Endothelial signals are essential during pancreas development. Goto-Kakizaki (GK) rats have a 70% decrease in β-cell mass at E18, while it is similar at E13 to that of Wistar control rats. Because adult diabetic GK rats are hypercholesterolemic, we hypothesized that maternal hypercholesterolemia together with maternal/fetal hyperglycemia might alter perinatal pancreas development through islet microangiopathy (atherosclerosis) programming. Our aims were to: 1) demonstrate alterations of vascularisation in islets from 1-week-old GK rats, during the so-called prediabetic period; 2) measure systemic levels of lipids and various cytokines and chemokines around birth. Sera were obtained from 1-week-old male Wistar and GK rats (except otherwise stated) for radioimmunoassays; 2) Islets from these rats were hand-picked after collagenase digestion; 3) Molecular approaches included Affymetrix gene array and low density arrays targeted at endothelium, angiogenesis and cardiovascular disease biomarkers (OligoGEArrayRat). Gene expression was confirmed by qRT-PCR. Results: Affymetrix gene array (230A) showed differential expression of several genes which might be involved in inflammation in GK versus Wistar islets. Notably, the gene encoding epoxide hydrolase, the enzyme responsible for epoxyeicosatrienoic acids (EETs) conversion was decreased by 90%. EETs have anti-inflammatory and protective vascular effects. We then analysed expression of genes present on the 3 targeted arrays mentioned above (128 different genes/array). We obtained 20 up- and 8 down-regulated genes. Among the up-regulated genes were those encoding: caspase 1 (IL-1-converting enzyme, x10) that cleaves IL-1 and IL-18 into their active forms; various cytokines/chemokines involved in macrophage/granulocyte movements: CXCL2 (MIP-2α, x4.1), CXCL-1 (chemokine KC, x3.9), IL-15 (x1.4) and IL- 18 (x3.7); also fibronectin 1 (x2.3), ICAM-1 (x2.6), VEGFR3 (x2), carboxypeptidase 2 (TAFI, x1.9) and angiotensinogen (x1.9). These 3 groups have pro-atherosclerotic effects. Among the down-regulated genes were those encoding: osteoproteogerin (x0.4), neuropilin 1 (x0.6), platelet-derived growth factor (x0.6), coagulation factor III (tissue factor, x0.4) and the neuropeptide Y (x0.1) that acts as vascular mitogen. These data suggest that angiogenesis is deficient in neonatal GK islets. Concomitantly, prediabetic 1-week old-GK rats had lower leptin and higher circulating cholesterol/HDL ratio, MCP-1 and MIP-1α levels than Wistar rats. The latter data might reflect systemic vascular disturbances in GK neonates. Soon after birth many pro-atherosclerotic genes were upregulated in GK islets, while pro-angiogenic genes were downregulated. These data highlight early deficient islet vascularisation that might be responsible for the GK β-cell mass defect and therefore may be of potential therapeutic value.