Is adrenomedullin a causal agent in some cases of type 2 diabetes? A. Martı ´nez a, *, T.H. Elsasser b , S.J. Bhathena b , R. Pı ´o a , T.A. Buchanan c , C.J. Macri d , F. Cuttitta a a Department of Cell and Cancer Biology, National Cancer Institute, Medicine Branch, Division of Clinical Sciences, National Institutes of Health, Building 10, Room 13N262. Bethesda, MD 20892, USA b U.S. Department of Agriculture, Agricultural Research Service, Beltsville, MD 20705, USA c Departments of Medicine and Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, CA 90033, USA d Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA Received 11 January 1999; accepted 24 August 1999 Abstract The study of two populations with a recent onset of type 2 diabetes showed that a subset of the patients had higher levels of adrenomedullin (AM) than the rest of the diabetics. In this subset, physiological elevations of AM might have triggered the disease in predisposed individuals. Diabetics showed higher levels of AM than healthy controls. In addition, glycemia was measured in diabetic rats after injection of saline, AM, or antiAM antibody. AM elevated glycemia, whereas the antibody reduced circulating glucose to normal. These results suggest that manipulation of AM levels could represent a new approach in the management of diabetes for the appropriate individuals. Published by Elsevier Science Inc. Keywords: Adrenomedullin; Gestational diabetes; Radioimmunoassay; Glucose tolerance; Glycemia regulation; Diabetic rat model 1. Introduction Diabetes mellitus is a chronic metabolic disorder that affected 16 million people in the United States in 1995, according to estimates of the National Institute of Diabetes (NIDDKD, NIH). Management costs for diabetes in 1992 was $92 billion [38]. The hallmark of diabetes, whether type 1 or type 2, is hyperglycemia. Clinical complications asso- ciated with diabetes, such are retinopathy, neuropathy, ne- phropathy, or atherosclerosis, are most likely the conse- quence of long-term hyperglycemia via both altered metabolic pathways and nonenzymatic glycation of proteins [48]. Under normal conditions, insulin released from the  cells of the pancreatic islets is constantly adjusted by neural [5] and humoral and nutritional [32] mechanisms, so that normoglycemia is maintained. However, in patients with diabetes, the regulation of blood glucose levels is impaired and the concentrations of circulating glucose are elevated. Type 2 diabetes is the most frequent form of the disease [70 –95% of all diabetic patients [38,48]], and is character- ized by insufficient insulin secretion to compensate for insulin resistance in target tissues [46]. These two charac- teristics may coexist in subjects before developing diabetes, and these people are more vulnerable to factors that further reduce insulin output or insulin action [7]. Many steps in the stimulus-secretion coupling of glucose-induced insulin re- lease have been implicated in the impaired insulin secretion in type 2 diabetes. These include the glucose transporter Glut 2, the glucokinase, the adenylate cyclase system, and various mitochondrial deficiencies, among others [26]. Adrenomedullin (AM) is a multifunctional peptide with many physiological actions, including hypotension [39], renal regulation [18], neurotransmission [2], growth [34, 47], and defense against microorganisms [45]. It has also been shown that AM and its related peptides are able to regulate the release of insulin [30] and other hormones, including catecholamines [21], adrenocorticotropin [41], al- dosterone [20,49], and atrial natriuretic peptide [43]. All these functions are exerted through a specific membrane receptor [19] that activates adenylate cyclase and modulates Ca 2+ flux in the target cells [44]. This receptor has been found in the rat pancreas through in situ hybridization and is expressed by the  cells of the islets of Langerhans [30]. For a recent review on AM, see Ref. [27]. * Corresponding author. Tel.: +1-301-402-3308; fax: +1-301-435- 8036. E-mail address: martineza@bprb.nci.nih.gov (A. Martínez) Peptides 20 (1999) 1471–1478 0196-9781/99/$ – see front matter Published by Elsevier Science Inc. PII: S0196-9781(99)00158-8