 translocation (132), Akt phosphorylation (133), and PI3K activity (131), respectively.
CONCLUSION Despite the controversies regarding the role of chromium in glucose metabolism, chromium alters a number of metabolic pathways and genes that regulate glucose homeostasis. However, most of the studies showing the beneficial effects are correlative in nature. More extensive molecular studies are essential to determine the causality of such relationship.
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5 Sreejayan Nair
University of Wyoming, School of Pharmacy, College of Health Sciences, Laramie, WY, United States
INTRODUCTION Diabetes is a chronic metabolic disease in which the body does not produce or adequately use the hormone insulin leading to a dysregulation of glucose. Despite the discovery and characterization of new chemical entities that work by novel mechanisms, the number of people with diabetes has doubled over the past three decades. The Center for Disease Control estimates that the prevalence of diabetes will rise sharply over the next 40 years with as many as 1 in 3 Americans afflicted by this condition by the year 2050 (1). As per the National Diabetes Statistics Report of 2014, 29.1 million people or 9.3% of the US population have diabetes of which 21.0 million people are diagnosed and a whopping 8.2 million people (which represents 27.8% of the people with diabetes) remain undiagnosed (2). According to the World Health Organization, the number of people with diabetes globally as of 2014 is 422 million, with a prevalence of 8.5% (3). Diabetes and uncontrolled blood glucose have been attributed to 1.5 and 2 million deaths, respectively, in the year 2012 (4). In addition to treating diabetes, the costs of treating the complication of diabetes add to the economic burden of this disease. The total costs of treating diabetes and its complications are an estimated $174 billion annually, including $116 billion in direct medical costs (5,6). Type 1 diabetes, which accounts for 5%–10% of the total cases of diabetes worldwide and is most common form of diabetes in childhood, is a condition characterized by autoimmune destruction of the insulin-producing beta cells (7,8). Consequently, this condition requires exogenous administration of insulin for the lifetime of the afflicted individual (9). Type 2 diabetes, on the other hand, affects about 90%–95% of diabetics and results when the body becomes resistant to the effects of insulin and/or does not produce sufficient insulin (10–12). The etiology of type 2 diabetes is multifactorial with the risk factors including environmental or genetic factors and a combination of both (13). A major contributor to increasing prevalence of diabetes is the epidemic of obesity. Two-thirds of the adult population in the United States are currently overweight or obese. Per the recent CDC estimate, the prevalence of obesity The Nutritional Biochemistry of Chromium(III). https://doi.org/10.1016/B978-0-444-64121-2.00005-2 © 2019 Elsevier B.V. All rights reserved.
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among children in the United States has been on the rise. In the years 2011–14, 17% of US children and adolescent (2–19 years) population were obese, which amounts to a staggering 12.7 million. Prediabetes is a condition that is observed long before the appearance of fullblown diabetes. Subjects with prediabetes are at higher risk for developing type 2 diabetes. Prediabetes is characterized by insulin resistance (impaired body’s ability to respond to insulin and is associated with elevated blood glucose levels, but not high enough to be diagnosed as overt diabetes) (14). In addition to insulin resistance, individuals with prediabetes may exhibit cardiometabolic anomalies (such as hypertension, dyslipidemia) and central obesity, and this symptom has also been collectively referred to as metabolic syndrome. A recent study indicates that more the half of American adults had either diabetes or prediabetes in the year 2012 (15–17). As alluded to earlier, poorly controlled diabetes can lead to a number of microvascular and macrovascular complications including atherosclerosis, retinopathy, nephropathy, and neuropathy (18,19). Atherosclerosis, the major macrovascular complication of diabetes, can lead to heart disease, circulatory disorders, and stroke, which is the major cause of morbidity and mortality in the developed world. Diabetic retinopathy, which affects about 28.5% of diabetic individuals 40 years and above, is also the most frequent cause of blindness (20–22). Diabetes is also the major risk factor for nephropathy and end-stage renal disease, which accounts for 44% of a newly diagnosed kidney failure (23–25). Uncontrolled diabetes is also a predisposing factor for vasculopathy, impaired wound healing, and neuropathy, which accounts for over 60% of nontraumatic lower limb amputations (26–28). Identifying and characterizing novel strategies to counter diabetes, is therefore, an important unmet challenge. Despite the availability of several pharmacological agents that are used to control diabetes and its complications, a large number of individuals use nutraceuticals and dietary supplements to complement conventional therapies (29–32). Unfortunately, most of the claims made by nutraceuticals have not been validated by controlled clinical studies. In contrast, however, several preclinical and clinical studies have been performed with chromium; and despite the existing controversies, taken together these studies tend to support the notation that chromium may have beneficial cardiometabolic effects.
CHROMIUM AND DIABETES Although the role of chromium in regulating blood glucose level was identified by Mertz and Schwarz in 1959 (33), the ‘essentiality’ of chromium in human nutrition was suggested about when Freund and coworkers demonstrated the need for chromium supplementation of the total parenteral nutrition in patients undergoing total parenteral nutrition after complete bowel resection for maintaining normal glucose tolerance (34). Five months of total parenteral nutrition without chromium supplementation in these patients lead to severe glucose intolerance, weight loss, and a metabolic encephalopathy-like confusional state. Quite dramatically, supplementation
Chromium and diabetes
of 150 micrograms of chromium per day reversed the glucose intolerance, reduced insulin requirements, and resulted in weight gain and the disappearance of encephalopathy. Since this time chromium has been added as a supplemental micronutrient in total parenteral nutrition (35). This also led to the belief that chromium is an ‘essential’ micronutrient for carbohydrate metabolism, although the notion of ‘essentiality’ has been recently questioned because of the ubiquitous nature of chromium and its low dietary requirement (36). Nevertheless, several preclinical and clinical studies have demonstrated the benefits of chromium in improving carbohydrate and lipid metabolism and chromium features as a micronutrient in multivitamin tablets and energy drinks (37–41). Despite these proposed benefits of chromium, several recent meta-analyses has indicated that the benefits of chromium in glycemic control may only be marginal, especially given the fact that not all studies with chromium are well controlled for chromium intake (42,43). Also randomized, placebo-controlled studies did not find any reductions in hemoglobin A1c following chromium supplementation (44,45). Subsequent meta-analyses also indicate that chromium may not have a beneficial effect in blood glucose regulation (46,47). Cefalu and coworkers, who have extensively studied chromium for its beneficial effects under hyperglycemic condition, argue that the discrepancies in the literature are attributable to the phenotype of the subjects that receive chromium (48). Whereas some patients with diabetes show improved response to chromium others may not, which may be based on the extent of insulin resistance, alterations in the rate of chromium excretion, and their genetic makeup. Vincent (the editor of this volume), who has done seminal studies on the molecular biochemistry of chromium over the last three decades, suggests the importance of delineating the physiological effects of chromium from its pharmacological effects seen with higher doses of chromium (49–51). Mclver and coworkers examined the publically available NHANES database for years 1999–2010 and the study cohort included 28,539 subjects based on their glycated hemoglobin levels (≥6.5%) or reported to having been diagnosed with diabetes and using chromium supplements (52). Data were obtained on all consumed dietary supplements and was analyzed with the odds ratio of having diabetes as the main outcome of interest based on chromium supplement use. The odds of having type 2 diabetes were lower in the subjects who consumed chromium supplements within the past 30 days as compared to those who did not consume chromium supplements (52). Furthermore, this study found that 28.8% of the adult population of US consumed a dietary supplement containing some form of chromium. However, these authors did not observe a dose–response relationship between chromium supplementation and diabetes. A recently published case–control study involving 1471 patients with newly diagnosed type 2 diabetes mellitus, 682 individuals with newly diagnosed prediabetic, and 2290 individuals with normal glucose tolerance extending from 2009 to 2014 showed that plasma chromium levels were lower in the type 2 diabetic and prediabetic groups compared to the control groups. This led to the suggestion that plasma chromium concentrations are inversely associated with diabetic and prediabetic
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subjects (53). Another recently published meta-analysis by Huang and coworkers which included 28 studies showed that chromium supplementation reduced levels of fasting plasma glucose, hemoglobin A1c, and triglycerides while increasing highdensity lipoprotein (54). Collectively, these large studies give credence to the argument that supplemental chromium may have beneficial effects in diabetic subjects.
LOW-MOLECULAR WEIGHT ORGANIC CHROMIUM COMPLEXES Trivalent chromium is potentially the biologically active form of chromium. Inorganic chromium is poorly (0.4%–2.8%) bioavailable (55), which has led to the synthesis and characterization of organic chromium complexes. Chromium picolinate is the most popular chromium supplement available in the market. Several chromium complexes of amino acids, nicotinic acid, and glutamic acids have been designed and tested based on the fact that the naturally occurring chromium in Brewer’s yeast (originally identified as the glucose tolerance factor) is in the form of complexes with these organic molecules. The potential genomic toxicities attributed to the picolinate ligand (56) encouraged the Nair group to synthesize and test a number of low-molecular-weight organic chromium complexes with amino acids and nicotinic acid as ligands (41). Among these compounds, we found that chromium dinicotinocysteinate was most potent in augmenting insulin signaling (unpublished data). Subsequent clinical studies showed the benefits of this molecule in reducing hemoglobin A1c and oxidative stress in diabetic subjects. This molecule is currently being marketed as Zychrome® (Interhealth) (57–60). Chromium in the body is transferred as a complex with transferrin. Endogenous chromium has been postulated to be bound to an oligopeptide low-molecular-weight chromium-binding substance, named chromodulin (akin to calmodulin) (61). Vincent and coworkers have proposed a model whereby the chromodulin–chromium complex activates the tyrosine kinase activity of insulin receptors, hence its activity (61,62). Recent work from Vincent and coworkers has characterized an endogenous low- molecular weight chromium-binding peptide as a heptapeptide containing the amino acid sequence Glu-Glu-Glu-Glu-Gly-Asp-Asp (EEEEGDD) (63). The Nair group subsequent studies in collaboration with Dr. Vincent’s laboratory demonstrated that the heptapeptide when administered intravenously to mice decreased the glucose area under the curve in an intravenous glucose tolerance test and restored insulin-stimulated glucose uptake in cultured myotubes that were rendered insulin resistant in the presence of highglucose conditions (64). However, the instability of the peptide in the systemic circulation is a major limitation in developing it as an agent to improve insulin sensitivity.
CHROMIUM AND INSULIN SIGNALING Studies from the Nair lab have consistently shown that chromium potentiates insulin signaling (57,65–71). Insulin mediates its metabolic effects by binding to the
Chromium and insulin signaling
extracellular alpha subunit of the cell surface insulin receptor (72). Binding of insulin to the alpha subunit results in the tyrosine phosphorylation of beta subunit of the insulin receptor, leading to the activation of the endogenous tyrosine kinase activity of the receptor. The activated insulin receptor subsequently phosphorylates insulin-receptor substrate-1, which when phosphorylated functions as a docking protein via its Src homology 2 domain to phosphatidylinositol 2-kinase, resulting in the recruitment of the kinase to the plasma membrane and resulting in the conversion of phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-triphosphate, which phosphorylates AKT of protein kinase B at threonine (308) and serine (473) residues, mediated by PI3-dependent kinases. Activated AKT phosphorylates a number of downstream effector including Rab-GTPase, which leads to the membrane translocation of GLUT-4 vesicles, which in turn causes glucose uptake. AKT also phosphorylates glycogen synthase kinase-3 to stimulate glycogen formation from glucose. Studies from the Nair lab and those from that of others have shown that chromium interferes with many processes in the insulin-signaling cascade. The first studies to show the effect of chromium on insulin signaling were reported by Yamamoto and coworkers, who identified that the low-molecular-mass chromium-binding oligopeptide isolated from the liver of mice injected with potassium chromate augmented insulin-mediated glucose metabolism in rat epididymal adipocytes (73). Vincent and colleagues who have worked on chromium and its biological activity for decades (39) showed that a low-molecular-weight oligopeptide chromium complex exhibited a 3–8 fold stimulation of insulin-dependent tryosine kinase activity in rat adipocytes in a chromium-dependent manner (74). Wang and coworkers used CHO-IR cells to demonstrate that chromium picolinate enhances the tyrosine phosphorylation of insulin receptors and enhances its kinase activity (75). In accordance to these studies, studies from the Nair lab demonstrated that a novel low-molecular-weight chromium complex of D-phenylalanine augmented the phosphorylation of insulin receptor substrate-1, AKT, and enhanced insulin-stimulated glucose uptake in cultured adipocytes and liver cells (71). Furthermore, this compound reduced the total area under the glucose curve following glucose challenge in leptin-deficient (ob/ob) mice, improved lipid abnormalities and insulin signaling in the liver and muscle (68,71,76). Using obese, insulin-resistant JCR:LA-cp rats Wang and coworkers showed that supplementation with chromium picolinate enhances skeletal muscle insulin signaling as evidenced by an increase in insulin-stimulated tyrosine phosphorylation of IRS-1 and PI-3-kinase activity, without altering the total protein levels of any of these molecules (77). In addition to the genetic model, the Nair group has also studied the efficacy of chromium in nutritional models involving a high sucrose diet or a high-fat diet and found that chromium improved AKT phosphorylation and PI3 kinase activity in these models (65,67). We also found that chromium supplementation improved membrane-associated GLUT-4 levels in a nutritional rodent model of diabetes (67). Similar effects were observed by Cefalu and coworkers (78) in the skeletal muscle of diabetic rats treated with chromium picolinate and by other investigators in myocardial and liver tissues (79–81). Similarly, Elmendorf and coworkers showed that
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chromium picolinate mediates GLUT-4 translocation to plasma membrane using cultured adipocytes (82). These authors argue that the GLUT-4 translocation is insulin independent and can be explained by the increase in the fluidity of the cellular membrane by a chromium-mediated decrease in the membrane cholesterol levels (82). Chromium treatment also caused a reciprocal decrease in cholesterol efflux protein ABCA1 leading to the suggestion that chromium plays a critical role in regulating cholesterol levels which may, in turn, affect glucose regulation (83,84). In addition to augmenting insulin signal transduction via a possible effect on insulin receptor phosphorylation and the phosphorylation of downstream effectors of the pathway, Nair group studies have demonstrated that chromium can blunt the negative regulators of insulin signaling. As indicated previously, while tyrosine phosphorylation of insulin receptor substrate-1 propagates insulin signaling, serine phosphorylation of the same protein prevents its association with the tyrosine-binding domain of insulin receptor abrogating insulin signaling (85). Furthermore, serine phosphorylation of insulin receptor substrate accelerates degradation of this protein via ubiquitination (86). The phosphorylation of insulin receptor substrate at the serine residue is catalyzed by Jun NH(2)-terminal kinase (JNK) (87). We have found that chromium supplementation of obese, insulin-resistant mice increased the insulin receptor tyrosine phosphorylation levels and caused a reciprocal reduction in cJun and IRS-serine phosphorylation levels (68). Similar observations were made by Chen and coworkers using skeletal muscles of KK/HIH mice, which were genetically obese and insulin resistant (88). Wang and coworkers demonstrated similar effects in 3 T3-L1 adipocytes with hyperinsulinemic and hyperglycemic conditions (89).
CHROMIUM AND PROTEIN TYROSINE PHOSPHATASE Protein tyrosine phosphates dephosphorylate phosphorylated tyrosine residues. Protein tyrosine phosphatase 1B (PTP1B) has been shown to be a major tyrosine phosphatase that dephosphorylates the insulin receptor and thereby functioning as a negative regulator of insulin signaling (90,91). Binding of insulin to its cognate receptors results in the transient release of hydrogen peroxide. This hydrogen peroxide reversibly oxidizes a critical cysteine residue in the catalytic domain of PTP1B, rendering it inactive, and therefore aiding in the insulin signal transduction (92,93). This has led to the search for agents that can oxidize the critical cysteine on the PTP1B molecule (94). McGuire and coworkers measured PTP1B activity in muscle tissue from obese insulin-resistant and nondiabetic patients and lean insulin-sensitive controls and found that PTP activity was 33% lesser in control subjects suggesting that an increased PTP1B activity may contribute to insulin resistance (95). The insulin mimetic activity of vanadium compounds has been attributed to its oxidation of this critical cysteine on PTP1B (96,97). Consequently, a number of vanadate derivatives have been tested for its insulin-sensitizing actions (98). Vincent and coworkers found that low-molecular-weight chromium enhanced protein tyrosine phosphatase activity in adipocytes (99). However, in in the Nair model,
Chromium and AMP-activated protein kinase signaling
we were unable to detect any changes in PTP1B (Yang and Nair, unpublished studies). Similarly, Wang and coworkers reported that chromium did not inhibit recombinant human PTP1B nor alter redox regulation of the phosphatase (75). In a r ecent study, Lipko and Debski evaluated the effects of chromium on insulin-stimulated glucose uptake in C2C12 myotubes. These authors found that both chromium and insulin elevated the formation of reactive oxygen species and promoted cellular glucose uptake (100). Interestingly, the addition of antioxidants to this system abrogated insulin and chromium-induced glucose uptake, and these authors found that chromium treatment augmented the activity of membrane phosphatases (100).
HROMIUM AND AMP-ACTIVATED PROTEIN KINASE C SIGNALING AMP-activated protein kinase (AMPK) functions as a molecular switch regulating insulin-independent glucose uptake in skeletal muscle and is responsible for c ellular energy homeostasis (101,102). Nair group studies have demonstrated that chromium can cause the phosphorylation and activation of the alpha-catalytic subunit of AMPK in cardiomyocytes (103). Furthermore, mice treated with chromium D–phenylalanine complex exhibited increased AMPK phosphorylation in the heart. In accordance with our results, studies by Penumathsa and coworkers reported that a niacin-bound chromium improvers ischemia/reperfusion by increasing the phosphorylation of AMPK (79). A recent study showed that chromium-loaded chitosan nanoparticles increased the mRNA of AMPK subunit gamma-3 and the protein of AMPK-alpha1 in the skeletal muscle of pigs (104). Using normal and insulin-resistant 3T3-L1 adipocytes, Wang and coworkers examined the effects of chromium picolinate on the gene transcription and secretion of adiponectin, resistin, and AMPK. Adiponectin is an adipocyte-derived protein which has antidiabetic properties (105–107). Adiponectin has been shown to cause body mass loss, reduction in plasma glucose, and modulation of hepatic gluconeogenesis and lipogenesis in obese rats (108). The adipokine resistin, on the other hand, has been shown to be implicated in insulin resistance and diabetes, as this adipokine is elevated in obese and diabetic patients (109,110), and has been demonstrated to inhibit insulin-induced glucose uptake in adipocyte and muscle cells (111,112). Furthermore, an antiresistin antibody treatment has been shown to decrease blood glucose level and improve insulin sensitivity in obese mice (113). While chromium picolinate failed to modulate the expression of adiponectin and resistin, it significantly inhibited the secretion of resistin by 3T3-L1 adipocytes in vitro. More importantly, chromium picolinate caused a marked elevation in the phosphorylation of AMPK and acetyl CoA carboxylase in 3 T3-L1 adipocytes. These effects on AMPK phosphorylation and resistin secretion were abrogated by pretreatment of the cells with compound C (114). Collectively, the studies by Wang and coworkers suggest that AMPK activation induced by chromium picolinate reduces resistin secretion, which may be yet another molecular explanation for the beneficial metabolic
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effects of chromium. Activation of AMPK by chromium has also been reported by Elmendorf and coworkers, who show that chromium picolinate increases AMPK signaling and siRNA-mediated depletion of AMPK abolishes the protective effects of chromium picolinate against GLUT4 and glucose transport dysregulation in L6 myotubes (115).
CHROMIUM AND ENDOPLASMIC RETICULUM STRESS Endoplasmic reticulum stress, which results in the formation of misfolded proteins, has been recognized as a common downstream pathway in the development of insulin resistance (116,117). Pharmacological agents that reduce endoplasmic reticulum stress or function as endoplasmic reticulum chaperons have been shown to have beneficial effects in insulin resistance (118–120). Nair group studies have demonstrated that chromium treatment attenuates endoplasmic stress both in vivo and in diabetic mice (68). Like endoplasmic reticulum stress, oxidative stress has been well documented as a key pathological event in the development of diabetes. Studies show that chromium dinicotinocysteinate treatment of diabetic subjects significantly reduced protein carbonyl levels which is a marker of oxidative stress (59,60). Chromium has also been shown to attenuate oxidative stress in cultured monocytes and isolated human mononuclear cells exposed to high-glucose conditions (121,122).
CHROMIUM AND GENE REGULATION Because of the strong genetic component of diabetes, a few studies have evaluated the effects of chromium on the regulation of genes relating to diabetes. Rink and coworkers used microarray studies to assess the gene expression pattern associated with leptin Db obese mice subjected to chromium treatment (38,123). The DNA microarray data was further validated by real-time PCR analysis of the candidate genes. Interestingly, of the over 45,000 genes evaluated in this genome-wide analysis, the expression of only a few genes was altered by chromium supplementation, suggesting a rather specific role of chromium in modulating gene expression. Chromium treatment resulted in upregulation of genes encoding proteins involved in glycolysis, muscle contraction, muscle metabolism, and muscle development. Chromium upregulated the myogenic genes including the calsequestrin, a calcium mediator for muscle contraction, tropomyosin-1, a myosin regulator, and key enzymes necessary for glycolysis such as enolase and glucose phosphate isomerase-1. Calsequestrin is an abundant calcium-binding protein found in the sarcoplasmic reticulum of skeletal and cardiac muscle. In addition, chromium suppressed genes included in celldeath-induced DNA fragmentation factor (CIDEA), thermogenic uncoupled protein 1 (UCP1), and tocopherol transfer protein (TPP). CIDEA is abundantly expressed in the brown adipose tissue, which is a major site for thermogenesis (124). UPC1, on
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the other hand, is expressed in brown adipose tissue and has been shown to mediate thermogenic activity (125). TTP helps in the transport and storage of tocopherol, which is a lipophilic chain-breaking antioxidant. A recent study showed that restriction of chromium in the mother induces insulin resistance and impaired glucose tolerance in the offspring in WNIN rats suggesting epigenetic programming (126). Zhang and coworkers found that restricting dietary chromium in pregnant mice changes the methylation status of hepatic genes involved in insulin signaling in the offspring (127). These authors find hypermethylation of several genes involved in the insulin signaling pathway including Akt1, Kras, Hras1, and Rims2 and genes involved in hepatic gluconeogenesis G6pc and Pepck. In addition to gene regulation, treatment with chromium has also been shown to alter a variety of microRNAs (128). MicroRNAs are small noncoding RNAs that bind to complementary 3’UTR regions of target mRNAs leading to the degradation of mRNA and repression of transcription of the targeted genes. miR-375 and miR30d, both of which have been shown to play a critical role in stimulating insulin secretion from the islet (129,130) and have been shown to be upregulated by chromium picolinate (128). In another recent study, Zhang and coworkers assessed liver microRNA levels and metabolic parameters in mice offsprings weaned from mothers that were subjected to low-chromium diet (131). They found that maternal low-chromium diet increased fasting serum glucose, insulin, homeostasis model of insulin resistance, and area under the glucose curve following oral glucose tolerance. In addition, miR-327, miR 466f-3p, and miR-223-3p were differentially expressed in the maternal chromium restriction group. Interestingly, miR-327, miR466gp, and miR-223-3p have been shown to downregulate key effectors in the insulin-signaling pathway viz. Glut4 translocation (132), Akt phosphorylation (133), and PI3K activity (131), respectively.
CONCLUSION Despite the controversies regarding the role of chromium in glucose metabolism, chromium alters a number of metabolic pathways and genes that regulate glucose homeostasis. However, most of the studies showing the beneficial effects are correlative in nature. More extensive molecular studies are essential to determine the causality of such relationship.
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