Insulin resistance and glycine metabolism in humans

Abstract

Plasma glycine level is low in patients with obesity or diabetes and the improvement of insulin resistance increases plasma glycine concentration. In prospective studies, hypoglycinemia at baseline predicts the risk of developing type 2 diabetes and higher serum glycine level is associated with decreased risk of incident type 2 diabetes. Consistently, plasma glycine concentration is lower in the lean offspring of parents with type 2 diabetes compared to healthy subjects. Among patients with type 2 diabetes, hypoglycinemia occurs before clinical manifestations of the disease, but the pathophysiological mechanisms underlying glycine deficit and its potential clinical repercussions are unclear. Glycine participates in several metabolic pathways, being required for relevant human physiological processes. Humans synthesize glycine from glyoxylate, glucose (via serine), betaine and likely from threonine and during the endogenous synthesis of L-carnitine. Glycine conjugates bile acids and other acyl moieties producing acyl-glycine derivatives. The glycine cleavage system catalyzes glycine degradation to carbon dioxide and ammonium while tetrahydrofolate is converted into 5,10-methylene-tetrahydrofolate. Glycine is utilized to synthesize serine, sarcosine, purines, creatine, heme group, glutathione, and collagen. Glycine is a major quantitative component of collagen. In addition, the role of glycine maintaining collagen structure is critical, as glycine residues are required to stabilize the triple helix of the collagen molecule. This quality of glycine likely contributes to explain the occurrence of medial arterial calcification and the elevated cardiovascular risk associated with diabetes and chronic kidney disease, as emerging evidence links normal collagen content with the initiation and progression of vascular calcification in humans.

Role of Cytosolic Serine Hydroxymethyl Transferase 1 (SHMT1) in Phosphate-Induced Vascular Smooth Muscle Cell Calcification

“…The reaction catalyzed by SHMT1 is an important source of glycine [14,15] and hypoglycinemia was shown to contribute to occurrence of vascular calcification and elevated cardiovascular risk in diabetes and CKD [47]. Furthermore, direct targets of SHMT1-mediated methylation [18][19][20][21] may be involved in osteoinductive signaling in VSMCs.…”

<p>Detection of Secondary Metabolites as Biomarkers for the Early Diagnosis and Prevention of Type 2 Diabetes</p>

“…12,15 Previous studies indicated that plasma glycine level is a negative biomarker in patients with diabetes mellitus. [18][19][20][21] Glycine metabolism pathway indicates the participation of many other important metabolites that mostly serve in the biosynthesis of glycine. However, many of these metabolites have not been proven to be associated with insulin resistance or diabetes.…”

“…28 In addition, the reduced plasma betaine level was also found to act as a positive biomarker of diabetes mellitus and proved to be associated with incident T2D. 16,21 Bile acid (BA) metabolism was reported to be involved in cholesterol as well as glucose metabolism homeostasis. 29 The latter authors claimed that insulin resistance is positively associated with hyperbileacidemia regardless of diabetes status, which indicates the important role of insulin resistance in the regulation of "bile secretion" pathway in human.…”

The Alzheimer’s Disease Metabolome: Effects of Sex andAPOEε4 genotype

“…Interestingly, the significant heterogeneity of association results between sexes for CSF p-tau and glycine, with higher levels of glycine being linked to higher levels of CSF p-tau in men, indicates that energy demands are equally upregulated in males as in females. In contrast to women, men, however, appear to compensate this demand by upregulation of glucose energy metabolism as glycine is a positive marker of active glucose metabolism and insulin sensitivity (67). Findings for acylcarnitines in females are further contrasted by the observed male-specific association of higher levels of the long-chain acylcarnitine C16:1 with decreased brain glucose uptake, which might indicate that in males there is a switch to provision of fatty acids as alternative fuel when glucose-based energy metabolism is less effective.…”