During normal metabolism, little glucose is lost unchanged from the body. Maintenance of plasma glucose concentrations within the relatively narrow range of 4-10 mmol/L, despite the widely varying input from the diet, depends on the balance between the glucose entering cells from the ECF and that leaving them into this compartment.

Some of the more important effects of hormones on glucose homeostasis are summarized in Table 12.2.

The liver is the most important organ maintaining a constant glucose supply for other tissues, including the brain. It is also of importance in controlling the postprandial plasma glucose concentration.

Portal venous blood leaving the absorptive area of the intestinal wall reaches the liver first, and consequently the hepatic cells are in a key position to buffer the hyperglycaemic effect of a high-carbohydrate meal (Fig. 12.5).

The entry of glucose into liver and cerebral cells is not directly affected by insulin, but depends on the extracellular glucose concentration. The conversion of glucose to glucose-6-phosphate (G6P), the first step in glucose metabolism in all cells, is catalysed in the liver by the enzyme glucokinase, which has a low affinity for glucose compared with that of hexokinase, which is found in most other tissues. Glucokinase activity is induced by insulin. Therefore, hepatic cells extract proportionally less glucose during fasting, when concentrations in portal venous plasma are low, than after carbohydrate ingestion. This helps to maintain a fasting supply of glucose to vulnerable tissues such as the brain.

The liver cells can store some of the excess glucose as glycogen. The rate of glycogen synthesis (glycogenesis) from G6P may be increased by insulin secreted by the β-cells of the pancreas in response to systemic hyperglycaemia. The liver can convert some of the excess glucose to fatty acids, which are ultimately transported as triglyceride in very low-density lipoprotein (VLDL) and stored in adipose tissue.

Under normal aerobic conditions, the liver can synthesize glucose by gluconeogenesis using the metabolic products from other tissues, such as glycerol, lactate or the carbon chains resulting from deamination of certain amino acids (mainly alanine) (Table 12.3). The liver contains the enzyme glucose-6-phosphatase, which, by hydrolysing G6P derived from either glycogenolysis or gluconeogenesis, releases glucose and helps to maintain extracellular fasting concentrations. Hepatic glycogenolysis is stimulated by the hormone glucagon, secreted by the α-cells of the pancreas in response to a fall in the plasma glucose concentration, and by catecholamines such as adrenaline or noradrenaline.

During fasting, the liver converts fatty acids, released from adipose tissue as a consequence of low insulin activity, to ketones. The carbon chains of some amino acids may also be converted to ketones (Table 12.3). Ketones can be used by other tissues, including the brain, as an energy source when plasma glucose concentrations are low.

The renal cortex is the only other tissue capable of gluconeogenesis, and of converting G6P to glucose. The gluconeogenic capacity of the kidney is particularly important in hydrogen ion homeostasis and during prolonged fasting.

Other tissues, such as muscle, can store glycogen but, because they do not contain glucose-6-phosphatase, they cannot release glucose from cells and so can only use it locally; this glycogen plays no part in maintaining the plasma glucose concentration.

The liver modifies the potential hyperglycaemic effect of a high-carbohydrate meal by extracting relatively more glucose than in the fasting state from the portal plasma. However, some glucose does pass through the liver and the rise in the systemic concentration
stimulates the β-cells of the pancreas to secrete insulin. Insulin may further enhance hepatic and muscle glycogenesis. More importantly, entry of glucose into adipose tissue and muscle cells, unlike that into liver and brain, is stimulated by insulin and, under physiological conditions, the plasma glucose concentration falls to near fasting levels. Conversion of intracellular glucose to G6P in adipose and muscle cells is catalysed by the enzyme hexokinase, which, because its affinity for glucose is greater than that of hepatic glucokinase, ensures that glucose enters the metabolic pathways in these tissues at lower extracellular concentrations than those in the liver. The relatively high insulin activity after a meal also inhibits the breakdown of triglyceride (lipolysis) and protein (proteolysis). If there is relative or absolute insulin deficiency, as in diabetes mellitus, these actions are impaired. Both muscle and adipose tissue store the excess post-prandial glucose, but the mode of storage and the function of the two types of cell are very different, as will be shown later.

Adipose tissue triglyceride is the most important longterm energy store in the body. Greatly increased use of fat stores, for example during prolonged fasting, is associated with ketosis. Adipose tissue cells, acting in conjunction with the liver, convert excess glucose to triglyceride and store it in this form rather than as glycogen. The components are both derived from glucose, fatty acids from the glucose entering hepatic cells and glycerol from that entering adipose tissue cells.

In the liver, triglycerides are formed from glycerol-3-phosphate (from triose phosphate or glyceraldehyde-3-phosphate) and fatty acids [from acetyl coenzyme A (CoA)]. The triglycerides are transported to adipose tissue cells incorporated in VLDL, where they are hydrolysed by lipoprotein lipase. The released fatty acids (of hepatic origin) are re-esterified within these cells with glycerol-3-phosphate, derived from glucose, which has entered this tissue under the influence of insulin. The resultant triglyceride is stored and is far more energy dense than glycogen (see Chapter 13).

During fasting, when exogenous glucose is unavailable and the plasma insulin concentration is therefore low, endogenous triglycerides are reconverted to free non-esterified fatty acids (NEFAs) and glycerol by lipolysis (Fig. 12.6). Both are transported to the liver in plasma, the NEFA being protein bound, predominantly to albumin. Glycerol enters the hepatic gluconeogenic pathway at the triose phosphate stage; the glucose synthesized can be released from these cells, thus minimizing the fall in glucose concentrations.

Most tissues, other than the brain, can oxidize fatty acids to acetyl CoA, which can then be used in the TCA cycle as an energy source. When the rate of synthesis exceeds its use, the hepatic cells produce acetoacetic acid by enzymatic condensation of two molecules of acetyl CoA; acetoacetic acid can be reduced to β-hydroxybutyric acid and decarboxylated to acetone. These ketones can be used as an energy source by brain and other tissues at a time when glucose is in relatively short supply.

Ketosis occurs when fat stores are the main energy source and may result from fasting or from reduced nutrient absorption, for example due to vomiting. Mild ketosis may occur after as little as 12 h of fasting. After short fasts, metabolic acidosis is not usually detectable, but, after longer periods, more hydrogen ions may be produced than can be dealt with by homeostatic buffering mechanisms, depleting the plasma bicarbonate concentration, which therefore falls (see Chapter 4).

The plasma glucose concentration is maintained principally by hepatic gluconeogenesis, but during prolonged starvation, such as that in anorexia nervosa or during childhood, ketotic hypoglycaemia may occur. The
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During gluconeogenesis, hydrogen ions are reused. Under aerobic conditions, the liver consumes much more lactate than it produces.

The physiological accumulation of lactic acid during muscular contraction is a temporary phenomenon and rapidly disappears at rest, when slowing of glycolysis allows aerobic processes to ‘catch up’.

Lactic acid, produced by anaerobic glycolysis, may either be oxidized to CO₂ and water in the TCA cycle or be reconverted to glucose by gluconeogenesis in the liver. Both the TCA cycle and gluconeogenesis need oxygen; anaerobic glycolysis is a non-oxygen-requiring pathway. Pathological accumulation of lactate may occur because:

Tissue hypoxia (Fig. 12.8) due to the poor tissue perfusion of the ‘shock’ syndrome is usually the most common cause of lactic acidosis. Hypoxia increases plasma lactate concentrations because:

The combination of impaired gluconeogenesis and increased anaerobic glycolysis converts the liver from an organ that consumes lactate and H+ to one that generates large amounts of lactic acid. Severe hypoxia, for example following a cardiac arrest, causes marked lactic acidosis. If diabetic ketoacidosis is associated with significant volume depletion, this hypoxic syndrome may aggravate the acidosis. (See Chapter 4 for a further discussion of lactic acidosis.)

The glycolytic pathway as well as the TCA cycle are summarized in Figures 12.1 and 12.2.

Previously called insulin-dependent diabetes mellitus, this is the term used to describe the condition in patients for whom insulin therapy is essential because they are prone to develop ketoacidosis. It usually presents during childhood or adolescence. Most of these cases are due to immune-mediated processes and may be associated with other autoimmune disorders such as Addison’s disease, vitiligo and Hashimoto’s thyroiditis. It has been suggested that many cases follow a viral infection that has damaged the β-cells of the pancreatic islets. Individuals most at risk are those with human leucocyte antigen (HLA) types DR3 and DR4 of the major histocompatibility complex. Autoantibodies to islet cells, insulin, tyrosine phosphatases IA-2 and IA-2β and glutamic decarboxylase (GAD) are found in about 90 per cent of cases. There is a form of type 1 diabetes called idiopathic diabetes mellitus that is not autoimmune mediated but is strongly inherited and more common in black and Asian people. The insulin requirement of affected people can fluctuate widely and the cause is unknown. There is also LADA (latent autoimmune diabetes of adults), sometimes called slow-onset type 1 diabetes.

Previously called non-insulin-dependent diabetes mellitus, this is the most common variety worldwide (about 90 per cent of all diabetes mellitus cases). Patients are much less likely to develop ketoacidosis than those with type 1 diabetes, although insulin may sometimes be needed. Onset is most usual during adult life; there is a familial tendency and an association with obesity. There is a spectrum of disorders ranging from mainly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance.

A variety of inherited disorders may be responsible for the syndrome, either by reducing insulin secretion or by causing relative insulin deficiency because of resistance to its action or of insulin receptor defects, despite high plasma insulin concentrations.