Hypoglycaemia in Clinical Diabetes

Brian M. Frier, Simon Heller, Rory McCrimmon, Brian M. Frier, Simon Heller, Rory McCrimmon

• Publisher: Wiley-Blackwell
• Year: 2013
• ISBN:
  9781118697870
• Edition: 3
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Hypoglycaemia in Clinical Diabetes

Hypoglycaemia in Clinical Diabetes

Third Edition

If you regularly see patients with diabetes who experience hypoglycaemia and need expert guidance, then this is the book for you.

Hypoglycaemia in Clinical Diabetes, Third Edition once again provides health professionals involved in the management of people with diabetes with an expertly written, comprehensive guide to hypoglycaemia, the most common and feared side effect of insulin treatment for diabetes.

With reference to ADA and EASD guidelines throughout, topics covered include the physiology of hypoglycaemia and the body's response to low blood glucose, its presentation and clinical features, potential morbidity and optimal clinical management in order to achieve and maintain good glycaemic control.

Particular attention is paid to the way hypoglycaemia is managed in different groups of patients, such as the elderly, in children, or during pregnancy.

New chapters in this edition include:

• Psychological effects of hypoglycaemia
• Technology for hypoglycaemia: CSII and CGM
• Exercise management and hypoglycaemia in type 1 diabetes
• Neurological sequelae of hypoglycaemia

Valuable for diabetologists, endocrinologists, non-specialist physicians and general practitioners, Hypoglycaemia in Clinical Diabetes, Third Edition provides expert clinical guidance to this extremely common and potentially serious complication associated with diabetic management.

Titles of related interst

Diabetes: Chronic Complications, 3rd edition Shaw, ISBN 9780470656181

Diabetes Emergencies: Diagnosis and Clinical Management Katsilambros, ISBN 9780470655917

1

Normal Glucose Metabolism and Responses to Hypoglycaemia

Ian A. Macdonald¹ and Paromita King²

¹ University of Nottingham Medical School, Nottingham, UK

² Derby Hospitals NHS Foundation Trust, Derby, UK

Normal Glucose Homeostasis

Humans evolved as hunter-gatherers, and, unlike people today, did not consume regular meals. Mechanisms therefore evolved for the body to store food when it was in abundance, and to use these stores to provide an adequate supply of energy, in particular in the form of glucose when food was scarce. Cahill (1971) originally described the ‘rules of the metabolic game’ which man had to follow to ensure his survival. These were modified by Tattersall (personal communication) and are:

1. Maintain glucose within very narrow limits.

2. Maintain an emergency energy source (glycogen) that can be tapped quickly in time of need; ‘Fight or Flight’ response.

3. Waste not, want not, i.e. store (fat and protein) in times of plenty.

4. Use every trick in the book to maintain protein reserves.

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

• Glycogen synthesis and breakdown (glycogenolysis): Glycogen, a carbohydrate, is the most readily accessible energy store and is mostly found in 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 most 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, respectively. Insulin is an anabolic hormone, reducing glucose output by the liver (hepatic glucose output), increasing 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 increase blood glucose concentrations.

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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
↑	uptake of amino acids
↑	uptake of ketone
↑	uptake of potassium
↑	glycolysis
↑	synthesis of glycogen
↑	synthesis of protein
↓	protein catabolism
↓	release of amino acids
Adipose tissue
↑	uptake of glucose
↑	uptake of potassium
↑	storage of triglyceride

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Box 1.2 Actions of glucagon

Liver
↑	glycogenolysis
↑	gluconeogenesis
↑	extraction of alanine
↑	ketogenesis
	No significant peripheral action

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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, increase hepatic glucose production and to provide non-glucose fuels for tissues not entirely dependent on glucose. After a short (e.g. overnight) fast, glucose production needs to be 5–6 g/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 as opposed 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 in 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 as a source of energy needed for the reactions involved in gluconeogenesis.

Figure 1.1 Metabolic pathways in glucose homeostasis in muscle, adipose tissue and liver. (a) Fasting; (b) post-prandial. FFA, free fatty acids; TG, triglyceride.

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 the hunter-gatherer have sufficient muscle power to pursue his next meal, but that brain function was optimally maintained to help him do this.

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). Rising glucose concentrations after a meal result 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 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 that does not need insulin. However, insulin does decrease cAMP concentrations, which result in an increase in glycogen synthesis and the inhibition of glycogenolysis and gluconeogenesis. These effects ‘retain’ excess glucose as glycogen in the liver.

While insulin and glucagon are the key hormones involved in glucose homeostasis in the fed state, there are a number of other glucoregulatory hormones released in response to an oral glucose load including Gastric Inhibitory Peptide, Glucagon-like peptide 1 (GLP-1), cholecystokinin Peptide Y and Ghrelin.

GLP-1, for example is made in the L-cells of the distal gut as well as in the brain. Peripheral GLP-1 is produced in response to a glucose load. Through vagally-mediated central and peripheral mechanisms, GLP-1 augments glucose-stimulated insulin production, reduces glucagon secretion, slows gastric emptying and promotes satiety.

A detailed discussion of the role of these peptides in glucose homeostasis is beyond the scope of this chapter, but has been reviewed by Heijboer et al. (2006), Drucker (2007) and Maggs et al. (2008). Some recently introduced antidiabetes drugs act through the GLP-1 receptor, either throug...

Table of contents

• Cover
• Title page
• Copyright page
• List of Contributors
• Preface
• 1: Normal Glucose Metabolism and Responses to Hypoglycaemia
• 2: Symptoms of Hypoglycaemia and Effects on Mental Performance and Emotions
• 3: Counterregulatory Deficiencies in Diabetes
• 4: Frequency, Causes and Risk Factors for Hypoglycaemia in Type 1 Diabetes
• 5: Nocturnal Hypoglycaemia
• 6: Impaired Awareness of Hypoglycaemia
• 7: Risks of Intensive Therapy
• 8: Management of Acute and Recurrent Hypoglycaemia
• 9: Technology for Hypoglycaemia: CSII and CGM
• 10: Hypoglycaemia in Children with Diabetes
• 11: Hypoglycaemia During Pregnancy in Women with Pregestational Diabetes
• 12: Hypoglycaemia in Type 2 Diabetes and in Elderly People
• 13: Mortality, Cardiovascular Morbidity and Possible Effects of Hypoglycaemia on Diabetic Complications
• 14: Long-Term Effects of Hypoglycaemia on Cognitive Function in Diabetes
• 15: Neurological Sequelae of Hypoglycaemia
• 16: Psychological Effects of Hypoglycaemia
• 17: Exercise Management and Hypoglycaemia in Type 1 Diabetes
• 18: Living with Hypoglycaemia
• Index