Free fatty acids, glucose, and insulin in type 2 diabetes mellitus.

Xu et al used the HOMA2 model to estimate the ß-cell function and insulin resistance levels in an individual from simultaneously measured fasting plasma glucose and fasting plasma insulin levels. This method is based on the assumption that the glucose-insulin axis is central for the metabolic activities, which led to type 2 diabetes. However, significant downregulation of both the NKX2-1 gene and the TPD52L3 gene force an increase in the release of free fatty acids (FFAs) into the blood circulation, which leads to a marked reduction in membrane flexibility. These data favor a FFA-glucose-insulin axis. The authors are invited to extend their study with the introduction of the saturation index (number of carbon-carbon double bonds per 100 fatty-acyl chains), as observed in erythrocytes.

Fundamentals about onset and progressive disease character of type 2 diabetes mellitus.

ResearchGate is a world wide web for scientists and researchers to share papers, ask and answer questions, and find collaborators. As one of the more than 15 million members, the author uploads research output and reads and responds to some of the questions raised, which are related to type 2 diabetes. In that way, he noticed a serious gap of knowledge of this disease among medical professionals over recent decades. The main aim of the current study is to remedy this situation through providing a comprehensive review on recent developments in biochemistry and molecular biology, which can be helpful for the scientific understanding of the molecular nature of type 2 diabetes. To fill up the shortcomings in the curricula of medical education, and to familiarize the medical community with a new concept of the onset of type 2 diabetes, items are discussed like: Insulin resistance, glucose effectiveness, insulin sensitivity, cell membranes, membrane flexibility, unsaturation index (UI; number of carbon-carbon double bonds per 100 acyl chains of membrane phospholipids), slow-down principle, effects of temperature acclimation on phospholipid membrane composition, free fatty acids, energy transport, onset of type 2 diabetes, metformin, and exercise. Based on the reviewed data, a new model is presented with proposed steps in the development of type 2 diabetes, a disease arising as a result of a hypothetical hereditary anomaly, which causes hyperthermia in and around the mitochondria. Hyperthermia is counterbalanced by the slow-down principle, which lowers the amount of carbon-carbon double bonds of membrane phospholipid acyl chains. The accompanying reduction in the UI lowers membrane flexibility, promotes a redistribution of the lateral pressure in cell membranes, and thereby reduces the glucose transporter protein pore diameter of the transmembrane glucose transport channel of all Class I GLUT proteins. These events will set up a reduction in transmembrane glucose transport. So, a new blood glucose regulation system, effective in type 2 diabetes and its prediabetic phase, is based on variations in the acyl composition of phospholipids and operates independent of changes in insulin and glucose concentration. UI assessment is currently arising as a promising analytical technology for a membrane flexibility analysis. An increase in mitochondrial heat production plays a pivotal role in the existence of this regulation system.

Three-dimensional structure of beta-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W.

BACKGROUND: We examined the effects of the R325W mutation on the three-dimensional (3D) structure of the beta-cell-specific Zn2+ (zinc) transporter ZnT-8. METHODS: A model of the C-terminal domain of the human ZnT-8 protein was generated by homology modeling based on the known crystal structure of the Escherichia coli (E. coli) zinc transporter YiiP at 3.8 A resolution. RESULTS: The homodimer ZnT-8 protein structure exists as a Y-shaped architecture with Arg325 located at the ultimate bottom of this motif at approximately 13.5 A from the transmembrane domain juncture. The C-terminal domain sequences of the human ZnT-8 protein and the E. coli zinc transporter YiiP share 12.3% identical and 39.5% homologous residues resulting in an overall homology of 51.8%. Validation statistics of the homology model showed a reasonable quality of the model. The C-terminal domain exhibited an alphabetabetaalphabeta fold with Arg325 as the penultimate N-terminal residue of the alpha2-helix. The side chains of both Arg325 and Trp325 point away from the interface with the other monomer, whereas the epsilon-NH3+ group of Arg325 is predicted to form an ionic interaction with the beta-COO- group of Asp326 as well as Asp295. An amino acid alignment of the beta2-alpha2 C-terminal loop domain revealed a variety of neutral amino acids at position 325 of different ZnT-8 proteins. CONCLUSIONS: Our validated homology models predict that both Arg325 and Trp325, amino acids with a helix-forming behavior, and penultimate N-terminal residues in the alpha2-helix of the C-terminal domain, are shielded by the planar surface of the three cytoplasmic beta-strands and hence unable to affect the sensing capacity of the C-terminal domain. Moreover, the amino acid residue at position 325 is too far removed from the docking and transporter parts of ZnT-8 to affect their local protein conformations. These data indicate that the inherited R325W abnormality in SLC30A8 may be tolerated and results in adequate zinc transfer to the correct sites in the pancreatic islet cells and are consistent with the observation that the SLC30A8 gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.