Phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating the key role played at these sites by the isoforms of CAAT/enhancer binding protein in patterning of PEPCK-C gene expression during the perinatal period. The PEPCK-C gene provides a model for the metabolic control of gene transcription.

Regulation of phosphoenolpyruvate carboxykinase (gtp) gene expression

Targeted gene mutations have established distinct, yet overlapping, developmental roles for receptors of the insulin/IGF family. IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. In rodents, unlike humans, insulin does not participate in embryonic growth until late gestation. The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. Evidence from genetically engineered mice does not support the view that insulin and IGF receptors promote cellular differentiation in vivo or that they are required for early embryonic development. The phenotypes of insulin receptor gene mutations in humans and in mice indicate important differences between the developmental roles of insulin and its receptor in the two species.

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Distinct and Overlapping Functions of Insulin and IGF-I Receptors

Growth-Promoting Interaction of IGF-II with the Insulin Receptor during Mouse Embryonic Development

Insulin resistance plays a key role in the pathogenesis of several human diseases, including diabetes, obesity, hypertension, and cardiovascular diseases. The predisposition to insulin resistance results from genetic and environmental factors. The search for gene variants that predispose to insulin resistance has been thwarted by its genetically heterogeneous pathogenesis. However, using techniques of targeted mutagenesis and transgenesis in rodents, investigators have developed mouse models to test critical hypotheses on the pathogenesis of insulin resistance. Moreover, experimental crosses among mutant mice have shed light onto the polygenic nature of the interactions underlying this complex metabolic condition.

https://www.physiology.org/doi/pdf/10.1152/physrev.00032.2003

Mouse models of insulin resistance.

To examine the role of the insulin receptor in fuel homeostasis, we and others have carried out genetic ablation studies in mice. Mice lacking insulin receptors are born with normal features, but develop early postnatal diabetes and die of ketoacidosis. In contrast, mice lacking insulin receptors in specific cell types as a result of conditional mutagenesis develop mild metabolic and reproductive abnormalities. These experiments have uncovered novel functions of insulin receptors in tissues such as brain and pancreatic beta-cells. Combined knockout studies of insulin and Igf1 receptors indicate that the insulin receptor also promotes embryonic growth. Experimental crosses of mice with insulin receptor haploinsufficiency have been instrumental to the genetic analysis of insulin action by enabling us to assign specific roles to different insulin receptor substrates and identify novel elements in insulin signaling.

Insulin receptor knockout mice.

Insulin (IRI) and glucagon (IRG) increased in the plasma of the rat fetus from 18½ to 20½ days of gestation and decreased on day 21½. The demonstrated failure of insulin and glucagon to cross the placenta of the rat allowed the conclusion that fetal rat pancreas secreted IRI and IRG in the plasma of the fetus at the end of gestation. Fetal hyperglycemia induced by perfusing pregnant rats with glucose for one hour produced a marked increase in fetal plasma IRI but did not modify plasma IRG. Fetal hypoglycemia induced by perfusing pregnant rats with insulin for one hour produced a fall in fetal plasma IRI but no rise in fetal plasma IRG. Chronic fetal hypoglycemia produced by fasting pregnant rats for ninety-six hours or by intrauterine growth retardation of fetuses increased fetal plasma IRG and decreased fetal plasma IRI. Norepinephrine injection in term rat fetus increased plasma IRG and decreased plasma IRI. Acetylcholine injection increased both plasma IRI and IRG, whereas serotonin remained without effect. These data suggest that IRI and IRG secretion by the fetal rat pancreas is controlled by both the blood glucose level and autonomic nervous system activity. Lower blood glucose levels and higher plasma IRI and IRG levels in pregnant than nonpregnant rats are also reported.

Elizabeth Soufflet

Papers

Factors Affecting the Secretion of Insulin and Glucagon by the Rat Fetus