Elevated Medium-Chain Acylcarnitines Are Associated With Gestational Diabetes Mellitus and Early Progression to Type 2 Diabetes and Induce Pancreatic β-Cell Dysfunction

Abstract

Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: ) women with gestational diabetes mellitus (GDM) and) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function.

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…93 In a separate study in which mouse islets were incubated with FA and high glucose in vitro, the accumulation of carnitine ester 3-hydroxytetradecenoic acids was noted. 95 Collectively, data suggest that accumulation of acylcarnitines appears to be an early event during the development of beta cell dysfunction in T2D. Moreover, exposure to medium-chain acylcarnitines at the levels seen in GDM blunted insulin secretion in mice in vivo and in human and mouse islets in vitro.…”

Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish

“…26,29,32 We speculate that Gpr27 regulates acylcarnitine metabolism and that the subsequent accumulation of acylcarnitines influences insulin-mediated glucose homeostasis ( Figure 4F-G). 26,29,32 We speculate that Gpr27 regulates acylcarnitine metabolism and that the subsequent accumulation of acylcarnitines influences insulin-mediated glucose homeostasis ( Figure 4F-G).…”

“…26,29,32 Using a metabolite profiling approach, we found that gpr27 knockouts manifested a specific acylcarnitine accumulation phenotype. 26,29,32 Using a metabolite profiling approach, we found that gpr27 knockouts manifested a specific acylcarnitine accumulation phenotype.…”

“…32 However, a glucose challenge revealed an underlying glucose intolerance phenotype. Therefore, the acylcarnitine profile of gpr27 knockouts raises the possibility that the primary defect in gpr27 knockout animals is altered lipid metabolism which subsequently leads to lipid-induced insulin resistance.…”

“…Insulin resistance in diabetic and nondiabetic individuals has been associated with elevations in free fatty acids such as acylcarnitines. 26,29,32 Using a metabolite profiling approach, we found that gpr27 knockouts manifested a specific acylcarnitine accumulation phenotype. Genetic deletion of gpr27 resulted in elevated medium-chain acylcarnitines, whereas short-and long-chain acylcarnitines were unaffected.…”