Benefits of Trivalent Chromium in Human Nutrition?

John B. Vincent

The University of Alabama

CONTENTS

  • 9.1 Introduction..........................................................................................................................147
  • 9.2 Glucose Tolerance Factor and Essential Chromium.............................................................148
  • 9.3 Chromium Picolinate and Body Mass Gain.........................................................................149
  • 9.4 Diabetes and Related Conditions..........................................................................................152
  • 9.4.1 Type 2 Diabetes........................................................................................................152
  • 9.4.2 Polycystic Ovarian Syndrome (PCOS).....................................................................153
  • 9.4.3 Depression and Related Conditions..........................................................................154
  • 9.5 Pharmacological Effects.......................................................................................................154
  • 9.6 Toxicity.................................................................................................................................156
  • 9.7 Conclusion............................................................................................................................157

References......................................................................................................................................157

Introduction

The answer to the title question is straightforward currently—no conclusively demonstrated benefits accompany supplementation of the diets of humans. This is true regardless of the health status of the individual. The European Food Safety Authority’s (EFSA) Panel on Dietetic Products, Nutrition and Allergies in 2014 determined “there is no convincing evidence for a role of chromium in human metabolism and physiology,” “there is no evidence that the general population is chromium deficient or has Cr(III)-responsive metabolic effects,” and “there is no proof that chromium is an essential element” (1). However, such an understanding was not always the case. This chapter will examine how and why the current understanding was achieved and what future potential may exist for chromium-based neutraceuticals or pharmaceuticals.

The stable form of chromium in an aqueous environment exposed to dioxygen is the +3 oxidation state. The trivalent or chromic ion is abbreviated as Cr3+; however, this notation is specifically for the ion itself. In contrast, when part of a coordination complex, the ion is written as Cr(III). In this chapter, the chromic ion can always be assumed to be part of a coordination complex and will be written as Cr(III). Even chromic chloride as added to human and animal diets is actually trans- [Cr(H20)4Cl2]Cl-2H20, not truly an inorganic salt but a coordination complex. While the term inorganic salts will be used to represent species of the general formula CrX, «H20 where X is an anion, these are all coordination complexes.

The story of how chromium was proposed to be essential and the problems with those proposals have been reviewed many times (2) and will only be briefly summarized. In 1955, Mertz and Schwarz reported feeding rats a Torula yeast-based diet that resulted in the rats apparently developing impaired glucose tolerance in response to an intravenous glucose load (3). The authors believed they had identified a new dietary requirement absent from the Torula yeast-based diet and responsible for the glucose intolerance, for which they coined the term glucose tolerance factor or GTF (4). They (5) followed their report in 1959 by identifying the active ingredient of “GTF” as Cr(III). Addition of several inorganic compounds containing several elements (200-500 pg/kg body mass) could not restore glucose tolerance, while some inorganic Cr(III) complexes (200 pg/kg body mass) restored glucose tolerance; Brewer’s yeast and acid-hydrolyzed porcine kidney powder were identified as natural sources of “GTF” (5).

However, these studies contain several flaws. The chromium content of the diet was not determined. Additionally, the rats were maintained in wire-mesh cages, possibly with stainless-steel components, allowing the rats to obtain chromium by chewing on these components. Consequently, the actual chromium intake of the rats in these studies is impossible to gauge, putting into great question the suggestion that the rats were chromium deficient. The use of the large amounts of metal ions is also of concern. As will be discussed, large doses of chromium may have pharmacological effects, not related to any nutritional requirements. Questions about data handling and the significance of the effect observed from the chromium treatment have also been raised (2, 6).

These initial studies led to efforts to isolate “GTF.” Mertz and coworkers (7) reported the details of the isolation of Brewer’s yeast “GTF” in 1977. This material from Brewer’s yeast became equated with the term GTF after this time. The isolation procedure needs to be examined here. Brewer’s yeast was extracted with boiling 50% ethanol. The ethanol was removed under vacuum, and the aqueous residual was applied to activated charcoal. Material active in bioassays (the ability of the species to potentiate the action of insulin to stimulate in vitro the metabolism of rat epididymal fat tissue) was eluted from the charcoal with a 1:1 mixture of concentrated ammonia and diethyl ether. After removal of the ammonia and ether under vacuum, the resulting solution was hydrolyzed by refluxing for 18 ft in 5M HCl. Finally, the HC1 was removed under vacuum, the solution was extracted with ether, and the pH of the solution was adjusted to three. The cationic orange-red material was further purified by ion-exchange chromatography (7). Unfortunately, these incredibly harsh conditions would have destroyed any proteins, peptides, complex sugars, or nucleic acids that initially could have been associated with the chromium. Thus, the possibility that the form of chromium recovered after the treatment resembles the form in the yeast is remote at best.

The chemical characterization of GTF was equally problematic. The isolated “GTF” possessed a distinct feature at 262 nm in its ultraviolet spectrum, while mass spectral studies (no data present) indicated the presence of a pyridine moiety (7). This led to identification of nicotinic acid as a component of “GTF”; nicotinic acid was sublimed from the material (no experimental information given) and identified by extraction with organic solvents (no data presented). Consequently, no data were actually presented that nicotinic acid is associated with “GTF.” Amino acid analyses indicated the presence of glycine, glutamic acid, and cysteine, as well as other amino acids, although neither the absolute or relative amounts were reported. Thus, the ratio of chromium to any of the amino acids or to nicotinic acid (i.e., any of the organic components) cannot be determined. Yet, the results were interpreted to indicate that “GTF” was a complex of chromium, nicotinate, glycine, cysteine, and glutamate (7).

In subsequent paper chromatography experiments (7), the material gave several bands, only one of which was active in the bioassays. The chromium in the active band represented only 6% of the total chromium. Thus, the chemical characterization was performed on an impure material, of which only a tiny fraction was active. Hence, the chemical data in no way is likely to reflect the makeup of the active species. Subsequent attempts to isolate “GTF” have found that the biologically active species from Brewer’s yeast can be separated from the chromium (reviewed in Ref. (2)), i.e., “GTF” from Brewer’s yeast does not contain chromium. The use of the term glucose tolerance factor (or GTF) should be discontinued. Curiously, the proposed presence of nicotinic acid, 3-carboxypyridine, inspired examination of the use of complexes made from chromium and pico- linic acid (2-carboxypyridine), most notably Cr(III) picolinate (normally used as the monohydrate [Cr(picolinate),] H20), as nutritional supplements and therapeutic agents.

 
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