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L eucine is the only physiologic amino acid that can stimulate insulin release by itself, and a great deal of evidence suggests that leucine does this by al-losterically activating glutamate dehydrogenase (GDH). GDH catalyzes the oxidative deamination of endog-enous glutamate, which is present at a high concentration in the pancreatic b-cell. Studies that(More)
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the(More)
OBJECTIVE Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS(More)
The 21-kD proteins encoded by ras oncogenes (p21Ras) are modified covalently by a palmitate attached to a cysteine residue near the carboxyl terminus. Changing cysteine at position 186 to serine in oncogenic forms produces a nonpalmitylated protein that fails to associate with membranes and does not transform NIH 3T3 cells. Nonpalmitylated p21Ras(More)
Nutrient secretagogues can increase the production of succinyl-CoA in rat pancreatic islets. When succi-nate esters are the secretagogue, succinyl-CoA can be generated via the succinate thiokinase reaction. Other secretagogues can increase production of suc-cinyl-CoA secondary to increasing ␣-ketoglutarate production by glutamate dehydrogenase or(More)
Leucine and glutamine were used to elicit biphasic insulin release in rat pancreatic islets. Leucine did not mimic the full biphasic response of glucose. Glutamine was without effect. However, the combination of the two did mimic the biphasic response. When the ATP-sensitive K+ (KATP) channel-independent pathway was studied in the presence of diazoxide and(More)
Succinic acid methyl esters are potent insulin secretagogues in rat pancreatic islets, but they do not stimulate insulin release in mouse islets. Unlike rat and human islets, mouse islets lack malic enzyme and, therefore, are unable to form pyruvate from succinate-derived malate for net synthesis of acetyl-CoA. Dimethyl-[2,3-(14)C]succinate is metabolized(More)
Pyruvate carboxylase (PC) is an enzyme that plays a crucial role in many biosynthetic pathways in various tissues including glucose-stimulated insulin secretion. In the present study, we identify promoter usage of the human PC gene in pancreatic beta cells. The data show that in the human, two alternative promoters, proximal and distal, are responsible for(More)
Tau aggregation is a common feature of tauopathies such as Alzheimer disease (AD). In AD, tau assembles into fibrillar polymers; it may also be present in other aberrant aggregates, including Hirano bodies. The mechanisms leading to tau polymerization in vivo are not understood. In this study, we found that coenzyme Q (ubiquinone) facilitates tau(More)
Pyruvate carboxylase (PC) is an anaplerotic enzyme that catalyzes the carboxylation of pyruvate to oxaloacetate, which is crucial for replenishing tricarboxylic acid cycle intermediates when they are used for biosynthetic purposes. We examined the expression of PC by immunohistochemistry of paraffin-embedded breast tissue sections of 57 breast cancer(More)