Toward the Decipherment of Molecular Interactions in the Diabetic Brain

Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed.

The Network Analysis of Peripheral Diabetic Neuropathy Involved Genes

Aim: Screening of candidate genes related to sural nerve diabetic neuropathy to find the critical ones is the aim of this study. Back Ground: Diabetes mellitus is a chronic disease causes by insulin uptake or deficiency. Side effects of diabetes are numerous according to severity of disease. Diabetes could harm the peripheral nerves with chronic pain, lead to nerve damage entitled diabetic neuropathy (DN). Signs and symptoms of DN are sharp pains, numbness, and tangling. Many patterns of nerve injuries could happen during DN but distal symmetric polyneuropathy (DSP) is most common. On the other hand, network analysis is a useful tool to assess incidences and progression of diseases. Methods: Expression of different genes in diabetic patients with and without progressive neuropathy of surreal nerve (GSE24290) is considered as including data. GEO2R was applied to first step analysis to find the significant differentially expressed genes (DEGs). The queried significant DEGs plus 100 first neighbors were included in a network by Cytoscape software. The network was analyzed by Network analyzed application of Cytoscape and the central nodes were determined. Results: The total 26 significant DEGs plus 100 first neighbors were interacted to form the network. INS, ALB, AKT1, APP, SNAP25, NEFL, GFAP, IL6, NEFM, TNF, MAPT, GAP43, and MBP were identified as 13 hubs of the network. NEFL and NEFM were highlighted as the queried hub genes. Insulin as the top hub node was determined among all interacted genes (the queried and added genes). Conclusions: INS, NEFL, and NEFM are key genes in DN which are involve in metabolism regulation and intra cellular transportation into axons and denderites respectively.

Association of Proteins Modulating Immune Response and Insulin Clearance during Gestation with Antenatal Complications in Patients with Gestational or Type 2 Diabetes Mellitus

Background: The purpose of the study is to establish and quantitatively assess protein markers and their combination in association with insulin uptake that may be have value for early prospective recognition of diabetic fetopathy (DF) as a complication in patients with diabetes mellitus during gestation. Methods: Proteomic surveying and accurate quantitative measurement of selected proteins from plasma samples collected from the patients with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) who gave birth of either healthy or affected by maternal diabetes newborns was performed using mass spectrometry. Results: We determined and quantitatively measured several proteins, including CRP, CEACAM1, CNDP1 and Ig-family that were significantly differed in patients that gave birth of newborns with signs of DF. We found that patients with newborns associated with DF are characterized by significantly decreased CEACAM1 (113.18 ± 16.23 ng/mL and 81.09 ± 10.54 ng/mL in GDM and T2DM, p < 0.005) in contrast to control group (515.6 ± 72.14 ng/mL, p < 0.005). On the contrary, the concentration of CNDP1 was increased in DF-associated groups and attained 49.3 ± 5.18 ng/mL and 37.7 ± 3.34 ng/mL (p < 0.005) in GDM and T2DM groups, respectively. Among other proteins, dramatically decreased concentration of IgG4 and IgA2 subclasses of immunoglobulins were noticed. Conclusion: The combination of the measured markers may assist (AUC = 0.893 (CI 95%, 0.785–0.980) in establishing the clinical finding of the developing DF especially in patients with GDM who are at the highest risk of chronic insulin resistance.

Peripheral Insulin Extraction in Non-Diabetic Subjects and Type 2 Diabetes Mellitus Patients

Background Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. Methods Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. Results In NDF, FEins was 18 (10–26) % at lower insulin levels (63 51–80] pmol/l), while in NDG at higher insulin levels (776 [543–1176] pmol/l), FEins was 9 (4–16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = − 0.575;p = 0.006) and fasting plasma glucose levels (rho = − 0.551;p = 0.01). In T2DF FEins was 6 (1–19) % and not different from FEins in T2DG (10 2–14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). Discussion We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D.

Insulin uptake and action in microvascular endothelial cells of lymphatic and blood origin

Whereas the blood microvasculature constitutes a biological barrier to the action of blood-borne insulin on target tissues, the lymphatic microvasculature might act as a barrier to subcutaneously administrated insulin reaching the circulation. Here, we evaluate the interaction of insulin with primary microvascular endothelial cells of lymphatic [human dermal lymphatic endothelial cells (HDLEC)] and blood [human adipose microvascular endothelial cells (HAMEC)] origin, derived from human dermal and adipose tissues, respectively. HDLEC express higher levels of insulin receptor and signal in response to insulin as low as 2.5 nM, while HAMEC only activate signaling at 100 nM (a dose that blood vessels do not normally encounter). Low insulin acts specifically through the insulin receptor, while supraphysiological insulin acts through both the IR and insulin growth factor-1 receptor. At supraphysiological or injection site-compatible doses pertinent to lymphatic microvessels, insulin enters HAMEC and HDLEC via fluid-phase endocytosis. Conversely, at physiologically circulating doses (0.2 nM) pertinent to blood microvessels, insulin enters HAMEC through a receptor-mediated process requiring IR autophosphorylation but not downstream insulin signaling. At physiological doses, internalized insulin is barely degraded and is instead released intact to the extracellular medium. In conclusion, we document for the first time the mechanism of interaction of insulin with lymphatic endothelial cells, which may be relevant to insulin absorption during therapeutic injections. Furthermore, we describe distinct action and uptake routes for insulin at physiological and supraphysiological doses in blood microvascular endothelial cells, providing a potential explanation for previously conflicting studies on endothelial insulin uptake.

Risk and Benefits of Statins in Glucose Control Management of Type II Diabetes

Worldwide statins are considered to be the first-line pharmacological treatment for dyslipidemia and reducing the risk of coronary heart disease. However, recently various studies have shown its adverse effect on glucose control among diabetic patients and the U.S. Food and Drug Administration have revised statin drug labels to include information that increases in fasting serum glucose and glycated hemoglobin levels have been reported. This systematic review objective is to evaluate the risks and benefits of statins in glucose control management of type 2 diabetes patients based on the 44 published journal articles included and obtained through MEDLINE full text, PubMed, Science Direct, Pro Quest, SAGE, Taylor and Francis Online, Google Scholar, High Wire, and Elsevier Clinical Key. Statins were found to affect glucose control through several ways, namely, by affecting insulin production and secretion by β-pancreatic cells, insulin resistance, insulin uptake by the muscles and adipocytes and production of adipokines. Current evidence available shows that most of the statins give unfavorable side effects with regards to glucose control among diabetic patients. A dose-dependent and time-dependent effect was also observed in some statins which may be present among other statins as well.

Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel–derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent.