Key points

• Diabetes is the modern pandemic. It represents a considerable global economic and social burden for the person with diabetes and the health system. The prevalence of both Type 1 and Type 2 is increasing.
  
• Primary prevention and early detection are essential to reduce the personal and community burden associated with the metabolic syndrome and Type 2 diabetes and its complications.
  
• Type 2 diabetes is a progressive disease and complications are often present at diagnosis. Thus, insulin will eventually be necessary in most people with Type 2 diabetes.
  
• The prevalence of obesity, the metabolic syndrome and Type 2 diabetes is increasing in children.

What is diabetes mellitus?

Prevalence of diabetes

Classification of diabetes

Overview of normal glucose homeostasis

Blood glucose regulation (glucose homeostasis) relies on a delicate balance between the fed and fasting states and is dependent on several simultaneously operating variables including hormones, nutritional status, especially liver and muscle glucose stores, exercise, tissue sensitivity to insulin, and the type of food consumed. Figure 1.1 shows the key features of the fed and fasting states. Note that insulin release occurs in two phases. The first phase is important to control the post prandial blood glucose rise and is lost early in the progression to Type 2 diabetes. Insulin action is mediated via two protein pathways: Protein 13-kinase through insulin receptors and influences glucose uptake into the cells; and MAP-kinase, which stimulates growth and mitogenesis.

The metabolic syndrome

The metabolic syndrome consists of a cluster of risk factors for cardiovascular disease and Type 2 diabetes. Several researchers have explored the factors that predict diabetes risk including the Paris Prospective Study, Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE), Epidemiology Study on the Insulin Resistance Syndrome (DESIR), and the European Group for the Study of Insulin

Figure 1.1 Overview of glucose homeostasis showing the key factors operating during the fed and fasting states. Usually the blood glucose is maintained within the normal range by the interplay of the anabolic and catabolic hormones, which are in turn influenced by other hormones and a number of factors such as nutritional status and intake.

The metabolic syndrome has been known as syndrome X, the deadly quartet, the awesome foursome, diabesity, and metabolic syndrome X. Currently, no agreed definition of the metabolic syndrome exists, particularly with respect to assessing risk or outcomes in children and adolescents. Four main definitions for adults have been described. They disagree about the predictive ability of the various metabolic features for cardiovascular disease and Type 2 diabetes due to ethnic, gender and age differences, which affect the syndrome components and may not identify groups at risk at lower waist circumference such as Asian people:

• World Health Organisation (1999).
  
• European Group for the Study of Insulin Resistance (2002).
  
• National Cholesterol Education Program – Adult Treatment Panel 111 (2001).
  
• International Diabetes Federation (IDF) (2005).
  
• The IDF Consensus Report on the Metabolic Syndrome in Children and Adolescents (2005).

Key features of the metabolic syndrome

• The metabolic syndrome appears to be a result of genetic predisposition and environmental factors, which include high saturated fat diets, inactivity, smoking, hormone imbalances contributing to metabolic stress, age and some medicines. These factors represent a cumulative risk and are largely modifiable.
  
• Central obesity – waist circumference: Europoids >94 cm in men and >80 cm in women. South Asian and South-East Asian men >90 cm, women >80 cm:(WHO 2004; Zimmet 2005) and childhood/adolescent Body Mass Index (BMI) 25–29 overweight, >30 obese.
  
• Raised serum triglycerides >1.7 mmol/L.
  
• Low serum HDL-c: <1.03 mmol/L males, <1.29 mmol/L women.
  
• Hypertension: systolic > 130 mmHg or diastolic >85 mmHg in women.
  
• IFG: >5.6 mmol/L or previously diagnosed diabetes (e.g. gestational diabetes (GDM). IFG is associated with a 20–30% chance of developing Type 2 diabetes within 5–10 years. The chance increases if FPG is also present.

Other key features include:

• Insulin resistance
  
• Hyperinsulinaemia, which occurs in the presence of insulin resistance and exaggerates the proliferative effects of the MAP-kinase pathway.
  
• Procoagulent state: elevated plasma fibrinogen and plasminogen activator inhibitor-1 (PAI-1).
  
• Vascular abnormalities: increased urinary albumin excretion and endothelial dysfunction, which affect vascular permeability and tone.
  
• Inflammatory markers such as cytokines, Interleukin, adhesion molecules, and TNF-alpha, which alter endothelial function. C-reactive protein is a significant predictor of cardiovascular disease and possibly depression, and there is an association among diabetes, cardiovascular diseases and depression. In fact some experts suggest depression could be an independent risk factor for Type 2 diabetes (Loyd et al. 1997) and accelerates the progression of coronary artery disease (Rubin 2002). Depression is associated with behaviours such as smoking, unhealthy eating, lack of exercise and high alcohol intake, which predisposes the individual to obesity and Type 2 diabetes. Peripheral cytokines induce cytokine production in the brain, which activates the hypothalamic–pituitary–adrenal axis and the stress response, which inhibits serotonin and leads to depression. Inflammation appears to be the common mediator among diabetes, cardiovascular disease and depression (Lesperance & Frasure-Smith 2007).
  
• Hyperuricaemia: More recently, liver enzymes such as sustained elevations of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), which are associated with non-alcoholc fatty liver disease and low adiponectin, have been associated with diabetes and cardiovascular disease. Therefore, the relationship is complex. Conversely, higher testosterone levels appear to be protective against diabetes in men but indicate greater risk in women and high oestradiol levels confer increased diabetes risk in both men and women (American Diabetes Association 2007 Preventing Diabetes).

Consequences of the metabolic syndrome include:

• A five-fold increased risk of Type 2 diabetes.
  
• A two to three fold increased risk of cardiovascular disease (myocardial events, stroke and peripheral vascular disease).
  
• Increased mortality, which is greater in men but women with Type 2 diabetes have a greater risk than non-diabetic women.
  
• Increased susceptibility to conditions such as:
  
  
  
  • Gestational diabetes (GDM)
    
  • Fetal malnutrition
    
  • Polycystic Ovarian Syndrome
    
  • Fatty liver
    
  • Gallstones
    
  • Asthma
    
  • Sleep problems
    
  • Some forms of cancer.

The risk of developing cardiovascular disease and Type 2 diabetes increases significantly if three or more risk factors are present (Eckel et al. 2005).

The metabolic syndrome in children and adolescents

Type 1 and Type 2 diabetes

Figure 1.2 is a schematic representation of the progression of Type 1 diabetes. It shows the progressive relentless destruction of the beta cells from the time of the initial triggering event. Five to ten per cent of first-degree relatives of people with Type 1 diabetes have beta cell antibodies, usually with normal glucose tolerance, and some progress to diabetes.

Immunosuppression with Azathioprine or Cyclosporin, and immunomodulation using Nicotinamide to prevent further beta cell destruction has been used in newly diagnosed or pre-Type 1 diabetes but these treatments are uncommon. These medicines are potent immunosuppressive agents and their use cannot be warranted in the long term. Insulin has also been used in an attempt to stimulate immune tolerance, but not successfully.

Latent autoimmune diabetes (LADA)

LADA is a genetically linked autoimmune disorder that occurs in ~10% of people initially diagnosed with Type 2 diabetes. The prevalence varies among ethnic groups (www.actionlada.org). LADA has some features of both Types 1 and 2 diabetes. The UKPDS (1998) identified that one in 10 adults aged between 25 and 65 presumed to have Type 2 diabetes were GAD antibody positive, and these findings have been evident in other studies (Zinman et al. 2004). LADA often presents as Type 2 but has many of the genetic and immune features of Type 1 (see the previous section and Table 1.2).

Figure 1.2  Schematic representation of the slow progressive loss of beta cell mass following the initial trigger event in Type 1 diabetes.

The progression to insulin dependency is usually rapid when GAD and IA-2A antibodies are present. The clinical features also resemble Type 1 in that people with LADA are not usually obese, are often symptomatic, and do not have a family history of Type 2 diabetes. A number of LADA trials are currently underway such as ACTIONLADA in Europe and the INIT 11 (LADA Trial) in Australia. LADA is also known as latent autoimmune diabetes of adulthood, late-onset autoimmune diabetes of adulthood, slow onset Type 1, and Type 1.5 (type one-and-a-half) diabetes.

Management includes:

• Testing non-obese people presenting with Type 2 diabetes for autoantibodies especially GAD, which has higher sensitivity to prevent episodes of ketoacidosis (Niskanen et al. 1995).
  
• Testing C-peptide levels in the blood to assess beta cell function. C-peptide is usually low in LADA indicating deficient insulin secretion, which predicts the need for insulin.
  
• Diet and exercise changes relevant to the individual.
  
• Avoiding metformin because of the potential risk of lactic acidosis in the presence of insulin deficiency.
  
• Introducing insulin early to support insulin secretion. Insulin is usually required within 4–6 years of diagnosis.
  
• Stress management and regular complication screening and mental health assessment (as per Types 1 and 2 diabetes).
  
• Appropriate education and support.

Type 2 diabetes

Type 2 diabetes is not ‘just a touch of sugar’ or ‘mild diabetes’. It is an insidious progressive disease that is often diagnosed late when complications are present. Therefore, population screening and education programs are essential. Type 2 diabetes often presents with an established long-term complication of diabetes such as neuropathy, cardiovascular disease, or retinopathy. Alternatively, diabetes may be diagnosed during another illness or on routine screening. The classic symptoms associated with Type 1 diabetes are often less obvious in Type 2 diabetes, however, once diabetes is diagnosed and treatment instituted, people often state they have more energy and are less thirsty. Other subtle signs of Type 2 diabetes especially in older people include recurrent candida infections, incontinence, constipation, symptoms of dehydration and cognitive changes. As indicated, insulin resistance often precedes Type 2 diabetes.

Insulin resistance is the term given to an impaired biological response to both endogenous and exogenous insulin that can be improved with weight loss and exercise. Insulin resistance is a stage in the development of impaired glucose tolerance. When insulin resistance is present, insulin production is increased (hyperinsulinaemia) to sustain normal glucose tolerance; however, the hepatic glucose output is not suppressed and fasting hyperglycaemia and decreased postprandial glucose utilisation results.

Insulin resistance is a result of a primary genetic defect and secondary environmental factors (Turner & Clapham 1998). When intracellular glucose is high, free fatty acids (FFAs) are stored. When it is low FFAs enter the circulation as substrates for glucose production. Insulin normally promotes tryglyceride synthesis and inhibits postprandial lipolysis. Glucose uptake into adipocytes is impaired in the metabolic syndrome and Type 2 diabetes and circulating FFAs as well as hyperglycaemia have a harmful effect on hepatic glucose production and insulin sensitivity. Eventually the beta cells do not respond to glucose and this is referred to as glucose toxicity. Loss of beta cell function is present in over 50% of people with Type 2 diabetes at diagnosis (United Kingdom Prospective Study (UKPDS) 1998) (Figure 1.2). Figure 1.3 depicts the consequences of insulin resistance.

Insulin is secreted in two phases: the first phase plays a role in limiting the post prandial rise in blood glucose. The first phase is diminished or lost in Type 2 diabetes leading to elevated post prandial blood glucose levels (Dornhorst 2001). Postprandial hyperglycaemia contributes to the development of atherosclerosis, hypertriglyceridaemia and coagulant activity, endothelial dysfunction, and hypertension, which add to the effects of chronic hyperglycaemia and contribute to long-term diabetes complications (Ceriello 2003).

Figure 1.3 Consequences of the insulin resistance syndrome.

Interestingly, the beta cells do respond to other secretagogues, in particular sulphonylurea medicines.

The net effects of these abnormalities is sustained hyperglycaemia as a result of:

• impaired glucose utilisation (IGT)
  
• reduced glucose storage as glycogen
  
• impaired suppression of glucose-mediated hepatic glucose production
  
• high fasting glucose (FPG)
  
• reduced postprandial glucose utilisation.

People most at risk of developing Type 2 diabetes:

• have the metabolic syndrome,
  
• are overweight: abdominal obesity, increased body mass index (BMI), and high waist-hip ratio (>1.0 in men and >0.7 in women). The limitations of the waist circumference in some ethnic groups are outlined later in the chapter. Elevated FFAs inhibit insulin signalling and glucose transport (see Figure 1.4) and are a source of metabolic fuel for the heart and liver. Binge eating precedes Type 2 diabetes in many people and could be one of the causes of obesity; however, the prevalence of eating disorders is similar in Type 1 and Type 2 diabetes (Herpertz et al. 1998):
  
• are over 40 years of age, but note the increasing prevalence in younger people (see also Chapter 13)
  
• are closely related to people with diabetes,
  
• are women who had gestational diabetes or who had large babies in previous pregnancies.

Other associated risk factors have already been described. In addition, active and former smoking and acanthosis nigricans are associated with hyperinsulinaemia (Kong et al. 2007). Baseline and hypertension progression are independent predictors (Conen et al. 2007). Recent research suggests insulin lack might be partly due to the enzyme PK Cepsilon (PKCe), which is activated by fat and reduces the production of insulin. Future medicines may target this deficiency and restore normal insulin function (Biden 2007). The characteristics of Type 1 and Type 2 diabetes are shown in Table 1.1.

The majority of people with Type 2 diabetes require multiple therapies to achieve and maintain acceptable blood glucose and lipid targets over the first nine years after diagnosis (UKPDS 1998). Between 50% and 70% require insulin, which is often used in combination with OHAs. This means diabetes management progressively becomes more complicated for people with Type 2 diabetes, often coinciding with increasing age when their ability to manage may be compromised, which increases the likelihood of non-compliance and the costs of managing the disease for both the patient and the health system.

Gestational diabetes

Figure 1.4 Diagrammatic representation of insulin binding, insulin signalling, translocation of GLUT-4 and glucose entry into the cell. GLUT-4 is a glucose transporter contained in vesicles in the cell cytoplasm. Once insulin binds to an insulin receptor GLUT-4 moves to the cell membrane and transports glucose into the cell. During fasting GLUT-4 is low and increases in response to the increase in insulin. Failure of GLUT-4 translocation could explain some of the insulin resistance associated with Type 2 diabetes. The effects of insulin are mediated by two protein pathways: P13-kinase through the insulin receptors (glucose uptake) and MAP-kinase, which stimulates growth and mitogenesis.

Table 1.1 Characteristics of Type 1 and Type 2 diabetes mellitus.

^aIncreasing incidence of the metabolic syndrome and Type 2 diabetes in children and adolescents.

^bOccurs in older people; see LADA.

Malnutrition-related (tropical) diabetes

Childhood malnutrition, genetic predisposition and environmental factors are implicated in the development of diabetes in people living in tropical countries. It is not included as a specific category in the revised classification but could fit into the ‘other’ category. ‘Tropical diabetes’ or malnutrition-related diabetes differs from Type 1 diabetes because ketoacidosis is rare, and from Type 2 diabetes because it often occurs in young, thin people with no family history of diabetes. However, researchers have not yet agreed about the underlying causal mechanisms.

Maturity onset diabetes of the young (MODY)

Maturity onset diabetes of the young is a rare group of diabetes disorders, formerly also called Mason-type diabetes and non-insulin-dependent diabetes of the young (NIDDY). MODY can develop at any age up to 55 in 2–2% of people with non-Type 1 diabetes. It has a genetic basis and there are at least six varieties in many ethnic groups (Dean & McEntyre 2004). MODY can be distinguished from Type 1 diabetes by the absence of GAD antibodies and ketosis and from Type 2 because MODY is caused by a single gene and Type 2 is caused by minor problems in several genes that occur simultaneously (Froguel & Velho 1999). Likewise, MODY people often do not have insulin resistance. The age at onset in at least one genetic type depends on which parent carries the mutant gene: it occurs at a younger age if the mother passed it on especially if she had GDM. Women with MODY are often diagnosed during pregnancy. The varieties of MODY are shown in Table 1.2.

Treatment is with oral hypoglycaemic agents, diet and exercise, although insulin may eventually be required. Interestingly, Ehilishan et al. (2004) suggested diabetes diagnosed in children younger than six years is likely to be a genetic defect rather than Type 1 diabetes. If that is the case, there are implications for diabetes education and management.

Recognition can be difficult and the diagnosis is often missed (Appleton & Hattersley 1996). This can have implications for the individual and their family in commencing appropriate treatment for the specific type of MODY and genetic counselling.

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