Effects of Body Mass Index, Glycemic Control, and Hypoglycemic Drugs on Serum Uric Acid Levels in Type 2 Diabetic Patients.

Background Plasma uric acid has been shown to be associated with an increased risk of hypertension, cardiovascular disease, chronic kidney disease, insulin resistance, and metabolic syndrome. Conflicting data regarding plasma uric acid levels in type 2 diabetes mellitus and their role in the development and progression of diabetic complications have been observed by many studies. The present study aimed to evaluate plasma uric acid levels in type 2 diabetic patients and to determine the effects of hypoglycemic drugs and pharmacologic insulin on plasma uric acid concentration. Subjects and methods The study included 162 type 2 diabetic patients divided into three groups (insulin taking group (N=58), glibenclamide taking group (N=40), and metformin taking group (N=64), and 47 normal healthy controls. A questionnaire that included variables such as age, sex, duration of disease, and body mass index (BMI) were answered by all the participants. Blood samples were collected and estimated for serum uric acid (SUA), fasting blood sugar (FBS), and glycated hemoglobin (HbA1c) using standard methods and the data were statistically analyzed. Results Diabetic patients showed a significant increase in serum uric acid, fasting blood sugar, glycated hemoglobin, and body mass index when compared to control subjects. The serum uric acid levels of metformin and glibenclamide taking groups were significantly higher than the control group. The difference of serum uric concentration between the insulin taking group and both the control and metformin groups was statistically non-significant. On the other hand, obese diabetics showed a significantly higher serum uric acid than overweight and lean diabetics. Furthermore, serum uric acid had a significant strong positive correlation with body mass index. Conclusion Type 2 diabetes mellitus (T2DM) is associated with high serum uric acid levels. Hypoglycemic drugs and pharmacologic insulin do not have a large impact on SUA concentration, but obesity seems to be the primary determinant of SUA levels in T2DM patients. The condition of diabetes may have a direct effect on the oxidation of the purine nucleotides resulting in the increased uric acid (UA) levels. In addition, hyperinsulinemia could lead to hyperuricemia by increasing the rate of xanthine oxidase synthesis. There is a strong relationship between T2DM and obesity with high uric acid levels.

Quantitative investigation of calcimimetic R568 on beta cell adhesion and mechanics using AFM single-cell force spectroscopy.

In this study we use a novel approach to quantitatively investigate mechanical and interfacial properties of clonal ß-cells using AFM-Single Cell Force Spectroscopy (SCFS). MIN6 cells were incubated for 48 h with 0.5 mM Ca(2+) ± the calcimimetic R568 (1 µM). AFM-SCFS adhesion and indentation experiments were performed by using modified tipless cantilevers. Hertz contact model was applied to analyse force-displacement (F-d) curves for determining elastic or Young's modulus (E). Our results show CaSR-evoked increases in cell-to-cell adhesion parameters and E modulus of single cells, demonstrating that cytomechanics have profound effects on cell adhesion characterization.

The calcium-sensing receptor and ß-cell function.

In addition to its central role controlling systemic calcium homeostasis, the extracellular calcium-sensing receptor (CaSR) can be found on multiple cell types not associated with controlling plasma calcium. The endocrine pancreas is one such tissue, and it is apparent that the receptor plays an important role in regulating ß-cell function. During exocytosis, divalent cations are coreleased with insulin and their concentration within the restricted intercellular compartments of the pancreatic islet increases sufficiently to activate the CaSR on neighboring cells. Acute and chronic activation of the receptor has multiple effects on the ß-cell, from increasing cadherin-based cell-cell adhesion to directly altering the expression and function of various potassium and voltage-dependent calcium channels. The promiscuous activation of multiple binding partners improves cell adhesion, cell coupling, and cell-to-cell communication within the islet and is the basis for the effect of the CaSR on ß-cell function and improved glucose responsiveness.

Calcium-sensing receptor activation increases cell-cell adhesion and ß-cell function.

BACKGROUND/AIMS: The extracellular calcium-sensing receptor (CaR) is expressed in pancreatic ß-cells where it is thought to facilitate cell-to-cell communication and augment insulin secretion. However, it is unknown how CaR activation improves ß-cell function. METHODS: Immunocytochemistry and western blotting confirmed the expression of CaR in MIN6 ß-cell line. The calcimimetic R568 (1µM) was used to increase the affinity of the CaR and specifically activate the receptor at a physiologically appropriate extracellular calcium concentration. Incorporation of 5-bromo-2'-deoxyuridine (BrdU) was used to measure cell proliferation, whilst changes in non-nutrient-evoked cytosolic calcium were assessed using fura-2-microfluorimetry. AFM-single-cell-force spectroscopy related CaR-evoked changes in epithelial (E)-cadherin expression to improved functional tethering between coupled cells. RESULTS: Activation of the CaR over 48hr doubled the expression of E-cadherin (206±41%) and increased L-type voltage-dependent calcium channel expression by 70% compared to control. These changes produced a 30% increase in cell-cell tethering and elevated the basal-to-peak amplitude of ATP (50µM) and tolbutamide (100µM)-evoked changes in cytosolic calcium. Activation of the receptor also increased PD98059 (1-100µM) and SU1498 (1-100µM)-dependent ß-cell proliferation. CONCLUSION: Our data suggest that activation of the CaR increases E-cadherin mediated functional tethering between ß-cells and increases expression of L-type VDCC and secretagogue-evoked changes in [Ca(2+)](i). These findings could explain how local changes in calcium, co-released with insulin, activate the CaR on neighbouring cells to help ensure efficient and appropriate secretory function.

Pseudoislets as primary islet replacements for research: report on a symposium at King's College London, London UK.

Laboratory-based research aimed at understanding processes regulating insulin secretion and mechanisms underlying ß-cell dysfunction and loss in diabetes often makes use of rodents, as these processes are in many respects similar between rats/mice and humans. Indeed, a rough calculation suggests that islets have been isolated from as many as 150,000 rodents to generate the data contained within papers published in 2009 and the first four months of 2010. Rodent use for islet isolation has been mitigated, to a certain extent, by the availability of a variety of insulin-secreting cell lines that are used by researchers world-wide. However, when maintained as monolayers the cell lines do not replicate the robust, sustained secretory responses of primary islets which limits their usefulness as islet surrogates. On the other hand, there have been several reports that configuration of MIN6 ß-cells, derived from a mouse insulinoma, as three-dimensional cell clusters termed 'pseudoislets' largely recapitulates the function of primary islet ß-cells. The Diabetes Research Group at King's College London has been using the MIN6 pseudoislet model for over a decade and they hosted a symposium on "Pseudoislets as primary islet replacements for research", which was funded by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), in London on 15th and 16th April 2010. This small, focused meeting was conceived as an opportunity to consolidate information on experiences of working with pseudoislets between different UK labs, and to introduce the theory and practice of pseudoislet culture to laboratories working with islets and/or ß-cell lines but who do not currently use pseudoislets. This short review summarizes the background to the development of the cell line-derived pseudoislet model, the key messages arising from the symposium and emerging themes for future pseudoislet research.