Beta Cell Function is Disrupted in Patients with Systemic Lupus Erythematosus

Introduction To investigate how markers of beta cell secretion (proinsulin-processing metabolites) are expressed in systemic lupus erythematosus (SLE) patients and their potential relation to features associated with the disease such as activity or damage. Methods 144 SLE patients and 69 nondiabetic sex- and age-matched controls were assessed. Beta-cell secretion molecules, as measured by insulin, split and intact proinsulins, and C-peptide levels were analyzed in both groups. Multiple regression analysis was performed to compare proinsulin propeptides between groups and to explore the interrelations with SLE features. Analyses were adjusted for glucocorticoid intake and for insulin resistance classic risk factors. Results Fully multivariable analysis demonstrated that regardless of glucocorticoid use, SLE patients exhibited higher levels of split proinsulin. Likewise, the split proinsulin-to-insulin ratio was upregulated in patients with SLE undergoing glucocorticoid therapy (beta coef. 0.19 [95%CI 0.07–0.30], p= 0.002) or not (beta coef. 0.09 [95%CI 0.01–0.17), p= 0.025). Similar results were found for the intact proinsulin-to-insulin ratio, although differences were only statistically significant for patients taking glucocorticoids (beta coef. 0.08 [95%CI 0.03–0.12], p= 0.001). SLE damage score was associated with higher serum levels of intact (beta coef. 0.51 [95%CI 0.17–0.86] pmol/l, p= 0.004) and split proinsulins (beta coef. 1.65 [95%CI 0.24–3.06] pmol/l, p= 0.022) after multivariable analysis, including disease duration and prednisone use. Conclusion Among patients with SLE, proinsulin-processing metabolites, a marker of beta-cell disruption, are upregulated compared with matched controls. This disproportionate hyperproinsulinemia can be explained by the damage produced by the disease and occurs independently of prednisone use.

Poor in-utero growth, reduced beta cell secretion and high plasma glucose in childhood are harbingers of glucose intolerance in young Indians

BackgroundIndia is the world’s paradoxical double capital for early life undernutrition and type 2 diabetes. The Pune Maternal Nutrition Study (PMNS) birth cohort offered a unique opportunity to investigate childhood growth and glucose-insulin metabolism as precursors to glucose intolerance in young adulthood.MethodsPMNS is a community-based pre-conceptional birth cohort established in 1993, with serial information on parents, and on their children through pregnancy, childhood and adolescence. We compared the children’s growth and glucose-insulin indices between those who were and were not glucose intolerant at age 18 years (ADA criteria). We developed a prediction model for 18-year glucose intolerance and replicated it in two other cohorts (Extended PMNS and Pune Children’s Study).FindingsAt age 18 years (N=619) 37% men and 20% women were glucose intolerant even though 48% were underweight (BMI<18.5 kg/m2). Glucose intolerant participants were shorter at birth, and had lower insulin secretion (both sexes) and insulin insensitivity (men) in childhood than those with normal glucose tolerance. Fasting plasma glucose (FPG) concentrations at 6- and 12-years of age strongly predicted glucose intolerance at 18 years. The risk was 2.5 times higher in the highest compared to the lowest quintile at 6 years, and 4.5 times at 12 years. Comparable findings were seen in the other cohorts. Mothers of glucose intolerant participants had higher glycemia in pregnancy.InterpretationGlucose intolerance in young rural Indians can be traced to linear growth faltering in-utero, reduced beta-cell secretion and higher glycemia since childhood. Our findings mandate a strategy for diabetes prevention starting much earlier than the current practice.