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John C Wallace, University of Adelaide, Adelaide, South Australia, Australia Greg J Barritt, Flinders University School of Medicine, Adelaide, South Australia, Australia The gluconeogenic pathway, which is found in the liver and kidney, involves the synthesis . Glucose-6-phosphatase, Fructose-1,6-bisphosphatase, Pyruvate Carboxylase and Phosphoenolpyruvate of glucose from three-carbon precursors such as lactate, alanine and glycerol. The main function of gluconeogenesis is to supply glucose to tissues, such as brain and red blood cells, that depend on glucose as their main or sole energy source.
. Biochemistry of Diabetes Drugs that Inhibit Glucose Glucose is a major fuel for the metabolism of skeletal andheart muscle, brain, blood cells, adipose tissue and most neogenic pathway is increased. These include exercise, other tissues of the body. An adequate supply of glucose is pregnancy and lactation. An increased demand for particularly important for brain and red blood cells gluconeogenesis also exists in starvation and in a number because, under normal conditions, glucose is the sole of pathological states such as traumatic injury, fever and substrate for these tissues. Only in starvation does the brain cachexia (severe muscle wasting) induced by cancer and metabolize ketone bodies as an additional source of human immunodeficiency virus infection.
energy. In all these tissues, the main outcome of glucose Hypoglycaemia (abnormally low blood glucose concen- metabolism is to yield energy in the form of adenosine tration) poses a particular problem for the body because triphosphate (ATP). However, some glucose is metabo- the brain and red blood cells depend on glucose as a source lized to yield precursors for biosynthetic reactions, such as of energy. Hypoglycaemia can be a life-threatening state.
the formation of some amino acids, nucleotides and other Gluconeogenesis is the key metabolic pathway that guards against hypoglycaemia. Examples of pathological situa- In the well-fed state (following a meal), glycogen stores tions that can lead to hypoglycaemia include inappropri- in the liver and skeletal muscle are replenished and, ately high insulin doses in insulin-dependent (type 1) together with glucose absorbed from the gut, provide the diabetes, severe alcoholic poisoning, some inborn errors of major source of glucose for peripheral tissues for the next metabolism, hypoxia, salicylate poisoning, and tumours few hours. However, between meals and especially during such as Wilms tumour, hepatoblastoma and Hodgkin the night, the stores of glycogen are usually depleted. As this happens, glucose is synthesized by the gluconeogenicpathway in the liver. Glucose moieties in muscle glycogencan be used to provide energy for muscle cells, but cannot be liberated as free glucose in the blood for utilization byother tissues.
The anaerobic metabolism of glucose by red blood cells, The purpose of the gluconeogenic pathway is to provide skeletal muscle and other peripheral tissues leads to the the body with a source of glucose under physiological formation of lactate. The amount of lactate formed conditions in which glycogen stores in the liver are depends on the balance between aerobic and anaerobic depleted and there is no glucose available from the gut. A metabolism. Lactate released from the tissues moves key feature of the gluconeogenic pathway is that it converts through the blood where it is taken up by the liver, three-carbon precursors such as lactate, alanine and converted to pyruvate and, through the gluconeogenic glycerol, formed by metabolism in peripheral tissues, to pathway, converted to glucose. This cycling of glucose glucose. The elements of the gluconeogenic pathway are from the liver to skeletal muscle and of lactate from skeletal shown in Figure 1. As discussed in more detail below, the muscle back to the liver, where it is resynthesized to pathway utilizes several reversible steps of the glycolytic glucose, is called the glucose–lactate or Cori cycle (red pathway but also includes steps that are unique to the arrows in Figure 2). The cycle was discovered by Carl and gluconeogenic pathway (Figure 1). The gluconeogenic pathway is located principally in the liver, although some The glucose–lactate cycle is particularly important in gluconeogenesis occurs in the kidney (Haymond and overnight fasting because, under these conditions, liver glycogen stores become depleted and the only source of There are a number of normal physiological situations in glucose for red blood cells and brain is the gluconeogenic which the demand for glucose synthesized by the gluco- pathway. This functions in collaboration with the elements ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / Schematic representation of the pathway of gluconeogenesis. The reactions catalysed by four key enzymes of gluconeogenesis – pyruvate carboxylase (PC), cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C) or mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M),fructose-1,6-bisphosphatase (F1,6BPase) and glucose-6-phosphatase (G6Pase) (circled) – are indicated by red arrows; the opposing reactions of glycolysiscatalysed by pyruvate kinase (PK), 6-phosphofructo-1-kinase (6PF-1K) and glucokinase (GK) (circled) are shown by blue arrows. The bifunctional enzyme6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF2K/F2,6BPase) is indicated by a ‘B’ (circled). The allosteric inhibition of F1,6BPase by fructose2,6-bisphosphate (F-2,6-BP) and PK by alanine are shown by dashed green arrows with a negative sign. The allosteric activation of 6PF-1K by F-2,6-BP, of PKby F-1,6-BP, and of PC by acetylcoenzyme A (AcCoA) is indicated by dashed green arrows with a positive sign. In the interests of clarity and simplicity, otherreactions and membrane transporters are shown by thin black arrows. Only the main substrates, alanine (Ala) and pyruvate (Pyr), as well as the keyintermediates phosphoenolpyruvate (PEP), fructose 1,6-bisphosphate (F-1,6-BP), fructose 6-phosphate (F-6-P) and glucose 6-phosphate (G-6-P) areshown. The plasma membrane, endoplasmic reticulum and mitochondrial membrane are shown schematically by thin parallel lines.
of the glucose–lactate cycle that deliver lactate, the major the glucose–alanine cycle. One is to provide carbon substrate for gluconeogenesis, to the liver. The function of as a precursor of glucose synthesis in the liver. The other this cycle is particularly important in fasting rodents as, is to transport nitrogen atoms to the liver for excretion as under these conditions, glucose is not available from glycogen, and hence the Cori cycle and gluconeogenesis are The use of glucose labelled isotopically with 3H or 14C at the only means of providing glucose. However, larger different positions, and 13C and 1H nuclear magnetic animals, including humans, appear to mobilize their resonance, has allowed the study of glucose homeostasis, glycogen reserves less urgently, and indeed coordinate the glucose–lactate and glucose–alanine cycles in the glycogenolysis and gluconeogenesis in a more complemen- whole animal and in humans (Shulman, 1999). These tary manner (Bergman and Ader, 2000).
experiments have helped to gain a better understanding of During starvation, considerable amounts of skeletal the cycles and have shown that the glucose–alanine cycle muscle protein are degraded to yield ammonia and also functions during and after prolonged exercise. It may also deliver alanine to skeletal muscle during recovery after glutamate yields alanine which, in turn, is transported through the blood to the liver. Here another transamina- The activity of the glucose–lactate and glucose–alanine tion reaction reforms pyruvate and glutamate. The cycles is regulated by hormones. Insulin and glucagon are pyruvate is a substrate for gluconeogenesis. The resulting particularly important in regulating the glucose–lactate glucose can be transported back to the skeletal muscle and cycle during the transition from the fed to the fasted state.
used in glycolysis to yield ATP (blue arrows in Figure 2).
Adrenaline, cortisol and insulin play major roles in This cycle, called the glucose–alanine cycle, was first regulating both cycles in starvation and prolonged identified by Philip Felig. There are two main purposes of ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / Skeletal muscle
The Cori (glucose–lactate) (red arrows) and the glucose–alanine (blue arrows) cycles. In the glucose–lactate cycle, pyruvate formed in skeletal muscle (and in a number of other tissues) is reduced to lactate, which is released into the blood, taken up by the liver, used to form glucose,then released to the blood and taken up by skeletal muscle and other peripheral tissues. Alanine is formed from pyruvate and glutamate in skeletal muscleand undergoes a similar cycling.
fructose 6-phosphate of fructose 2,6-bisphosphate, an important allosteric effector (see below), and for itsreconversion to fructose 6-phosphate by dephosphoryla- tion. Fructose 2,6-bisphosphate is a very powerful allosteric activator of 6-phosphofructo-1-kinase, and alsoan allosteric inhibitor of fructose-1,6-bisphosphatase.
Thus, although not a catalytic component of the gluconeo- The pathway of gluconeogenesis (see Figure 1), which genic pathway, 6PF2K/F2,6BPase nevertheless plays such occurs in the periportal cells of the liver and in the kidney an integral role in influencing the net activities of one of the cortex, utilizes most of the enzymes of the glycolytic substrate cycles that its own regulation in liver also pathway except those catalysing the steps between (a) phosphoenolpyruvate and pyruvate, (b) fructose 6-phos-phate and fructose 1,6-bisphosphate, and (c) glucose andglucose 6-phosphate.
To circumvent the large free energy changes in these glycolytic reactions catalysed respectively by (a) pyruvate kinase (PK), (b) 6-phosphofructo-1-kinase (6PF-1K) and (c) hexokinase/glucokinase (GK), the gluconeogenic path- way employs (1) a tandem combination of pyruvate carboxylase (PC) and phosphoenolpyruvate carboxyki- nase (PEPCK), (2) fructose-1,6-bisphosphatase (FBPase), and (3) glucose-6-phosphatase (G6Pase).
PC, a member of the biotin-dependent carboxylase While these two sets of enzymes catalysing opposing family, catalyses the ATP-dependent carboxylation of reactions would appear to represent potentially ‘futile pyruvate to form oxaloacetate, which is used both in cycles’, they are in fact known to be targets of short-term gluconeogenesis by liver and kidney, and in lipogenesis by and long-term regulation, as discussed below, and are also liver, adipose tissue and lactating mammary gland, and neurotransmitter synthesis by the brain. PC is a homo- The bifunctional enzyme 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (6PF2K/F2,6BPase) is re- encoded by a single nuclear gene. It occurs exclusively in sponsible both for the ATP-dependent formation from the mitochondria of mammalian tissues where its activity is ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / very dependent on the concentration of its allosteric activator, acetylcoenzyme AcCoA (Jitrapakdee and Wal-lace, 1999).
Glucose-6-phosphatase (G6Pase) [EC] catalysesreaction [IV].
G6Pase is a multisubunit microsomal enzyme which catalyses the hydrolysis of glucose 6-phosphate to releaseglucose for transport by the bloodstream (Nordlie et al., in liver, kidney cortex, small intestine and the b cells of the Where GTP is guanosine triphosphate and GDP is endocrine pancreas. It is located on the luminal side of the endoplasmic reticulum in association with at least four membrane-spanning translocases which allow substrates varying extents, depending on species, in both the access to the active site. The best characterized translocase, mitochondria and cytosol of liver, kidney cortex, white albeit incompletely as yet, is the 46-kDa putative glucose 6- and brown adipose tissue, lactating mammary gland and phosphate transporter, T1, which occurs in multiple small intestine. For example, in liver the cytosolic isoforms and may well have a wider range of functions component of PEPCK activity (PEPCK–C) in rat is 80– 90%, in humans 30–50% and in guinea-pig 15–20%,whereas in chickens about 95% is mitochondrial. Inkidney, PEPCK–C activity is 75% in rat, 20% in guinea- pig and 40% in chicken. The mitochondrial and cytoplas-mic isoforms have similar kinetic properties and approxi- As with all metabolic pathways, the regulation of mately similar molecular weights but are immunologically gluconeogenesis can be achieved at three levels: (1) the distinct, each being encoded by a separate nuclear gene supply of substrate(s); (2) the short-term (minute to (Hanson and Reshef, 1997). Whereas the role of PEPCK– minute) control of the activities of the existing enzyme or C in liver and kidney is clearly related to the body’s need for transporter molecules by allosteric effectors or by covalent gluconeogenesis, its role in the other tissues appears to be modifications (e.g. phosphorylation and dephosphoryla- related to a high demand for glycerol 3-phosphate tion); and (3) the long-term (hours to days) control of the number and distribution (intracellular, cellular and tissue)of enzyme or transporter molecules. This last means can be effected by increased or decreased rates of transcriptionand/or translation of specific mRNA species, and by Fructose-1,6-bisphosphatase (FBPase) [EC] cata- control over the the rates of degradation of the resulting mRNA or protein molecules respectively. The hormones insulin and glucagon are the major opposing endocrine controllers of glucose production and utilization, with In mammals, FBPase, a homotetramer (subunit M glucocorticoids playing a permissive role in support of 37 kDa), is encoded by two distinct genes which are glucagon. Starvation, a low carbohydrate diet, and expressed with significant tissue specificity. The FBP1- exercise reduce insulin release from the b cells of the encoded isoform occurs in the cytoplasm principally of pancreas while increasing the secretion of glucagon by the liver, kidney and monocytes. Monocytes, therefore, represent a useful alternative source of messenger ribonu-cleic acid (mRNA) of the liver isoform for diagnosis of this enzyme’s deficiency as a cause of childhood hypoglycae-mia. FBPase deficiency may be one of the inherited Even in a fed human, the liver is required to reconvert into metabolic diseases responsible for up to 25% of cases of glucose approximately 40 g of lactate produced per day by sudden infant death syndrome. FBPase activity has also essentially anaerobic tissues such as erythrocytes, kidney been reported in brain, adipose tissue, lung, some muscles medulla and retina. Approximately twice this amount is and intestine. At least the last two tissue isoforms are produced daily by other tissues, depending on their level of encoded by distinct transcripts from a separate gene, activity, with skeletal muscle being capable of producing FBP2. FBPase is inhibited synergistically by fructose 2,6- much more than this if its aerobic capacity for ATP bisphosphate and adenosine monophosphate (AMP) production is exceeded during vigorous exercise. Low plasma insulin levels favour lipolysis with the release of free ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / fatty acids and glycerol, as well as the breakdown of been described (Hanson and Reshef, 1997), the acute (predominantly) muscle protein with the release of amino regulation of G6Pase has many candidate effectors acids. Thus, in fasting humans at rest, about 19 g of whose relative importance has yet to be determined glycerol are released per day from adipose tissue and most is converted to glucose, but this figure is greatly increasedby exercise or stress. Similarly, in each of the first few daysof starvation around 75 g of muscle protein is broken downto release amino acids, which are converted by the liver and kidney to glucose required by the brain. However, thisdebilitating and unsustainable loss of muscle is reduced to All seven key enzymes catalysing the three substrate cycles 20 g per day after 3 days as the plasma concentrations of (Figure 1), as well as the bifunctional 6PF2K/F2,6BPase, ketone bodies rise and meet about one-third of the brain’s are regulated coordinately, principally by insulin and energy needs, thereby reducing its demand for glucose.
glucagon, by transcriptional and in some cases also byposttranscriptional means. Expression of the key enzymesof gluconeogenesis (PC, PEPCK, FBPase and G6Pase) is inhibited by insulin but stimulated by glucagon, whereasexpression of their glycolytic counterparts (PK, 6PF–1K As is evident in Figure 1, there are three places where the and GK) is stimulated by insulin and inhibited by glucagon opposing pathways of gluconeogenesis and glycolysis bifurcate. Control of these ‘substrate cycles’ is crucial todetermining the net flux in glucose production or utiliza-tion by the liver and kidney. In situations requiring an Phosphenolpyruvate carboxykinase and pyruvate increased rate of gluconeogenesis this is achieved by several PEPCK is by far the most comprehensively characterized Glucagon, via its intracellular messenger cyclic AMP of the gluconeogenic enzymes at the level of gene (cAMP), activates protein kinase A to phosphorylate expression (Hanson and Reshef, 1997). Synthesis of the liver pyruvate kinase, thereby decreasing its activity.
cytoplasmic isoform of the enzyme (PEPCK-C) is induced The phosphorylated pyruvate kinase is less sensitive to in liver by fasting, low carbohydrate diet and diabetes, activation by fructose 1,6-bisphosphate and more whereas it is repressed by a high carbohydrate diet in a sensitive to inhibition by ATP and alanine.
normal animal or by insulin administration to a diabetic Phosphorylation of a single serine residue in each animal. In the kidney it is also regulated by the animal’s acid–base status. Expression of the gene encoding F2,6BPase by glucagon-activated protein kinase A PEPCK-C in the periportal region of the liver is rapidly results in an increase of F2,6BPase activity and a upregulated (10-fold in 20 min) by glucagon (via cAMP), concomitant loss of kinase activity. This dual effect glucocorticoids and thyroid hormone, but is decreased by explains the very low levels of fructose 2,6-bisphos- insulin. Glucagon also stabilizes the usually short-lived phate found in the livers of starved or diabetic rats.
mRNA by 5–8-fold. The transcriptional regulatory A decrease in the concentration of fructose 2,6- elements of the PEPCK-C gene promoter have been bisphosphate results simultaneously in inhibition of investigated very intensively (Hanson and Reshef, 1997), 6-phosphofructo-1-kinase and activation of fructose- and these studies have gone a long way towards explaining its tissue-specific regulation by multiple hormones. The The decline in plasma levels of insulin leads to mitochondrial PEPCK is expressed constitutively, and is increased levels of plasma free fatty acids that undergo b-oxidation, thereby increasing the level of mitochon- PC is also upregulated by the same stimuli as PEPCK-C, drial acetyl-CoA that allosterically activates pyruvate although usually less rapidly and to a lesser extent. The human and rat genes encoding PC have only recently been Increased b oxidation of fatty acids also leads to isolated and sequenced, and hence the characterization of ketone body formation, which induces a mild meta- their promoter regions is as yet much less well developed.
bolic acidosis that increases renal gluconeogenesis.
As the anaplerotic functions of PC serve pathways other The major hepatic isoform of hexokinase, glucokinase than gluconeogenesis, we can anticipate that the interac- (also known as hexokinase IV), has been shown to be tions of the various regulatory elements in their promoters inhibited by long-chain acyl–CoA compounds, by will be even more complex. Thus it is not surprising that association with a ‘glucokinase regulatory protein’ two human and five rat mRNA isoforms with distinct 5’ and by sequestration to the nucleus (Nordlie et al., untranslated regions have been identified as being alter- 1999). Whereas no allosteric effector of either the native transcripts expressed in a tissue-specific manner cytosolic or mitochondrial isoform of PEPCK has ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / As the potential catalytic activity of the PK expressed in its mRNA level is markedly increased by refeeding and liver (PK–L) (approximately 50 units g 2 1 in rat liver) far exceeds the levels of both PEPCK-C and PC activities (about7 units g 2 1), it is essential, if pyruvate or its precursors are tobe converted to glucose, that the activity of PK be controlled efficiently. This is achieved in starvation and diabetes byglucagon acting via cAMP to inhibit transcription of the PK- Only odd-chain free fatty acids (FFAs) can contribute L gene and to accelerate the degradation of PK-L mRNA.
carbon to glucose synthesis via the production of Conversely, upon refeeding or administration of insulin, PK- propionate in the b-oxidation pathway. Propionate is L catalytic activity is regained as mRNA levels are restored metabolized via propionyl-CoA, methylmalonyl-CoA, by increased transcription and stabilization (Yamada and succinyl-CoA, succinate and fumarate to malate, which can exit the mitochondrion and give rise to cytoplasmicoxaloacetate the substrate of PEPCK. This pathway is well Fructose-1,6-bisphosphatase versus 6-phosphofructo-1- developed in ruminants whose starch and cellulose-rich diet is fermented largely in the rumen to a mixture of short-chain fatty acids, thereby leaving little if any carbohydrate The liver isoform of fructose-1,6–bisphosphatase is to be absorbed from the gut. Hence, ruminants must meet regulated in a manner similar to PEPCK-C: starvation all their glucose needs, including the prodigious amounts and diabetes increase its activity as a result of cAMP needed for lactose synthesis by milking cows, from increasing the level of the FBP1 mRNA, whereas insulin can repress this effect. However, in keeping with the Plasma FFAs can influence the concentration of glucose absence of consensus glucocorticoid response elements in in the blood in several ways. First, FFAs can suppress the 5’ flanking region of this gene, glucocorticoids have no glucose uptake and utilization by the allosteric inhibition of pyruvate dehydrogenase by acetyl-CoA and reduced Conversely, the activity of 6-phosphofructo-1-kinase in nicotinamide–adenine dinucleotide (NADH) produced by liver is decreased by starvation and diabetes, but is b oxidation of FFAs, and the allosteric inhibition of 6PF- regained upon refeeding or treatment with insulin. The 1K by citrate formed from that acetyl-CoA. However, control of expression of the three genes encoding 6PF-1K from the timing of the effect of FFAs on glucose uptake in in liver during development and during different nutri- humans, it appears this may involve translational or tional regimens appears to involve transcript-specific posttranslational events (Bergman and Ader, 2000).
alterations in the rates of transcription and translation, Raised levels of FFAs are often associated with hyperli- as well as in mRNA stability, under the reciprocal control pidaemia, which itself can reduce the effect of insulin on of insulin and cAMP (Pilkis and Granner, 1992).
blood flow in insulin-sensitive tissues. In rodents there isevidence that chronic exposure to increased levels of plasma FFAs will impair the insulin secretory function of the pancreas. In humans there are some supportive data The level of this bifunctional enzyme is decreased by from longitudinal studies of Pima Native Americans and of starvation, diabetes and adrenalectomy but restored by Parisian police officers that raised plasma FFA levels are refeeding, insulin administration and treatment with predictive of a transition from normal glucose tolerance to glucocorticoids, respectively. These latter effects are the type 2 diabetes (Bergman and Ader, 2000). These endo- result of increased mRNA synthesis, which in the case of crine effects of FFAs could, therefore, be superimposed on insulin and glucocorticoids also requires the presence of the direct stimulatory effects that FFAs can have on hepatic gluconeogenesis. Raised plasma levels of FFAs canlead to an increase in hepatic acetyl-CoA concentration and hence to an increase in pyruvate carboxylase activity.
Fasting increases liver G6Pase activity, and both gluco- b-Oxidation of FFAs also provides a ready source of corticoids and cAMP increase the level of its mRNA.
NADH with which to reduce oxaloacetate to malate for However, both its mRNA and activity are low in fed and refed animals in which insulin levels are raised. Conversely,both the enzyme’s activity and its mRNA levels areincreased in diabetes, but insulin administered to diabetic rats or to rats treated with glucocorticoids and cAMPreduces G6Pase expression to normal levels.
GK, which is expressed only in liver and pancreatic b cells, responds to fasting and to streptozotocin-induced Diabetic subjects exhibit abnormally high blood glucose diabetes by its mRNA level being depressed. Conversely, concentrations after a meal. This is principally due to ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / enhanced gluconeogenesis in the liver, and decreased inhibits G6Pase activity. The drug also acts at other disposal of glucose by peripheral tissues. Diabetes is tissues, including skeletal muscle where there is evidence usually classified as insulin dependent (type 1) or insulin that it enhances glucose uptake by increasing glucose independent (type 2). The former is characterized by transport across the plasma membrane. Metformin also insulin insufficiency in the pancreas and the latter by insulin suppresses the action of glucagon. An important aspect of resistance in the liver and peripheral tissues. The likelihood metformin action is that it does not cause the onset of of a person developing diabetes is probably determined by hypoglycaemia. Treatment with metformin is effective in mutations or polymorphisms in a number of ‘suscept- lowering blood glucose concentrations, reducing the risk of ibility’ genes. In this sense, diabetes is a ‘complex’ disease.
microangiopathy, and reducing the mortality rate from Insulin-dependent diabetes is treated by insulin injec- cardiovascular disease (Wiernsperger and Bailey, 1999).
tion. The injected hormone enhances glucose oxidationand glycogen synthesis in skeletal muscle and otherperipheral tissues, and inhibits gluconeogenesis in the liver. Insulin replacement therapy by injection is effectiveprovided that blood glucose levels are tightly controlled The pathway of gluconeogenesis is found in the liver and within the normal physiological levels. This prevents kidney where it converts three-carbon precursors, such as complications due to high blood glucose concentrations.
lactate, alanine and glycerol, into glucose.
Insulin-independent diabetes is characterized by high The main function of gluconeogenesis is to supply blood glucose and insulin concentrations. Despite the high glucose to tissues, such as brain, red blood cells, white insulin concentration, the liver and peripheral tissues are blood cells, kidney medulla and the eyes, that depend on relatively insensitive to insulin action. Frequently subjects glucose as their main or sole energy source.
also exhibit some impairment of insulin release from the The gluconeogenic pathway utilizes most of the enzymes pancreas. As a result of insensitivity to insulin, high rates of of the glycolytic pathway except glucokinase, 6PF-1K and gluconeogenesis and glucose release from the liver are PK. To circumvent the large free energy changes in these maintained. This is the major contributor to the high blood particular glycolytic reactions, the gluconeogenic pathway employs four different enzymes: PC, PEPCK, fructose-1,6- In addition to changes to the patient’s dietary and bisphosphatase and G6Pase to catalyse bypass reactions.
exercise habits, several pharmacological interventions are The hormones insulin and glucagon are the major employed to treat noninsulin-dependent diabetes. These opposing endocrine controllers of glucose utilization and include insulin injection, which increases plasma insulin production, respectively, with glucocorticoids playing a concentrations, and the use of several oral hypoglycaemic permissive role in support of glucagon. Starvation, a low drugs. The latter include (i) the biguanide metformin, carbohydrate diet and exercise reduce insulin release from which inhibits gluconeogenesis; (ii) sulphonylureas, which the b cells of the pancreas, while increasing the secretion of enhance insulin secretion from the pancreas; (iii) acarbose, an inhibitor of the enzyme a-glucosidase which inhibits A high glucagon : insulin ratio in the blood stimulates carbohydrate digestion in the gut, and (iv) thiazolidene- gluconeogenesis at all levels of control. Conversely, upon diones, which facilitate insulin action on skeletal muscle.
refeeding, especially on a high carbohydrate diet, insulin While these oral hypoglycaemic agents are used to treat secretion is stimulated and has the effect of inhibiting diabetes in the clinic, they cannot completely mimic the gluconeogenesis while also stimulating glucose utilization normal physiology of insulin secretion and action, so that for energy production, for the repletion of liver and muscle some patients may have poorly controlled blood glucose The action of metformin (dimethylbiguanide) on the liver requires the presence of insulin. Metformin princi- pally inhibits the gluconeogenic pathway by enhancing the Bergman RN and Ader M (2000) Free fatty acids and pathogenesis of activity of PK. This presumably increases the cycling of type 2 diabetes mellitus. Trends in Endocrinology and Metabolism 11: carbon around the potential futile cycle created by PK, PEPCK and PC (Figure 1). It is hypothesized that Hanson RW and Reshef L (1997) Regulation of phosphoenolpyruvate metformin potentiates the activation of PK by fructose carboxykinase (GTP) gene expression. Annual Review of Biochemistry 1,6-bisphosphate. Metformin also acts at other sites, and these actions also contribute to the inhibition of gluco- Haymond MW and Sunehag A (1999) Controlling the sugar bowl.
neogenesis. Thus it reduces lipolysis, lowers the concentra- Regulation of glucose homeostasis in children. Endocrinology andMetabolism Clinics of North America 28: 663–696.
tion of FFAs in the blood, and inhibits FFA oxidation.
Herdt TH (2000) Ruminant adaptation to negative energy balance.
This indirectly inhibits the gluconeogenic pathway. There Veterinary Clinics of North America 16: 215–230.
is evidence that metformin also enhances insulin-receptor Jitrapakdee S and Wallace JC (1999) Structure, function and regulation tyrosine kinase activity, inhibits glycogenolysis and of pyruvate carboxylase. Biochemical Journal 340: 1–16.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / Lteif AN and Schwenk WF (1999) Hypoglycemia in infants and children.
van de Werve G, Lange A, Newgard C et al. (2000) New lessons in the Endocrinology and Metabolism Clinics of North America 28: 619–646.
regulation of glucose metabolism taught by the glucose 6-phosphatase Nordlie RC, Foster JD and Lange AJ (1999) Regulation of glucose system. European Journal of Biochemistry 267: 1533–1549.
production by the liver. Annual Review of Nutrition 19: 379–406.
Wiernsperger NF and Bailey CJ (1999) The antihyperglycaemic effect of Pilkis SJ and Granner DK (1992) Molecular physiology of the regulation metformin – therapeutic and cellular mechanisms. Drugs 58(1): 31–39.
of hepatic gluconeogenesis and glycolysis. Annual Review of Physiol- Yamada K and Noguchi T(1999) Nutrient and hormonal control of pyruvate kinase gene expression. Biochemical Journal 337: 1–11.
Shulman GI (1999) Cellular mechanisms of insulin resistance in humans.
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