Sur1 knockout mouse ␤-cells lack K ATP channels and show spontaneous Ca 2؉ action potentials equivalent to those seen in patients with persistent hyperinsulinemic hypoglycemia of infancy, but the mice are normoglycemic unless stressed. Sur1 -/-islets lack first phase insulin secretion and exhibit an attenuated glucose-stimulated second phase secretion. Loss of the first phase leads to mild glucose intolerance, whereas reduced insulin output is consistent with observed neonatal hyperglycemia. Loss of K ATP channels impairs the rate of return to a basal secretory level after a fall in glucose concentration. This leads to increased hypoglycemia upon fasting and contributes to a very early, transient neonatal hypoglycemia. Whereas persistent hyperinsulinemic hypoglycemia of infancy underscores the importance of the K ATP -dependent ionic pathway in control of insulin release, the Sur1 -/-animals provide a novel model for study of K ATP -independent pathways that regulate insulin secretion.ATP-sensitive potassium channels (K ATP channels) 1 are a unique combination of a K ϩ inward rectifier (either K IR 6.1 or K IR 6.2) and a sulfonylurea receptor (SUR1 or SUR2) transport ATPase superfamily members (1-3). These channels respond to changes in ATP/ADP and can couple metabolism to membrane electrical activity. SUR1 and K IR 6.2 comprise the K ATP channels in pancreatic ␤-cells that regulate the ionic pathway mediating glucose-stimulated insulin secretion by setting the resting membrane potential below the activation threshold for voltage-gated Ca 2ϩ channels (4). Mutations in human Sur1 or K IR 6.2 cause a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) characterized by oversecretion of insulin despite severe hypoglycemia (1, 5). Surprisingly, two recent studies involving disruption of K ATP channels in mice produced a quite different picture. Targeted overexpression of a dominant-negative K IR 6.2 subunit, K IR 6.2 G132S , in ␤-cells reduced channel activity producing animals that were hypoglycemic at birth but became increasingly hyperglycemic secondary to ␤-cell death (6).K IR 6.2 null mice, K IR 6.2 -/-, on the other hand, completely lack ␤-cell K ATP channels but exhibit a less severe phenotype (7). The K IR 6.2 -/-animals have nearly normal blood glucose levels, showing mild glucose intolerance when challenged with glucose. These animals are reported to release a small amount of insulin in response to glucose, whereas isolated, perifused islets show a small first phase of glucose-stimulated insulin secretion and no second phase. The normal blood glucose levels have been attributed to insulin hypersensitivity secondary to the loss of SUR2A/K IR 6.2 K ATP channels in skeletal muscle.SUR1 null mice, Sur1 -/-, unlike their K IR 6.2 -/-counterparts, are not insulin-hypersensitive. Isolated Sur1 -/-islets exhibit a pattern of glucose-stimulated insulin release consistent with regulation by an underlying K ATP -independent pathway (or pathways), the nature of which is unknown (8 -12). The Sur...

Whereas the loss of ATP-sensitive K؉ channel (K ATP channel) activity in human pancreatic ␤-cells causes severe hypoglycemia in certain forms of hyperinsulinemic hypoglycemia, similar channel loss in sulfonylurea receptor-1 (SUR1) and Kir6.2 null mice yields a milder phenotype that is characterized by normoglycemia, unless the animals are stressed. While investigating potential compensatory mechanisms, we found that incretins, specifically glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic peptide (GIP), can increase the cAMP content of Sur1KO islets but do not potentiate glucose-stimulated insulin release. This impairment is secondary to a restriction in the ability of Sur1KO I nsulin secretion is a unique example of exocytosis controlled by metabolic, ionic, and hormonal pathways. An imbalance in insulin release due to disruption of these pathways can produce the profound changes in glucose homeostasis associated with either hyperglycemia (diabetes) or hypoglycemia (e.g., hyperinsulinemic hypoglycemia [HI]). In pancreatic ␤-cells, ATPsensitive K ϩ channels (K ATP channels), composed of Kir6.2 and the sulfonylurea receptor-1 (SUR1), and voltage-gated Ca 2ϩ channels are key players linking increased glucose metabolism to elevation of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ). Membrane depolarization induced by closure of K ATP channels, secondary to changes in ADP/ ATP resulting from glucose metabolism, leads to the generation of Ca 2ϩ -dependent action potentials and [Ca 2ϩ ] i oscillations, which are considered to be a major mediator of insulin secretion. Sulfonylureas that block ␤-cell K ATP channels are commonly used to restore insulin secretion in type 2 diabetes. The loss or constitutive closure of ␤-cell K ATP channels, as a result of mutations in either subunit, is a cause of both dominant and recessive forms of HI (HI-SUR1 or HI-Kir6.2), characterized by elevated plasma insulin values inconsistent with the observed hypoglycemia (reviewed in 1,2). Studies on islets isolated from patients diagnosed with HI are consistent with hypersecretion of insulin (3,4). By comparison, the clinical phenotype of mice lacking ␤-cell/neuronal K ATP channels is strikingly normal. Kir6.2 null (Kir6.2KO) (5) and Sur1KO (6) mice are normoglycemic when fed, displaying only mild glucose intolerance, consistent with their loss of first phase and attenuated second phase of insulin release. Sur1KO mice exhibit greater hypoglycemia upon fasting, consistent with their inability to rapidly repolarize their ␤-cells and reduce insulin release (6). No compensating ionic mechanisms have been identified, and the electrophysiological phenotype of isolated K ATP KO mouse ␤-cells, i.e., constant membrane depolarization, presence of Ca 2ϩ -dependent action potentials, and elevated oscillating [Ca 2ϩ ] i in low glucose, is quite similar to that of ␤-cells from HI neonates (compare 5-7); therefore, it is unclear why K ATP KO islets lack the elevated basal insulin release observed in HI islets (3,4).In a search for dif...

PREAMBLE The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association founded in 1985 to facilitate communication worldwide among individuals pursuing clinical and academic excellence in nuclear medicine. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine. The SNMMI and EANM will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process, entailing extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents, and are not inflexible rules or requirements of practice. They are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that action differing from what is laid out in the standards/guidelines, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure a successful outcome. All that sho...

The mechanisms of control of glucagon secretion are largely debated. In particular, the paracrine role of somatostatin (SST) is unclear. We studied its role in the control of glucagon secretion by glucose and K channel blockers, using perifused islets and the in situ perfused pancreas. The involvement of SST was evaluated by comparing glucagon release of control tissue or tissue without paracrine influence of SST (pertussis toxin-treated islets, or islets or pancreas from mice). We show that removal of the paracrine influence of SST suppresses the ability of K channel blockers or K channel ablation to inhibit glucagon release, suggesting that in control islets, the glucagonostatic effect of K channel blockers/ablation is fully mediated by SST. By contrast, the glucagonostatic effect of glucose in control islets is mainly independent of SST for low glucose concentrations (0-7 mmol/L) but starts to involve SST for high concentrations of the sugar (15-30 mmol/L). This demonstrates that the glucagonostatic effect of glucose only partially depends on SST. Real-time quantitative PCR and pharmacological experiments indicate that the glucagonostatic effect of SST is mediated by two types of SST receptors, SSTR2 and SSTR3. These results suggest that alterations of the paracrine influence of SST will affect glucagon release.