The Unger lab produced the first glucagon antibody to determine if, as was widely believed, glucagon was an contaminent of insulin extraction or rather a true hormone. Immunocytochemical studies localized glucagon to pancreatic alpha cells, while the first radioimmunoassay, proved glucagon to be a true hormone secreted in response to glucose need. The correlation between hyperglucagonemia and hyperglycemia suggested a diabetogenic role, and in 1975, the group reported that somatostatin suppression of hyperglucagonemia in the insulin deficient state eliminated the hyperglycemia and hyperketonemia. In1978 a human trial with somastotatin in type 1 diabetic humans demonstrated complete elimination of hyperglycemia, but the side effects of somastotatin precluded clinical use in human therapy. Twenty years later the lab discovered that leptin was superior to somastotatin as a glucagon suppressor and was devoid of undesirable side effects. Extensive studies by Drs. Wang and Yu, proved the efficacy of leptin in treating type 1 diabetes. Studies by Dr. Lee extended the importance of glucagon‘s role in diabetes, demonstrating that when glucagon action is absent, total insulin lack has no deleterious effect on any facet of glucose metabolism—even glucose tolerance.
In addition to glucagon and T1DM, the Unger lab studied the interrelationships between obesity and type 2 diabetes (T2DM) and metabolic syndrome. It introduced the concept of lipotoxicity, which attributes T2DM and metabolic syndrome diseases to ectopic accumulation of lipids. Palmitoyl CoA accumulation leads to apoptosis of the islets by increasing ceramide formation, which results in apoptosis mediated by enhanced peroxynitrite production. This phenomenon, called lipoapoptosis, occurs only in fat-laden beta-cells. Diabetes results when a slowly declining population of beta-cells cannot meet the increased demands for insulin imposed by the lipid-induced insulin resistance of its target tissues. The same abnormalities occur in the heart, leading to lipotoxic cardiomyopathy with congestive failure and dilatation. Llipid overload in the lungs may contribute to Pickwickian syndrome, in the gall bladder to bile stasis and gall stones and in the kidneys to hypertension. This laboratory has demonstrated that a major role of hyperleptinemia of obesity is to prevent lipid overaccumulation and lipotoxicity in nonadipose tissues such as the pancreatic islets and liver, by upregulating fatty acis oxidation.