Diabetes Mellitus
Introduction
Diabetes mellitus is a group of metabolic disorders characterized by chronic hyperglycaemia due to relative insulin deficiency, or resistance or both. It is common and affects approximately 30 million people worldwide. Diabetes is usually irreversible and, although patients can have a reasonably normal life-style, its late complications result in reduced life expectancy and considerable uptake of health resources. Macrovascular disease leads to an increased prevalence of coronary artery disease, peripheral vascular disease and stroke, while microvascular damage results in diabetic retinopathy and contributes to nephropathy.
Insulin secretion
Insulin is the key hormone involved in the storage and controlled release within the body of the chemical energy available from food. It is synthesized in the f3 cells of the pancreatic islets in the form of proinsulin, which is stored in secretory granules close to the cell membrane. A biochemically inert peptide fragment known as connecting (C) peptide breaks off from proinsulin in the secretory process, so that equimolar quantities of insulin and Cpeptide are released into the circulation. Insulin enters the portal circulation and is carried to the liver, its prime target organ. About 50% of secreted insulin is extracted and degraded in the liver; the residue is broken down by the kidney. C-peptide is only partially extracted by the liver (and hence provides a useful index of the rate of insulin secretion), but is mainly degraded by the kidney. An outline of glucose metabolism Blood glucose levels are closely regulated in health and rarely stray outside the range of 3.5-8.0 mmollitre -I (63- 44 mg dr ‘), despite the varying demands offood, fasting and exercise. The principal organ of glucose homeostasis is the liver, which absorbs and stores glucose (as glycogen) in the postabsorptive state and releases it into the circulation between meals to match the rate of glucose utilization by peripheral tissues. The liver also manufactures glucose (6 carbons) from 3-carbon molecules derived from breakdown of fat and protein by the process of gluconeogenesis.
GLUCOSE PRODUCTION. About 200 g of glucose is produced and utilized each day. More than 90% is derived from the liver, three-quarters from glycogen and onequarter from gluconeogenesis. The remaining 5-10% derives from renal gluconeogenesis.
GLUCOSE UTILIZATION. The brain is the major consumer of glucose. Its requirement is 1 mg kg-I body weight per minute, or 100 g daily in a 70 kg man. Glucose uptake by the brain is obligatory and is not dependent on insulin, and the glucose used is oxidized to carbon dioxide and water.
Other tissues, such as muscle and fat, are facultative glucose consumers. The effect of insulin peaks associated with meals is to lower the threshold for glucose entry into cells; at other times, energy requirements are largely met by fatty-acid oxidation. Glucose taken up by muscle is stored as glycogen or broken down to lactate, which reenters the circulation and becomes an important substrate for hepatic gluconeogenesis. Glucose is used by fat tissue as a source of energy and as a substrate for triglyceride synthesis; lipolysis releases fatty acids from triglyceride together with glycerol, another substrate for hepatic gluconeogenesis.
HORMONAL REGULATION. Insulin is the major regulator of intermediary metabolism, although its actions are modified in important respects by other hormones. Dose-response curves for the production and utilization of glucose.
At low insulin levels, glucose production is maximal and utilization is minimal; at high levels the situation is reversed. At intermediate plasma insulin levels of 40- 50 mU litre-I, hepatic glucose production is largely suppressed but peripheral utilization remains low. This observation forms the theoretical basis for the low-dose insulin regimen used to treat diabetic ketoacidosis.
The effect of counter-regulatory hormones (glucagon, adrenaline, cortisol and growth hormone) is to shift the dose-response curves to the right, resulting in greater production of glucose and less utilization for a given level of insulin.
The insulin receptor is a glycoprotein (400 kDa) which straddles the cell membrane of many target cells. It consists of a dimer with two ex subunits, which include the binding sites for insulin, and two f3 subunits, which traverse the cell membrane and initiate at least some of the intracellular actions of insulin. The DNA sequence coding for the receptor has been isolated and sequenced and is located on the short arm of chromosome 19.
Insulin molecules bind to these receptors forming complex that promotes glucose uptake. This insulinreceptor complex is internalized by the cell with subsequent degradation of insulin and recycling of the receptor to the cell surface.
TYPES OF DIABETES
Diabetes may be primary or secondary.
Although insulin-dependent diabetes mellitus (IDDM, type I diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) represent two distinct diseases from the epidemiological point of view, clinical distinction may sometimes be difficult. The two disease processes should, in clinical terms, be visualized as opposite ends of a continuous spectrum.
Insulin-dependent diabetes mellitus (type I diabetes)
EPIDEMIOLOGY
Approximately one person in 300 in the UK is treated with insulin, but some of these would be considered to have NIDDM by the criteria shown in Table 17.2. IDDM is most common in populations of European extraction, and within Europe there is a marked increase in incidence as one moves north. The highest incidence occurs in northern Scandinavia, but there is an unexplained hotspot in the island of Sardinia which has the second highest rate in the world. The frequency of IDDM in various countries.
The incidence in childhood is maximal at 10-13 years of age. Presentation is more common in the spring and autumn than in the summer, and it has been suggested that this might be related to the greater prevalence of viral infections at these times. The incidence of mOM is rising, in Europe, with an approximate doubling over the past 20-30 years.
Liver disease
Cirrhosis
Pancreatic disease
Cystic fibrosis
Chronic pancreatitis
Tropical diabetes
Pancreatectomy
Haemochromatosis
Carcinoma of the pancreas
Endocrine disease
Cushing’s syndrome
Acromegaly
Thyrotoxicosis
Phaeochromocytoma
Glucagonoma
Drug-induced disease
Thiazide diuretics
Corticosteroid therapy
Insulin-receptor abnormalities
Congenital lipodystrophy
Acanthosis nigricans
Genetic syndromes, e.g. Friedreich’s ataxia, myotonic
dystrophy
