Metabolic pathways at the crossroads of diabetes and inborn errors

Abstract

Research over the past two decades has led to advances in our understanding of the genetic and metabolic factors that underlie the pathogenesis of type 2 diabetes mellitus (T2DM). While T2DM is defined by its hallmark metabolic symptoms, the genetic risk factors for T2DM are more immune-related than metabolism-related, and the observed metabolic disease may be secondary to chronic inflammation. Regardless, these metabolic changes are not benign, as the accumulation of some metabolic intermediates serves to further drive the inflammation and cell stress, eventually leading to insulin resistance and ultimately to T2DM. Because many of the biochemical changes observed in the pre-diabetic state (i.e., ectopic lipid storage, increased acylcarnitines, increased branched-chain amino acids) are also observed in patients with rare inborn errors of fatty acid and amino acid metabolism, an interesting question is raised regarding whether isolated metabolic gene defects can confer an increased risk for T2DM. In this review, we attempt to address this question by summarizing the literature regarding the metabolic pathways at the crossroads of diabetes and inborn errors of metabolism. Studies using cell culture and animal models have revealed that, within a given pathway, disrupting some genes can lead to insulin resistance while for others there may be no effect or even improved insulin sensitivity. This differential response to ablating a single metabolic gene appears to be dependent upon the specific metabolic intermediates that accumulate and whether these intermediates subsequently activate inflammatory pathways. This highlights the need for future studies to determine whether certain inborn errors may confer increased risk for diabetes as the patients age.

Interaction between dietary branched-chain amino acids and genetic risk score on the risk of type 2 diabetes in Chinese

“…Research about a cluster of BCAA metabolites also suggested a primary alteration of BCAA metabolism in insulin resistance [ 14 ]. Therefore, mitochondrial dysfunction in those with or at T2D risk will reduce the capacity of mitochondria to catabolize BCAAs, leading to the BCAAs levels raising in blood [ 15 , 18 ], supporting our result that the higher GRS was associated with higher circulating BCAAs levels. Under this condition, heavy BCAAs intakes appear particularly detrimental as they increase the substrate load for mitochondrial oxidation then results in mitochondrion dysfunction as well as impaired insulin secretion and action [ 56 ].…”

“…Circulating BCAAs and toxic metabolites can impair mitochondrial oxidation of glucose, leading to mitochondrial stress and impaired insulin excretion and action [ 15 ]. Meanwhile, in T2D and IFG patients, damaged mitochondrial function may reduce the capacity of the mitochondria to catabolize BCAAs, resulting in elevated levels of BCAAs and related metabolite in a vicious cycle [ 18 ]. Dietary BCAAs influenced plasma level along with individual metabolism ability [ 19 ] and showed conflicting relationships with T2D.…”

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street

“…These inborn errors cause a much larger increase of BCAA and related metabolites compared to those observed in obesity-related metabolic diseases (many-fold increases compared to 40–50% increases), and are usually accompanied by a range of complex co-morbidities including developmental disturbances, neurological disorders, and ketoacidosis, making it difficult to parse out the impact of BCAA on core metabolic functions. Detailed reviews of these syndromes have been published elsewhere [ 26 , 27 ].…”

Newborn Screening Samples for Diabetes Research: An Underused Resource

“…Three of the eight studies examined pre-existing results and did not use the DBS as a biobank. One retrospective case control study utilizing pre-existing newborn screening results showed an association between low acylcarnitine levels and type 1 diabetes [ 2 , 28 ]. A study from Spain demonstrated a trend of higher total carnitine, free carnitine and short and medium-chain acylcarnitines in infants exposed to gestational diabetes (GDM), which paralleled some of the results of the HAPO cohort on cord blood [ 11 ] but found no differences in acylcarnitines between mothers who were on dietary treatments versus those on insulin [ 29 ].…”

“…Despite their rarity, inborn errors of metabolism (IEM) share commonalities with diabetes, such as insulin resistance, hyperglycemia and acidosis and target-organ damage [ 1 , 2 ]. Both IEM and diabetes involve derangements in the intermediates of protein, carbohydrate and lipid metabolic pathways.…”