A Role for <i>SPARC</i> in the Moderation of Human Insulin Secretion

<div><p>Aims/Hypothesis</p><p>We have previously shown the implication of the multifunctional protein SPARC (Secreted protein acidic and rich in cysteine)/osteonectin in insulin resistance but potential effects on beta-cell function have not been assessed. We therefore aimed to characterise the effect of SPARC on beta-cell function and features of diabetes.</p><p>Methods</p><p>We measured <i>SPARC</i> expression by qRT-PCR in human primary pancreatic islets, adipose tissue, liver and muscle. We then examined the relation of <i>SPARC</i> with glucose stimulated insulin secretion (GSIS) in primary human islets and the effect of <i>SPARC</i> overexpression on GSIS in beta cell lines.</p><p>Results</p><p><i>SPARC</i> was expressed at measurable levels in human islets, adipose tissue, liver and skeletal muscle, and demonstrated reduced expression in primary islets from subjects with diabetes compared with controls (p< = 0.05). SPARC levels were positively correlated with GSIS in islets from control donors (p< = 0.01). Overexpression of <i>SPARC</i> in cultured beta-cells resulted in a 2.4-fold increase in insulin secretion in high glucose conditions (p< = 0.01).</p><p>Conclusions</p><p>Our data suggest that levels of <i>SPARC</i> are reduced in islets from donors with diabetes and that it has a role in insulin secretion, an effect which appears independent of SPARC’s modulation of obesity-induced insulin resistance in adipose tissue.</p></div

The association of <i>SPARC</i> expression on glucose stimulated insulin secretion in primary human islets.

<p>The figures on the Y axis refer to insulin stimulation index (SI) following a 28 mM glucose challenge. The expression level of <i>SPARC</i> is given on the X axis. Expression levels were calculated relative to the endogenous controls <i>GUSB, B2M</i> and <i>PP1A</i> and normalised to the mean level of <i>SPARC</i> across the cohort.</p

Glucose stimulated insulin secretion and basal insulin according to <i>SPARC</i> expression in primary human islet cultures.

<p>Associations between Glucose-stimulated insulin secretion and basal insulin levels were assessed by linear regression analysis, adjusted for BMI. Significant associations are indicated in bold italic type.</p

Changes in the insulin stimulation index in <i>SPARC</i>-transfected rat beta cells under different glucose conditions.

<p>The figure shows the stimulation index (SI) of transfected rat beta cells (INS-1) in response to 2.8 mM, 5.6 mM and 16.7 mM glucose or IBMX/forskolin. Results from cells transfected with empty vector are given in light grey, and those from <i>SPARC</i>-transfected cells are given in dark grey. Error bars represent standard error of measurements. Data are combined results from the two transfected cell lines. Statistical significance is indicated by stars.</p

Characteristics of donors and samples for human primary islet collection.

<p>M = Male, F = female, N = number of samples tested. BMI = Body Mass Index. HbA1c = Glycosylated haemoglobin.</p