170 INSULIN RESISTANCE IN GLUCOSE DISPOSAL AND PRODUCTION IN MAN different approach Lewis et al. 90 also found evidence of resistance to the direct suppressive effect of insulin on hepatic glucose production in T2D. In addi- tion, we found that suppression of both plasma FFA and glucagon levels were markedly impaired in T2D (Figure 6.3). 41 This may reflect impaired insulin- mediated suppression of lipolysis in adipocytes and impaired suppression of glucagon secretion from the α-cells. Since elevated FFA levels per se have been shown to stimulate both glycogenolysis as well as gluconeogenesis, 91, 92 impaired insulin-mediated suppression of FFA may obviously influence hepatic insulin sensitivity. Similarly, because hepatic glucagon sensitivity is normal in T2D, 93, 94 impaired insulin-mediated suppression of glucagon secretion may also influence hepatic insulin sensitivity. 95 Using the tracer technique in combina- tion with the 2 H 2 O technique, Gastaldelli et al. have quantitated gluconeogenesis in obesity and in T2D. In obese subjects, the gluconeogenic rate was directly related to the degree of obesity, 96 and in clamp studies of type 2 diabetic sub- jects gluconeogenic fluxes were elevated in the basal state and suppression in response to insulin was markedly impaired during the clamp. 97 Thus, from in vivo studies, there is evidence of hepatic insulin resistance both in the direct and in the indirect actions (through FFA and glucagon), and both in the glycogenolytic and in the gluconeogenic pathways. Biochemical defects in hepatic insulin action Control of hepatic glucose output may occur through regulation of gluconeo- genesis or glycogenolysis. However, glucose-6-phosphatase [G6Pase] and glu- cokinase [GK] are believed to play prominent roles in the regulation of glucose production by controlling the rate of glucose efflux and uptake in hepatocytes. The competing activity between the two enzymes has been described as the glucose cycle and represents an important potential site of regulation. 98 Glucose cycling has been found to be increased in mild T2D. 98 Insulin sensitivity of the glucose cycle is reduced in obese non-diabetic and more so in obese type 2 dia- betic patients, 99 suggesting that G6Pase activity is increased in both groups. 99 This increased activity may be secondary to a decreased insulin-induced sup- pression of the enzyme activity at the level of the liver cell. Alternatively, it may possibly be secondary to the increased peripheral lipolysis and enhanced plasma FFA concentrations, since chronically elevated plasma FFAs have been shown to enhance liver G6Pase gene expression. 100 Moreover, in liver biopsies from type 2 diabetic patients, G6Pase activity has been found to be increased 101 and GK activity to be reduced. 101, 102 Increased hepatic VLDL production Another important aspect of hepatic insulin resistance is an atherogenic dys- lipidaemia profile characterized by hypertriglyceridaemia, low plasma HDL- cholesterol and raised small dense LDL-cholesterol profile. The physiologic CONCLUSION AND PERSPECTIVES 171 basis for this metabolic dyslipidaemia appears to be hepatic overproduction of apoB-containing VLDL particles, which may result from a composite set of fac- tors including increased flux of FFAs from adipose tissue to the liver and directly from lipoprotein remnant uptake, increased de novo fatty acid synthesis, pref- erential esterification versus oxidation of fatty acids, reduced post-translational degradation of apo-B and overexpression of microsomal triglyceride transfer protein (MTP). 103, 104 These conditions, together with resistance to the normal suppressive effect of insulin on VLDL secretion, act in concert to channel fatty acids into secretory and storage rather than degradative pathways. 105, 106 Primary/genetic defects in insulin action in liver Whether hepatic insulin resistance is a primary trait or a secondary phenomenon is as yet undetermined. However, if hepatic insulin resistance is a secondary phe- nomenon it may be reversible. Given the serious consequences of hepatic insulin resistance, both for glucose metabolism and, in particular, for development of dyslipidaemia, the answer to this question and possible rational treatments might be quite important. 6.4 Conclusion and perspectives Insulin resistance in glucose disposal and production seems to play an important role for the development of the metabolic syndrome and T2D. Both diseases dis- pose to cardiovascular disease and cardiovascular mortality. Therefore, insulin resistance may be considered as a serious risk factor in the modern society, and because insulin resistance is in itself symptomless it has been named ‘the secret killer’. In this short description of insulin resistance, and glucose disposal and hep- atic glucose production, we have focused on various aspects of methodologies to measure insulin resistance, in order to alert researchers and clinicians to the importance of accurate diagnosis of insulin resistance. We have also focused on the potential cellular mechanisms that could explain the development of insulin resistance. In skeletal muscle, insulin-mediated glucose disposal is clearly dependent on glycogen synthesis. This pathway is impaired, due to hyperphos- phorylation of the key enzyme, glycogen synthase. Therefore, regulation of glycogen synthase activity may be central to our understanding of insulin resis- tance in the metabolic syndrome and T2D. We believe that obesity is linked to insulin resistance, metabolic syndrome and T2D, through the accumulation of lipids, particularly long chain acylCoAs in the skeletal muscle, and that these intracellular fatty acids and triglycerides may directly inhibit the dephosphory- lation of glycogen synthase and thereby impair glucose disposal. Thus, future studies will need to examine the relationship between intramy- ofibril lipid accumulation, skeletal muscle glycogen synthase activity and GLUT4 172 INSULIN RESISTANCE IN GLUCOSE DISPOSAL AND PRODUCTION IN MAN translocation. Although hepatic insulin resistance may play only a minor role in the development of the metabolic syndrome per se, the role of the liver in the dyslipidaemia of the syndrome is important. Also, the altered peripheral regu- lation of FFAs and their effect on hepatic glyconeogenesis and glycogenolysis is a critical factor in the dysregulation of glucose metabolism in the metabolic syndrome. 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(1997) Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM. Diabetologia 40, 454–462. 106. Lewis, G. F., Carpentier, A., Adeli, K. and Giacca, A. (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23, 201–229. 7 Central Regulation of Peripheral Glucose Metabolism Stanley M. Hileman and Christian Bjørbæk 7.1 Introduction Glucose is the primary and preferred fuel for the brain. Thus, maintaining glu- cose homeostasis is of critical concern for this organ. Mechanisms in the central nervous system (CNS) have evolved both to detect changes in available energy and to initiate appropriate responses, including effects on appetite and modula- tion of peripheral glucose levels, to ensure sufficient supply of glucose. Plasma glucose level is the most important determinant of the secretion of classical glucoregulatory hormones, such as insulin and glucagon. Clearly, hypoglycaemia can be sensed directly by the brain and counter-regulatory mech- anisms can be mounted in the CNS to drive glucose levels back toward the normoglycaemic range. Activation of neuroendocrine systems and the auto- nomic nervous system are the main effector pathways invoked by the brain. Combined, these central and peripheral regulatory events result in increased production of glucose by the liver and decreased utilization by peripheral tis- sues. Counter-regulatory responses are relevant during prolonged starvation and are particularly important for diabetic patients using insulin, where hypogly- caemia often occurs inadvertently. We will herein discuss the role of the brain in counter-regulation to severe hypoglycaemia and mechanisms whereby the CNS may sense small day-to-day changes in glucose levels. This chapter will also focus on a number of other afferent signals to the CNS, including leptin, insulin and free fatty acids, that may influence glucose homeostasis independent of their effects on feeding behaviour. Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly  2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6 [...]... supporting a physiological role for central insulin signalling Neurons that are inhibited by insulin are present in the ARC and VMH Like leptin, insulin activates ATP-sensitive K+ channels in hypothalamic brain slices178 and a role of K+ -ATP channels in decreasing hepatic glucose production in response to insulin has recently been reported.176 Interestingly, insulinsensitive neurons also have glucosensing... frequency .45 ICV injection of insulin reduces food intake and body weight in baboons and rodents171, 172 and administration of anti -insulin antibodies into the rat hypothalamus increases food intake.173 In more recent studies, complete loss of neuronal insulin receptors by conditional knockout in mice or partial loss by hypothalamic injection of insulin receptor anti-sense oligonucleotides results in hyperphagia... glucosensing capabilities .45 , 178 Moreover, insulin does not affect the activity of neurons from rats lacking functional leptin receptors, suggesting that aspects of insulin action in the CNS require leptin signalling, and opening the possibility that receptors for insulin and leptin are co-expressed in glucosensing neurons.179 Indeed, insulin receptors have recently been identified in hypothalamic POMC... rate and intracarotid infusion is more effective than intravenous administration.80 Stimulation of parasympathetic inputs increases insulin release in the dog and the baboon81, 19 and increases glucagon release from α-cells in dogs and calves.82, 83 Furthermore, stimulation of the mixed pancreatic nerve increases insulin levels in the pancreatic duodenal vein and vagal stimulation increases insulin release... it has in counter-regulation remains to be defined Leptin Leptin, the fat-derived hormone discovered in 19 94, 122 circulates at levels proportional to body fat mass and delivers information to the brain about energy stores.29, 30, 123 – 125 Mutations in leptin or its receptor cause morbid obesity and severe insulin resistance.122, 126 In addition to decreasing food intake and body weight, leptin in uences... Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain FEBS Lett 40 1, 59– 64 62 Dunn-Meynell, A A., Rawson, N E and Levin, B E (1998) Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain Brain Res 8 14, 41 – 54 63 Matschinsky, F M., Glaser, B and Magnuson, M A (1998) Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental... W L and Baskin, D G (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization Endocrinology 127, 32 34 3236 170 Werther, G A., Hogg, A., Oldfield, B J., McKinley, M J., Figdor, R., Allen, A M and Mendelsohn, F A (1987) Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry Endocrinology... are activated by leptin and glucose Whether POMC neurons increase or decrease firing rates in response to insulin is unknown, although activation seems more likely since the melanocortin system appears to be required for insulin- mediated inhibition of food intake180 and fat mass.181 In addition, central administration of melanocortin receptor agonists rapidly reduces serum insulin levels, an effect... 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