1. It has been suggested that adenosine may play a role in insulin-dependent glucose uptake into cells, but the adenosine receptor subtypes involved in this effect are unclear. We have therefore explored the role of adenosine 1 receptors (A1AR) in glucose homeostasis by comparing wild type(WT) and A1AR-deficient mice. We noted that the body weight gain with age was significantly greater in A1AR-/- than WT mice so that at 35 weeks of age A1AR-/- mice were 7 grams heavier than WT animals. This was mostly due to a greater gain of body fat content. Fasting glucose levels were elevated in A1AR-- compared to wild type at both 8 and 20 weeks of age as was fasting plasma insulin. Following an i.v. glucose load we observed that the area under the plasma glucose curve was about 40% greater in A1AR-- than wild type mice, and that this difference was highly significant. Using the so-called Belfiore index as measure of insulin sensitivity we determined that A1AR deficient mice were significantly less insulin-sensitive than WT in all age groups. A high fat diet caused a further deterioration of insulin sensitivity in both A1AR-/- and WT mice. Our results show that adenosine signaling via A1AR contributes to insulin-controlled glucose homeostasis.[unreadable] [unreadable] 2. IA-2 and IA-2beta are major autoantigens in type 1 diabetes, but their physiological functions aside from their antigenic properties are not well understood. IA-2 and IA-2beta are transmembrane proteins in dense core vesicles and their expression has been shown to influence the secretion of hormones and neurotransmitters. We performed experiments to examine whether IA-2 and IA-2beta modulate the release of renin from dense core vesicles of juxtaglomerular granular cells in the kidney. We found that plasma renin concentration (PRC; ng angiotensin I/ml hr) was significantly reduced in mice with null mutations in IA-2, IA-2beta, or both IA-2 and IA-2beta compared to wild type mice (876 plus/minus 113, 962 plus/minus 130, and 596 plus/minus 82 vs. 1367 plus/minus 93; p <0.01, p<0.02 and p< 0.001). Renin mRNA levels were reduced to 26.4 plus/minus 5.1%, 39 plus/minus 5.4%, and 35.3 plus/minus 5.5% of wild type in IA-2-/-, IA-2beta-/-, and IA2/ IA-2beta-/- mice. Surprisingly, plasma aldosterone levels were not different between genotypes. 24 hour mean arterial blood pressures and heart rates were not different between wild type, IA-2-/-, and IA-2/ IA-2beta-/- mice, but were significantly lower in IA-2beta-/- mice. The regulation of PRC by furosemide, and salt intake, and of aldosterone by salt intake was maintained in all genotypes. While propranolol reduced plasma renin in wild type mice, it had no effect in IA-2/IA-2beta-/- mice. Renal tyrosine hydroxylase mRNA and immunopositivity was reduced in IA-2/ IA-2beta-/- mice. Since the expression of IA-2 and IA-2beta did not colocalize with renin, their effect on renin secretion and expression appears to be indirect. We conclude that IA-2 and IA-2beta are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.[unreadable] [unreadable] 3. E-NTPDase1 (also known as CD39) is a vascular ectonucleotidase strongly expressed in the arteries, arterioles, and glomeruli of the kidney. ENTPD1 hydrolyzes extracellular ATP and ADP to AMP, initiating an enzymatic cascade leading to the generation of adenosine. Mice with a deletion mutation of ENTPDase1 have been found to develop a more severe diabetic nephropathy than wild-type mice in a type 1 model of diabetes. Since non-diabetic ENTPDase1-/- mice also showed a tendency toward glomerular injury, we examined whether ENTPD1-null mice would develop overt renal injury with aging alone. At baseline, ENTPD1-null mice had mild systolic hypertension compared to controls. The null mice developed glomerular and renal hypertrophy during their lifespan. ENTPD1-null mice had mildly elevated albuminuria at baseline that progressively worsened with aging. The null mice also developed glomerular hyperfiltration, as demonstrated by decreased creatinine and increased creatinine clearance. Because ATP and adenosine are critical mediators for renal autoregulation, we suspected abnormal renal autoregulation might explain hyperfiltration and glomerular injury in these mice. Using one-step kinetics as well as dynamic transfer function studies, we have observed that ENTPD1-null mice have a defective myogenic response in addition to previously demonstrated defects in tubuloglomerular feedback. We suggest that ENTPD1 protects the kidney from glomerular injury in part via regulation of afferent arteriolar tone.