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Context: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking., Objective: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes., Design: Human MSCs were isolated and characterized. Peripheral blood mononuclear cells (PBMCs) were obtained from nine type 1 diabetic patients at disease onset and 13 healthy control subjects. IFN-gamma, IL-10, and IL-4 enzyme-linked immunospot responses of lymphocytes incubated with glutamic acid decarboxylase 65 (GAD65) were investigated in PBMC cultures and PBMC/MSC cocultures. Levels of prostaglandin E2 (PGE2), IFN-gamma, IL-4, and IL-10 in supernatants were measured by ELISA. PGE2 inhibition experiments with NS-398 and indomethacin were also performed., Results: Five diabetic patients were identified with a positive PBMC IFN-gamma response to GAD65 and negative IL-10 and IL-4 response. PBMC/MSC cocultures resulted in a significant decrease in the number of spots and in detection of IL-4-secreting cells. PGE2 inhibitors abrogated the immune-suppressive effect, indicating an involvement of PGE2 production, and the constitutive production of PGE2 by MSCs was enhanced in PBMC/MSC coculture. Moreover, in GAD-responder patients, GAD-stimulated PBMC/MSC cocultures significantly decreased secretion of IFN-gamma and IL-10 and increased secretion of IL-4., Conclusions: These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.

Background: The DD genotype of the ACE gene predisposes to faster diabetic nephropathy (DN) progression but its role in DN development is more controversial. We reported previously, in type 1 diabetic patients, an association between faster DN progression and the PC-1 gene Q121 variant, which associates with insulin resistance in non-diabetic subjects. We investigated here whether the combination of the ACE DD genotype and the PC-1 Q121 variant predicts the development and/or progression of DN in type 1 diabetic patients., Methods: Type 1 diabetic patients either with (n=159) or without (n=122) nephropathy were evaluated in a cross-sectional study. DN was defined as the presence of microalbuminuria or persistent proteinuria in a subject with more than 10-year duration of disease and concomitant diabetic retinopathy, and with no evidence of heart failure or other renal disease. Seventy-five (47 male/28 female) type 1 diabetic patients with nephropathy in whom retrospective information with repeated measurements of serum creatinine was available, were analysed in a longitudinal study., Results: No association of the PC-1 Q121 variant and the ACE D/D genotype with DN development was observed. However, the ACE DD genotype and the PC-1 Q121 variant were associated, both independently (P=0.02 and P=0.025, respectively) or in combination (P=0.02), with a faster rate of glomerular filtration rate decline. An interaction (P=0.03) was observed between the two genes in increasing the individual patient's risk of being a fast progressor., Conclusion: Our data suggest that, in type 1 diabetic patients, the ACE and the PC-1 genes interact in increasing the individual risk of having a faster DN progression.

Background: Elderly diabetics on dialysis are dramatically increasing in number. Their late referral reduces efficacy of therapeutic interventions; early referral is fundamental for their survival on dialysis. However, need for nephrological follow-up in case of early referral is not assessed. The objective was to define the need for follow-up in the nephrology setting of Type 2 diabetics, according to the early referral criteria of serum creatinine > or = 1.5 mg/dl or macroproteinuria., Methods: The setting of the study was an outpatient diabetic care unit (University of Torino), where approximately 25% of the Type 2 diabetics of a 900,000-inhabitant city (Torino, Northern Italy) were followed. At the time of the study (1998-1999) the unit followed 5182 Type 2 diabetics whose serum creatinine and proteinuria were tested at least yearly. A total of 3826 prevalent and 478 incident patients with one or more analyses in the same laboratory were included in the study. Demographic data were not statistically different between selected and excluded patients. We calculated the stepwise need for nephrological follow-ups calculated according to our usual policy (4-12 evaluations/ year, on serum creatinine and proteinuria, and 30 min/evaluation)., Results: The prevalence of increased serum creatinine and macroproteinuria was high (in the prevalent cohort: serum creatinine > or = 1.5 mg/dl, 8.1%; proteinuria 0.3 g/day, 25.2%; serum creatinine > or = 3 mg/dl, 1.2%; nephrotic proteinuria 3.4%). Projecting data to the entire unit, with adherence to our evaluation protocol, early nephrological follow-up of Type 2 diabetics requires approximately 1300 h/year (one full-time nephrologist); five nephrologists are needed for our city, and 24 for the region (4350 000 inhabitants)., Conclusions: Early nephrological referral and follow-up of Type 2 diabetics is time consuming and expensive. Meeting the outpatient care needs of this critical cohort requires considerable resources.