Hypoglycaemia in Clinical Diabetes

Hypoglycaemia in Clinical Diabetes

(Parte 2 de 7)

2 NORMAL GLUCOSE METABOLISM AND RESPONSES

Insulin and glucagon are the two hormones controlling glucose homeostasis, and therefore the mechanisms enabling the ‘rules’ to be followed. The most important processes governed by these hormones are:

• Glycogen synthesis and breakdown (glycogenolysis): Glycogen, a carbohydrate, is an energy source stored in the liver and skeletal muscle. Liver glycogen is broken down to provide glucose for all tissues, whereas the breakdown of muscle glycogen results in lactate formation.

• Gluconeogenesis: This is the production of glucose in the liver from precursors: glycerol, lactate and amino acids (in particular alanine). The process can also occur in the kidneys, but this site is not important under physiological conditions.

• Glucose uptake and metabolism (glycolysis) by skeletal muscle and adipose tissue.

The actions of insulin and glucagon are summarised in Boxes 1.1 and 1.2. Insulin is an anabolic hormone, reducing glucose output by the liver (hepatic glucose output), increasing the uptake of glucose by muscle and adipose tissue (increasing peripheral uptake) and increasing protein and fat formation. Glucagon opposes the actions of insulin in the liver. Thus insulin tends to reduce, and glucagon to increase, blood glucose concentrations.

Box 1.1 Actions of insulin

Liver ↑ Glycogen synthesis (↑ glycogen synthetase activity)

↑ Glycolysis

↑ Lipid formation

↑ Protein formation ↓ Glycogenolysis (↓ phosphorylase activity)

↓ Gluconeogenesis

↓ Ketone formation

Muscle ↑ Uptake of glucose amino acids ketone potassium ↑ Glycolysis

↑ Synthesis of glycogen protein ↓ Protein catabolism

↓ Release of amino acids

Adipose tissue ↑ Uptake glucose potassium Storage of triglyceride

NORMAL GLUCOSE HOMEOSTASIS 3

Box 1.2 Actions of glucagon

Liver ↑ Glycogenolysis

↑ Gluconeogenesis

↑ Extraction of alanine

↑ Ketogenesis No significant peripheral action

The metabolic effects of insulin and glucagon and their relationship to glucose homeostasis are best considered in relationship to fasting and the postprandial state (Siegal and Kreisberg, 1975). In both these situations it is the relative and not absolute concentrations of these hormones that are important.

Fasting (Figure 1.1a)

During fasting, insulin concentrations are reduced and glucagon increased, which maintains blood glucose concentrations in accordance with rule 1 above. The net effect is to reduce peripheral glucose utilisation, to increase hepatic glucose production and to provide non-glucose fuels for tissues not entirely dependent on glucose. After a short (for example overnight) fast, glucose production needs to be 5–6g/h to maintain blood glucose concentrations, with the brain using 80% of this. Glycogenolysis provides 60–80% and gluconeogenesis 20–40% of the required glucose. In prolonged fasts, glycogen becomes depleted and glucose production is primarily from gluconeogenesis, with an increasing proportion from the kidney compared to the liver. In extreme situations renal gluconeogenesis can contribute as much as 45% of glucose production. Thus glycogen is the short term or ‘emergency’ fuel source (rule 2), with gluconeogenesis predominating during more prolonged fasts. The following metabolic alterations enable this increase in glucose production to occur:

• Muscle: Glucose uptake and oxidative metabolism are reduced and fatty acid oxidation increased. Amino acids are released.

• Adipose tissue: There are reductions in glucose uptake and triglyceride storage. The increase in the activity of the enzyme hormone-sensitive lipase results in hydrolysis of triglyceride to glycerol (a gluconeogenic precursor) and fatty acids, which can be metabolised.

• Liver: Increased cAMP concentrations result in increased glycogenolysis and gluconeogenesis thus increasing hepatic glucose output. The uptake of gluconeogenic precursors (i.e. amino acids, glycerol, lactate and pyruvate) is also increased. Ketone bodies are produced in the liver from fatty acids. This process is normally inhibited by insulin and stimulated by glucagon, thus the hormonal changes during fasting lead to an increase in ketone production. Fatty acids are also a metabolic fuel used by the liver and provide a source of energy for the reactions involved in gluconeogenesis.

4 NORMAL GLUCOSE METABOLISM AND RESPONSES

Amino acids

Free FA

Glycogen

Glucose Glycerol

Hepatic glucose output

FFA, TG, lipoprotein

Ketones

Muscle

Glucose

Free FA Triglyceride

Adipose Tissue

Glycogen

Glucose Glycerol

Hepatic glucose output

FFA, TG, Liver

FA Glycerolphosphate FA Glycerolphosphate

Glycerol Triglyceride

Ketones glucagon, insulin Insulin, glucagon lactateGlycogen

Protein Amino acidsProtein

GlucoseGlycogen lactate Amino acids

(a) (b)

Figure 1.1 Metabolic pathways for glucose homeostasis in muscle, adipose tissue and liver during fasting (left) and postprandially (right). FA=fatty acids; TG=triglyceride (associated CO2 production excluded for clarity)

The reduced insulin : glucagon ratio favours a catabolic state, but the effect on fat metabolism is greater than protein, and thus muscle is relatively preserved (rule 4). These adaptations meant that not only did hunter-gatherers have sufficient muscle power to pursue their next meal, but also that brain function was optimally maintained to help them do this.

EFFECTS OF GLUCOSE DEPRIVATION 5

Fed state (Figure 1.1b)

In the fed state, in accordance with the rules of the metabolic game, excess food is stored as glycogen, protein and fat (rule 3). The rise in glucose concentrations results in an increase in insulin and reduction in glucagon secretion. This balance favours glucose utilisation, reduction of glucose production and increases glycogen, triglyceride and protein formation. The following changes enable these processes to occur:

• Muscle: Insulin increases glucose transport, oxidative metabolism and glycogen synthesis. Amino acid release is inhibited and protein synthesis is increased.

• Adipose tissue: In the fat cells, glucose transport is increased, while lipolysis is inhibited.

At the same time the enzyme lipoprotein lipase, located in the capillaries, is activated and causes triglyceride to be broken down to fatty acids and glycerol. The fatty acids are taken up into the fat cells and re-esterified to triglyceride (using glycerol phosphate derived from glucose) before being stored.

• Liver: Glucose uptake is increased in proportion to plasma glucose, a process which does not need insulin. However, insulin does decrease cAMP concentrations, which results in an increase in glycogen synthesis and the inhibition of glycogenolysis and gluconeogenesis. These effects ‘retain’ glucose in the liver and reduce hepatic glucose output.

This complex interplay between insulin and glucagon maintains euglycaemia and enables the rules of the metabolic game to be followed, ensuring not only the survival of the hunter-gatherer, but also of modern humans.

The brain constitutes only 2% of body weight, but consumes 20% of the body’s oxygen and receives 15% of its cardiac output (Sokaloff, 1989). It is almost totally dependent on carbohydrate as a fuel and since it cannot store or synthesise glucose, depends on a continuous supply from circulating blood. The brain contains the enzymes needed to metabolise fuels other than glucose such as lactate, ketones and amino acids, but under physiological conditions their use is limited by insufficient quantities in the blood or slow rates of transport across the blood-brain barrier. When arterial blood glucose falls below 3mmol/l, cerebral metabolism and function decline.

Metabolism of glucose by the brain releases energy, and also generates neurotransmitters such as gamma amino butyric acid (GABA) and acetylcholine, together with phospholipids needed for cell membrane synthesis. When blood glucose concentration falls, changes in the synthesis of these products may occur within minutes because of reduced glucose metabolism, which can alter cerebral function. This is likely to be a factor in producing the subtle changes in cerebral function detectable at blood glucose concentrations as high as 3mmol/l, which is not sufficiently low to cause a major depletion in ATP or creatine phosphate, the brain’s two main sources of energy (McCall, 1993).

6 NORMAL GLUCOSE METABOLISM AND RESPONSES

Isotope techniques and Positron Emission Tomography (PET) allow the study of metabolism in different parts of the brain and show regional variations in metabolism during hypoglycaemia. The neocortex, hippocampus, hypothalamus and cerebellum are most sensitive to hypoglycaemia, whereas metabolism is relatively preserved in the thalamus and brainstem. Changes in cerebral function are initially reversible, but during prolonged severe hypoglycaemia, general energy failure (due to the depletion of ATP and creatine phosphate) can cause permanent cerebral damage. Pathologically this is caused by selective neuronal necrosis most likely due to ‘excitotoxin’ damage. Local energy failure induces the intrasynaptic release of glutamate or aspartate, and failure of reuptake of the neurotransmitters increases their concentrations. This leads to the activation of N-methyl-D-aspartate (NMDA) receptors causing cerebral damage. One study in rats has shown that an experimental compound called AP7, which blocks the NMDA receptor, can prevent 90% of the cerebral damage associated with severe hypoglycaemia (Wieloch, 1985). In humans with fatal hypoglycaemia, protracted neuroglycopenia causes laminar necrosis in the cerebral cortex and diffuse demyelination. Regional differences in neuronal necrosis are seen, with the basal ganglia and hippocampus being sensitive, but the hypothalamus and cerebellum being relatively spared (Auer and Siesjö, 1988; Sieber and Traysman, 1992).

The brain is very sensitive to acute hypoglycaemia, but can adapt to chronic fuel deprivation. For example, during starvation, it can metabolise ketones for up to 60% of its energy requirements (Owen et al., 1967). Glucose transport can also be increased in the face of hypoglycaemia. Normally, glucose is transported into tissues using proteins called glucose transporters (GLUT) (Bell et al., 1990). This transport occurs down a concentration gradient faster than it would by simple diffusion and does not require energy (facilitated diffusion). There are several of these transporters, with GLUT 1 being responsible for transporting glucose across the blood-brain barrier and GLUT 3 for transporting glucose into neurones (Figure 1.2). Chronic hypoglycaemia in animals (McCall et al., 1986) and in humans (Boyle et al., 1995) increases cerebral glucose uptake, which is thought to be promoted by an increase in the production and action of GLUT 1 protein. It has not been

Figure 1.2 Transport of glucose into the brain across the blood–brain barrier

COUNTERREGULATION DURING HYPOGLYCAEMIA 7 established whether this adaptation is of major benefit in protecting brain function during hypoglycaemia.

The potentially serious effects of hypoglycaemia on cerebral function mean that not only are stable blood glucose concentrations maintained under physiological conditions, but also if hypoglycaemia occurs, mechanisms have developed to combat it. In clinical practice, the principal causes of hypoglycaemia are iatrogenic (as side-effects of insulin and sulphonylureas used to treat diabetes) and excessive alcohol consumption. Insulin secreting tumours (such as insulinoma) are rare. The mechanisms that correct hypoglycaemia are called counterregulation, because the hormones involved oppose the action of insulin and therefore are the counterregulatory hormones. The processes of counterregulation were identified in the mid 1970s and early 1980s, using either a bolus injection or continuous infusion of insulin to induce hypoglycaemia (Cryer, 1981; Gerich, 1988). The response to the bolus injection of 0.1U/kg insulin in a normal subject is shown in Figure 1.3. Blood glucose concentrations decline within minutes of the administration of insulin and reach a nadir after 20–30 minutes, then gradually rise to near normal by two hours after the insulin was administered. The fact

Figure 1.3 (a) Glucose and (b) insulin concentrations after intravenous injection of insulin 0.1U/kg at time 0. Reproduced from Garber et al. (1976) by permission of the Journal of Clinical Investigation

8 NORMAL GLUCOSE METABOLISM AND RESPONSES that blood glucose starts to rise when plasma insulin concentrations are still ten times the baseline values means that it is not simply the reduction in insulin that reverses hypoglycaemia, but active counterregulation must also occur. Many hormones are released when blood glucose is lowered (see below), but glucagon, the catecholamines, growth hormone and cortisol are regarded as being the most important.

Several studies have determined the relative importance of these hormones by producing isolated deficiencies of each hormone (by blocking its release or action) and assessing the subsequent response to administration of insulin. These studies are exemplified in Figure 1.4 which assesses the relative importance of glucagon, adrenaline (epinephrine) and growth hormone in the counterregulation of short term hypoglycaemia. Somatostatin infusion blocks glucagon and growth hormone secretion and significantly impairs glucose recovery (Figure 1.4a). If growth hormone is replaced in the same model to produce isolated glucagon deficiency (Figure 1.4b), and glucagon replaced to produce isolated growth hormone deficiency (Figure 1.4c), it is clear that it is glucagon and not growth hormone that is responsible for acute counterregulation. Combined alpha and beta adrenoceptor blockade using phentolamine and propranolol infusions or adrenalectomy (Figure 1.4d), can be used to evaluate the role of the catecholamines. These and other studies demonstrate that glucagon is the most important counterregulatory hormone whereas catecholamines provide a backup if glucagon is deficient (for example in type 1 diabetes, see Chapters 6 and 7). Cortisol and

Figure 1.4 Glucose recovery from acute hypoglycaemia. Glucose concentration following an intravenous injection of insulin of 0.05 U/kg at time 0; after (a) saline infusion (continuous line) and somatostatin, (b) somatostatin and growth hormone (GH), (c) somatostatin and glucagon, (d) combined alpha and beta blockade with phentolamine and propranolol infusions or adrenalectomy, (e) somatostatin with alpha and beta blockade, and (f) somatostatin in adrenalectomised patients. Saline infusion=continuous lines; experimental study=broken lines. Reproduced from Cryer (1981) courtesy of the American Diabetes Association (epinephrine = adrenaline)

COUNTERREGULATION DURING HYPOGLYCAEMIA 9 growth hormone are important only in prolonged hypoglycaemia. Therefore if glucagon and catecholamines are both deficient, as in longstanding type 1 diabetes, counterregulation is seriously compromised, and the individual is defenceless against acute hypoglycaemia (Cryer, 1981).

Glucagon and catecholamines increase glycogenolysis and stimulate gluconeogenesis.

(Parte 2 de 7)

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