Diabetes and other metabolic disorders

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17 Diabetes and other metabolic disorders

Tahseen A. Chowdhury

Introduction

The study of metabolism (Box 17.1) began as long ago as the fifteenth century bc, with the first description of diabetes in the Ebers Papyrus. Metabolic diseases comprise a variety of disorders encompassing a number of medical specialties. They contribute significantly to mortality and morbidity, predominantly from cardiovascular disease. Diabetes and metabolic disorders have become more prevalent in both developed and developing countries, leading to a significant burden of chronic disease and complications related to those diseases. This increased prevalence is related to excessive calorific intake coupled with reduced physical activity. Whereas in the past metabolic diseases such as diabetes were deemed diseases of the rich, in developed countries they are now frequently diseases of lower social class, as access to healthier foods may be expensive and difficult.

Box 17.1 Metabolism

The act or process by which living tissues or cells take up and convert into their own proper substance the nutritive material brought to them by the blood, or by which they transform their protoplasm into simpler substances, which are fitted either for excretion or for some special purpose, as in the manufacture of the digestive ferments. Hence, metabolism may be either constructive (anabolism) or destructive (catabolism). (Webster’s English Dictionary 1996.)

The major metabolic disorders considered in this chapter are:

image diabetes mellitus and the metabolic syndrome
image lipid disorders.

Diabetes mellitus and the metabolic syndrome

Diabetes is a Greek word meaning ‘a passer through; a siphon’, and mellitus derives from the Greek word for ‘sweet’. The Greeks named it thus due to the excessive amounts of urine produced by sufferers which attracted insects because of its glucose content. The ancient Chinese tested for diabetes by observing whether ants were attracted to a person’s urine.

Diabetes mellitus is the most common metabolic disorder encountered in clinical practice. It is strongly linked to obesity. Diabetes mellitus is characterized by abnormal carbohydrate and lipid homoeostasis, leading to elevation in plasma glucose, or hyperglycaemia, and abnormality of serum lipids, or dyslipidaemia. Glucose homoeostasis is modulated mainly by the release of insulin from the islet cells (β cells) of the pancreas. Diabetes develops as a result of a variable combination of absolute insulin deficiency as a result of pancreatic islet cell dysfunction and tissue insulin resistance due to reduced cellular responsiveness to insulin.

The World Health Organization (WHO) has developed a classification of diabetes mellitus based on its pathogenesis (Table 17.1). The two predominant classes of diabetes are type 1 and type 2, and clinical differences between the two are listed in Table 17.2. Type 1 is characterized by absolute insulin deficiency due to autoimmune-mediated pancreatic islet cell destruction. In contrast, type 2 diabetes is associated with a variable degree of tissue insulin resistance, leading – at least in the early stages – to high plasma insulin levels, then subsequently to relative insulin deficiency as pancreatic islet cell function fails to overcome this resistance. The diagnostic criteria for disorders of glucose metabolism based on the 75-g oral glucose tolerance test are shown in Table 17.3. Note that glycosuria itself (glucose in the urine) is not a reliable diagnostic test for diabetes mellitus.

Table 17.1 The World Health Organization classification of diabetes mellitus

Type Common subtypes/pathogenesis Treatment
Type 1 Destruction of pancreatic islet cells leading to insulin deficiency Insulin
Type 2 Ranges from predominantly insulin resistance with relative insulin deficiency (often associated with obesity) to predominantly insulin deficiency Diet/oral hypoglycaemic agents/insulin
Other types
Genetic defects of β-cell function Diabetes associated with glucokinase, hepatic nuclear factor (HNF) 1α, HNF1β, HNF4α, Neurod1 and insulin promotor factor mutations (all previously grouped under maturity-onset diabetes of the young (MODY))
Mitochondrial diabetes		 Tablets or insulin depending upon genetic defect
Genetic defects of insulin action Insulin-resistance syndromes (type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome lipoatrophic diabetes) Insulin-sensitizing agents and insulin
Diseases of the exocrine pancreas Fibrocalculous pancreatic diabetes, pancreatitis, trauma/pancreatectomy, neoplasia, cystic fibrosis, haemochromatosis, others Frequently insulin required
Endocrinopathies Cushing’s syndrome, acromegaly, phaeochromocytoma, glucagonoma, hyperthyroidism, somatostatinoma, others Treatment of underlying cause
Drug or chemical induced Glucocorticoids, α-adrenergic agonists, β-adrenergic agonists, thiazides, interferon-α therapy Avoid
Uncommon forms of immune-mediated diabetes Insulin autoimmune syndrome (antibodies to insulin), anti-insulin receptor antibodies, ‘stiff man’ syndrome Variable
Other genetic syndromes associated with diabetes Down’s, Friedreich’s ataxia, Huntington’s chorea, Klinefelter’s, Lawrence-Moon-Biedl, myotonic dystrophy, porphyria, Prader-Willi, Turner’s, Wolfram’s Variable
Gestational diabetes   Diet/insulin

Table 17.2 Clinical differences between type 1 and type 2 diabetes

  Type 1 Type 2
Ketosis prone Yes Uncommon
Insulin requirement Yes (absolute insulin deficiency) Often later in disease (insulin resistance ± deficiency)
Onset of symptoms Acute Often insidious
Obese Uncommon Common
Age at onset (years) Usually <30 Usually >30
Family history of diabetes 10% 30%
Concordance in monozygotic twins 30-50% 90-100%

Table 17.3 The oral glucose tolerance test in diagnosing diabetes mellitus

image

It has long been recognized that many people have a clustering of risk factors for cardiovascular disease. Thus, the term metabolic syndrome has been coined, with various pseudonyms of syndrome X or insulin resistance syndrome. Clinical and biochemical characteristics of the metabolic syndrome are shown in Box 17.2. People with the syndrome are at high risk of diabetes and cardiovascular disease. The condition is common among certain ethnic groups (African-Americans, Mexican-Americans, Asian Indians, Australian Aboriginals), and features can be present for up to 10 years before hyperglycaemia is detected. Vigorous treatment can reduce mortality and morbidity from cardiovascular disease.

Box 17.2 The International Diabetes Federation definition of metabolic syndrome

For a person to be defined as having the metabolic syndrome they must have:

Central obesity:

image Waist circumference:
– >94 cm for Europid men
– >80 cm for Europid women
image With ethnic-specific values for other groups

Plus any two of the following four factors:

1. Raised triglyceride level: >150 mg/dl (1.7 mmol/l), or specific treatment for this lipid abnormality
2. Reduced high density lipoprotein cholesterol: <40 mg/dl (0.9 mmol/l) in males and <50 mg/dl (1.1 mmol/l) in females, or specific treatment for this lipid abnormality
3. Raised blood pressure: systolic BP >130 or diastolic BP >85 mmHg, or treatment of previously diagnosed hypertension
4. Raised fasting plasma glucose (FPG) >100 mg/dl (5.6 mmol/l), or previously diagnosed type 2 diabetes

Presenting symptoms of diabetes

Many people with type 2 diabetes may be asymptomatic at diagnosis, for example by routine screening of blood or urine, when there may be only mildly increased levels of hyperglycaemia. Once diagnosed, however, many patients do admit to some longstanding, often mild symptoms. Acute metabolic decompensation, leading to marked hyperglycaemia, occurs infrequently.

In contrast, type 1 diabetes is often abrupt in onset, and characterized by severe hyperglycaemia with acute life-threatening decompensation (diabetic ketoacidosis).

The cardinal symptoms of diabetes mellitus are weight loss, polyuria and polydipsia, and their presence should always result in an immediate test for blood glucose and urine for ketones.

Polyuria, polydipsia and nocturia

Acute hyperglycaemia causes increased urine excretion (polyuria) and, as a result, excessive thirst and water ingestion (polydipsia). These presenting symptoms of diabetes mellitus are also termed osmotic symptoms. Raised plasma glucose leads to increased renal tubular delivery of glucose, which then exceeds the resorptive capacity of the renal tubule, leading to glycosuria. Therefore, despite hyperglycaemia, people with an increased renal threshold for glucose may have no osmotic symptoms. Conversely, people with a low renal threshold for glucose may have glycosuria despite being normoglycaemic. It is for this reason that glycosuria is an unreliable feature in the diagnosis of diabetes mellitus. Nocturia is also common in patients presenting with osmotic symptoms of diabetes, and enquiry regarding the frequency of passing urine at night can be helpful in evaluating symptoms.

Other conditions can cause polyuria and polydipsia (Table 17.4). Diabetes insipidus (DI) is characterized by loss of renal concentrating capacity, owing to either loss of secretion of antidiuretic hormone (arginine vasopressin) from the posterior pituitary gland (cranial DI) or to poor renal tubular responsiveness to antidiuretic hormone (nephrogenic DI). This leads to loss of free water which, if uncorrected by increased water ingestion, can lead to severe dehydration and plasma hypertonicity. Electrolyte disturbance, such as hypercalcaemia or hypokalaemia, can impair antidiuretic hormone action and hence lead to polyuria and polydipsia. In addition, polyuria and nocturia are common symptoms of chronic renal failure.

Table 17.4 Causes of polyuria

Osmotic diuresis Diabetes mellitus, chronic renal failure, drugs
Polydipsia Psychogenic
Lack of antidiuretic hormone (ADH) Cranial diabetes insipidus due to: idiopathic, surgery, pituitary/hypothalamic tumour, familial, postpartum
Failure of response to ADH Nephrogenic diabetes insipidus due to: primary, renal tubular disorders, hypokalaemia, hypercalcaemia, drugs

Weight loss and lethargy

Loss of more than 5% of total body weight should be considered clinically important in a subject not deliberately attempting to lose weight. Weight loss is a common presenting symptom in people with type 1 diabetes, and occasionally in type 2 diabetes with marked hyperglycaemia. Loss of weight in diabetes is predominantly due to renal glucose loss as a result of lack of insulin to enable cellular uptake of glucose. The weight loss usually occurs despite a normal appetite and dietary intake. This is in contrast to the weight loss of malignant disease, which is usually associated with reduced appetite and oral intake, or thyrotoxicosis which is associated with increased appetite and oral intake.

Lethargy and fatigue are also common presenting symptoms of diabetes mellitus, particularly type 2, where the symptoms may have been present for some time.

Skin problems

Dermatological manifestations of diabetes are common at diagnosis, especially in patients with poor glycaemic control. Skin infections, such as staphylococcal infection leading to boils, carbuncles or abscesses, which are often recurrent, may occur. Severe infection itself can lead to hyperglycaemia, and a new diagnosis of diabetes should be reconsidered once the acute infection has cleared.

Oral and genital candidiasis can also be presenting features of diabetes mellitus. The presence of the characteristic white plaques on the tongue and oropharynx in a previously healthy person not on antibiotic therapy should alert the physician to the possibility of diabetes mellitus, although other conditions leading to immune paresis, such as HIV infection or haematological malignancy, can also lead to candidiasis. Genital candidiasis in women leads to a thick white discharge and vaginal soreness. Similarly, in men it can lead to a severe balanitis (inflammation of the glans penis). Always check the blood glucose in people with recurrent candidiasis.

Visual disturbance

Hyperglycaemia can lead to blurred vision, owing to osmotic changes within the aqueous humour of the lens of the eye. This can also occur when chronic hyperglycaemia is treated, causing further osmotic shifts in the lens. The symptom usually settles once normoglycaemia is achieved.

Other important aspects of a diabetic history

Family history

A history of diabetes in first-degree relatives is a potent risk factor for diabetes. Type 2 diabetes appears to have a stronger genetic component than type 1, with around a third of patients having a positive family history compared to around 10% of type 1 diabetic patients.

A family history of premature cardiovascular disease is also important. Patients with diabetes are at risk of cardiovascular disease, and this risk is increased when there is a family history of vascular disease in fathers or brothers aged less than 55 years, or mothers or sisters aged under 65.

Diet and lifestyle history

The cornerstone of management of diabetes is lifestyle; accordingly, periodic re-assessment is important. Regularity of meals, the quality and quantity of foods eaten and the frequency of snacks should be known. Enquire about the following:

image Regularity of meals – three meals a day is ideal.

image Content of fatty/greasy foods – particularly discourage saturated (animal) fats, as this type of fat is linked to heart disease.

image Content of fruit and vegetables – at least five portions a day are recommended.

image Content of sugar and sugary foods – avoid carbonated drinks, cakes, sweets and biscuits.

image Content of salt – a high salt intake can lead to hypertension.

image Alcohol intake – a maximum of two units of alcohol per day for a woman and three units per day for a man.

The smoking history is of paramount importance, as smoking with diabetes is strongly linked to cardiovascular disease. Occupational history may be important, because if insulin therapy is required, this may have an impact on legal requirements for driving. Assess physical activity, to ascertain whether increased activity may improve glycaemia and weight. At least 30 minutes of moderate exercise, for example brisk walking, per day is recommended.

Assessment of other cardiovascular risk factors

Cardiovascular risk is greatly increased in people with diabetes, and additional cardiovascular risk factors multiply the risk. Thus, any history of hypertension, hyperlipidaemia or previous vascular disease (cerebro-, cardio- or peripheral vascular) should be noted. Take a full medication history, including the use of antiplatelet, antihypertensive and lipid-lowering drugs.

Home glucose testing

In a patient previously diagnosed with diabetes, assess his self-monitoring of glucose. This will enable a reasonable judgement of glycaemic control. Self-monitoring can be done by home capillary blood testing, or by urine testing for glycosuria (Fig. 17.1).

image

Figure 17.1 Home glucose testing is an important part of diabetes care.

Insulin injections

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