Biomaterial Database

Impaired insulin action in adipocytes of New Zealand obese mice: a role for postbinding defects in pyruvate dehydrogenase and insulin mediator activity. 1988

S L Macaulay, and R G Larkins

University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Australia.

This study investigated possible mechanisms underlying insulin resistance in the New Zealand Obese (NZO) mouse, an animal model for obese, non-insulin-dependent diabetes. Insulin binding, mediator generation, and action both at the level of glucose utilization and enzyme modulation were compared in adipocytes from lean control New Zealand Chocolate (NZC) mice and NZO mice during the development of the syndrome. Abnormalities of insulin stimulation of glucose transport and utilization in NZO mouse adipocytes were found which involved both decreased sensitivity and responsiveness to insulin. The defects were evident at an early age (4 weeks) and could not be attributed to differences in nonstimulated glucose metabolism, which was similar in the control NZC and obese NZO strains of mouse. Insulin binding to its receptor was only moderately decreased in adipocytes of NZO mice. Pyruvate dehydrogenase (PDH) activity of NZO mouse adipocytes was totally unresponsive to insulin in contrast to the impaired but still significant insulin stimulation of glucose transport and utilization, suggesting a postreceptor defect at the level of insulin stimulation of this enzyme. Insulin stimulated the production of a low molecular weight factor which activated pyruvate dehydrogenase in NZC mouse adipocytes (insulin mediator) but, paradoxically, caused a decrease in mediator production or activity in adipocytes from NZO mice. Thus, insulin either inhibited mediator production or stimulated generation of an inhibitory mediator in adipocytes from this strain. No evidence for the latter mechanism was found. This study demonstrates in adipocytes of NZO mice: (1) a receptor defect and (2) a postreceptor defect of insulin action at the level of pyruvate dehydrogenase activation.(ABSTRACT TRUNCATED AT 250 WORDS)

UI	MeSH Term	Description	Entries
D007328	Insulin	A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).	Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D007333	Insulin Resistance	Diminished effectiveness of INSULIN in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent HYPERGLYCEMIA or KETOSIS.	Insulin Sensitivity,Resistance, Insulin,Sensitivity, Insulin
D008297	Male		Males
D008820	Mice, Obese	Mutant mice exhibiting a marked obesity coupled with overeating, hyperglycemia, hyperinsulinemia, marked insulin resistance, and infertility when in a homozygous state. They may be inbred or hybrid.	Hyperglycemic Mice,Obese Mice,Mouse, Hyperglycemic,Mouse, Obese,Hyperglycemic Mouse,Mice, Hyperglycemic,Obese Mouse
D009765	Obesity	A status with BODY WEIGHT that is grossly above the recommended standards, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).
D011768	Pyruvate Dehydrogenase Complex	A multienzyme complex responsible for the formation of ACETYL COENZYME A from pyruvate. The enzyme components are PYRUVATE DEHYDROGENASE (LIPOAMIDE); dihydrolipoamide acetyltransferase; and LIPOAMIDE DEHYDROGENASE. Pyruvate dehydrogenase complex is subject to three types of control: inhibited by acetyl-CoA and NADH; influenced by the energy state of the cell; and inhibited when a specific serine residue in the pyruvate decarboxylase is phosphorylated by ATP. PYRUVATE DEHYDROGENASE (LIPOAMIDE)-PHOSPHATASE catalyzes reactivation of the complex. (From Concise Encyclopedia Biochemistry and Molecular Biology, 3rd ed)	Complex, Pyruvate Dehydrogenase,Dehydrogenase Complex, Pyruvate
D011972	Receptor, Insulin	A cell surface receptor for INSULIN. It comprises a tetramer of two alpha and two beta subunits which are derived from cleavage of a single precursor protein. The receptor contains an intrinsic TYROSINE KINASE domain that is located within the beta subunit. Activation of the receptor by INSULIN results in numerous metabolic changes including increased uptake of GLUCOSE into the liver, muscle, and ADIPOSE TISSUE.	Insulin Receptor,Insulin Receptor Protein-Tyrosine Kinase,Insulin Receptor alpha Subunit,Insulin Receptor beta Subunit,Insulin Receptor alpha Chain,Insulin Receptor beta Chain,Insulin-Dependent Tyrosine Protein Kinase,Receptors, Insulin,Insulin Receptor Protein Tyrosine Kinase,Insulin Receptors
D003920	Diabetes Mellitus	A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE.
D005947	Glucose	A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement.	Dextrose,Anhydrous Dextrose,D-Glucose,Glucose Monohydrate,Glucose, (DL)-Isomer,Glucose, (alpha-D)-Isomer,Glucose, (beta-D)-Isomer,D Glucose,Dextrose, Anhydrous,Monohydrate, Glucose
D000273	Adipose Tissue	Specialized connective tissue composed of fat cells (ADIPOCYTES). It is the site of stored FATS, usually in the form of TRIGLYCERIDES. In mammals, there are two types of adipose tissue, the WHITE FAT and the BROWN FAT. Their relative distributions vary in different species with most adipose tissue being white.	Fatty Tissue,Body Fat,Fat Pad,Fat Pads,Pad, Fat,Pads, Fat,Tissue, Adipose,Tissue, Fatty