Type 2 diabetes mellitus (T2DM) is associated with increased total plasma free fatty acid (FFA) concentrations and an elevated risk of cardiovascular disease. The exact mechanisms by which the plasma FFA profile of subjects with T2DM changes is unclear, but it is thought that dietary fats and changes to lipid metabolism are likely to contribute. Therefore, establishing the changes in concentrations of specific FFAs in an individual’s plasma is important. Each type of FFA has different effects on physiological processes, including the regulation of lipolysis and lipogenesis in adipose tissue, inflammation, endocrine signalling and the composition and properties of cellular membranes. Alterations in such processes due to altered plasma FFA concentrations/profiles can potentially result in the development of insulin resistance and coagulatory defects. Finally, fibrates and statins, lipid-regulating drugs prescribed to subjects with T2DM, are also thought to exert part of their beneficial effects by impacting on plasma FFA concentrations. Thus, it is also interesting to consider their effects on the concentration of FFAs in plasma. Collectively, we review how FFAs are altered in T2DM and explore the likely downstream physiological and pathological implications of such changes.

Diabetes (both type-1 and type-2) affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory proteins, hyper-activation of platelets, changes in metal ion homeostasis, alterations in lipid metabolism (leading to lipotoxicity in the heart and atherosclerosis), the presence of pro-coagulatory microparticles and endothelial dysfunction. In this review, we explore the different mechanisms by which diabetes leads to an increased risk of developing coagulatory disorders and how this differs between type-1 and type-2 diabetes.

The glycosaminoglycans (GAGs) heparan sulfate, dermatan sulfate, and heparin are important anticoagulants that inhibit clot formation through interactions with antithrombin and heparin cofactor II. Unfractionated heparin, low-molecular-weight heparin, and heparin-derived drugs are often the main treatments used clinically to handle coagulatory disorders. A wide range of proteins have been reported to bind and neutralize these GAGs to promote clot formation. Such neutralizing proteins are involved in a variety of other physiological processes, including inflammation, transport, and signaling. It is clear that these interactions are important for the control of normal coagulation and influence the efficacy of heparin and heparin-based therapeutics. In addition to neutralization, the anticoagulant activities of GAGs may also be regulated through reduced synthesis or by degradation. In this review, we describe GAG neutralization, the proteins involved, and the molecular processes that contribute to the regulation of anticoagulant GAG activity.

Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis. "Ischemia-modified albumin" (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. More recent work suggested that Co2+ ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co2+ to sites A and/or B. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels.

Glycemia and insulin resistance are important regulators of multiple physiological processes and their dysregulation has wide-ranging consequences, including alterations in plasma concentrations of metal micronutrients. Here, magnesium, zinc, copper, selenium and glycated albumin (HbA1c) concentrations and quartile differences were examined in 45 subjects with type-I diabetes (T1DM), 54 subjects with type-II diabetes (T2DM) and 62 control subjects in order to assess potential differences between sexes and between T1DM and T2DM. Plasma magnesium concentration was decreased in T1DM subjects, with the second, third and fourth quartiles of magnesium concentrations associated with the absence of T1DM. This effect was observed in females but not males. In T2DM, the highest quartile of selenium concentrations and the third quartile of copper concentrations associated with the absence of diabetes in males. The highest quartile of magnesium concentrations was associated with the absence of T2DM in males but not females. HbA1c correlated with plasma concentrations of magnesium (negatively, in both sexes together in T1DM and T1DM males), copper (positively, in T1DM males and in both sexes together in T2DM), selenium (positively, in both sexes together in T1DM and T2DM, and T2DM females) and with zinc/copper ratio (negatively, in both sexes together in T1DM and T2DM). This study shows that plasma magnesium concentration is altered to the highest degree in T1DM, while in T2DM, plasma selenium and copper concentrations are significantly affected. This work increases our understanding of how T1DM and T2DM affects plasma metal concentrations and may have future implications for diabetes management.

Zn²⁺ is an essential regulator of coagulation. In plasma, Zn²⁺ availability is fine-tuned by human serum albumin (HSA). Here we show that elevated fatty acid levels contribute to altered coagulation in type-2 diabetes through Zn²⁺ mishandling by HSA.