Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21HOMEOSTATIC CONTROL OF METABOLISM•Primary control mechanism is endocrine [Review hormones: Ch. 7, pp. 208-9]Stimulus ResponseEndocrine cells in pancreas secrete insulin and glucagon[Ch. 22, Fig. 22.13, p. 753]Fasting: ↓ glucose, ↓insulin, ↑ glucagonFed: ↑ glucose, ↑ insulin, ↓ glucagon[Fig. 22.14, p. 754]Insulin dominatesduring fed (anabolic)state•↑ glucose uptake•↑ glycogenesis•↑ glycolysis•↑ lipogenesis•↑ TG storage•↑ protein synth- esis•↓ blood glucose•↓ glycogenolysis•↓ gluconeogenesis•↓ FA oxidation•↓ TG hydrolysis•↓ protein catabolism•↓ ureogenesis•↓ ketogenesisGlucagon dominatesduring fasting/starving(catabolic) state•↓ glycogenesis•↓ glycolysis•↓ lipogenesis•↓ TG storage•↓ protein synthesis•↑ blood glucose•↑ glycogenolysis•↑ gluconeogenesis•↑ FA oxidation•↑ TG hydrolysis•↑ protein catabolism•↑ ureogenesis•↑ ketogenesis[pp. 754-759] [pp. 759-60]Stimulation of insulin release•Increased plasma glucose•Increased plasma amino acids•Incretin release from small intestine (GLP-1, GIP)•Parasympathetic, vagally-mediated reflexes originating in liver Inhibition of insulin release•Sympathetic stimulation (e.g. “fight or flight”)•Catecholamines (epi-, norepinephrine) from adrenal medulla1) Insulin binds to receptor with tyrosine kinase activity2) phosphorylation- mediated activa- tion of IRS’s3) Coupled to diverse array of signal transduction cascades4) ↑ glucose uptake/utilization, ↑ expression of anabolic genes Cellular mechanisms of insulin action[Fig. 22.16, p. 757]Insulin activates glucose uptake by inducing translocation of Glucose Transport Protein 4 (GLUT4) to the cell membrane[Fig. 22.17b, p. 758]Cultured adipocytes--transfected with a genefor GLUT4 fused to green fluorescent protein,treated with or without insulin, then viewed viaconfocal fluorescent microscopyPhoto credit: Saltiel, AR & Kahn, R. Nature 414:799-806, 2001Stimulation of glucagon release•↓ plasma glucose•↑ plasma amino acids [e.g. if ↑ dietary protein, but ↓ dietary glucose]•↑ sympathetic activity•↑ epinephrine release from adrenalInhibition of glucagon release•↑ plasma glucose•↑ parasympathetic activity•↑ plasma insulin--glucagon counteracts insulin effect on glucose uptake by muscle, adipose [pp. 759-60]Cellular mechanisms of glucagon action--receptor coupled to guanyl nucleotide (GTP) binding protein 1) Activation of G protein activates A.C.2) Activated A.C. produces cAMP3) cAMP activates P.K.4) P.K. phosphorylates P’ase kinase (activation)5) P’ase kinase phosphorylates glycogen phosphorylase (activation) & glycogen synthase (inactivation)Dysfunctional hormonal control of metabolism—diabetes•Hyperglycemia due to inadequate insulin secretion, decreased responsiveness to insulin, or both•Diagnosed by measuring a) fasting levels of glucose in plasma and b) kinetics of glucose removal after defined oral glucose load—glucose tolerance test [Fig. 22.19, p 761] Fasting blood glucose Aftr 2h glucose tolerance testNormal< 100 mg/dL < 140 mg/dLPre-diabetic100-125 mg/dL 140-199 mg/dLDiabetic>125 mg/dL >199 mg/dL--Type I•formerly called juvenile-onset diabetes•most severe form•failure of pancreatic β-cells to produce/release insulin•Incompletely understood autoimmune destruction of β-cells, associated with genetic and/or environmental factors•treatment: exogenous administration of insulin—resolves gluco- regulation, but other complications (e.g. peripheral vascular disease) persist--Type II•formerly adult-onset diabetes, now insulin-resistant diabetes•accounts for about 90% of cases of diabetes worldwide•precise cause uncertain, but is associated with obesity-induced inflammation•progressive: insulin resistance in target cells  compensatory hypersecretion of insulin  eventual loss of β-cell function•tissues with most prominent insulin resistance: skeletal muscle, liver, adiposeDiabetes [pp. 760-5]As a dysfunction in fundamental energy metabolism, diabeteshas wide-ranging pathophysiological consequences [Fig. 22.20, p. 762]•Muscle protein breakdown due to need for glucose/ATP•Ketoacidosis due to incomplete oxidation of FA•Hyperglycemia due to little or no glucose uptake + liver output of glucose derived from gluconeogenesis•Extreme thirst due to hyperosmolar state created by hyperglycemia•Overeating due to failure of insulin-dependent central satiety mechansims to “see” glucose, despite hyperglycemia•Glucosuria due to exceeding renal threshold for glucose reabsorption•Osmotic diuresis & dehydration due to ↑glucose in renal distal tubule•Diuresis accompanied by loss of electrolytescardiovascular complications•Microvascular disease (damage to small blood vessels)  retinopathy, neuropathy, nephropathy•Macrovascular disease (damage to large vessels)  accelerated CV disease, M.I., stroke•Myocardial dysfunction (independent of atherosclerosis)Insulin resistance  Type II diabetes—partly a response toobesity-induced inflammation originating from adipose tissueunder conditions of increasing fat contentObesity-induced inflammation—compromises insulin-dependent processes throughout the bodyEndocrine, inflammatory, and neuronal pathways link obesityto insulin resistancePrecise mechanistic linkage between obesity and insulinresistance/diabetes is not yet fully understood•Only about 75% of severely obese patients are insulin resistant; about 25% have normal insulin sensitivity•Adipose from resistant vs non-resistant obese patients shows differences in specific cellular processes (e.g. TG storage/lipolysis, oxidant stress, mitochondrial function, and inflammation)—reason(s) for these differences is unknown•Deleterious effects of expanding adipose appears to depend upon its location (i.e. visceral vs subcutaneous—e.g. increasing fat content in visceral adipose is associated with greater inflammatory response than in subQ adipose)Lipoprotein MetabolismHealthy state depends on HDL / LDL;If instead have HDL / LDL   atherosclerosis scavenger(e.g. artery