Diabetes and endocrinology

Embryology

The pancreas plays a major role in the regulation of blood glucose concentrations. The pancreas is endodermal in origin, arising from the embryonic foregut. Islet cell clusters differentiate from pancreatic bud endoderm, on the edge of which pancreatic islets form. Under the influence of Pax-6 β- and δ-cells, insulin and somatostatin are produced, respectively, whereas Pax-0 facilitates development of α- and γ-cells responsible for glucagon and pancreatic polypeptide production, respectively. Endocrine function is evident from 10–15 weeks' gestation, though what contribution this makes to fetal development is unknown.

Normal anatomy

Pancreatic endocrine function is regulated in the human by approximately one million clusters of cells known as the islets of Langerhans. Insulin-secreting β-cells occupy the central part of the islets of Langerhans and are surrounded by a ‘rind’ of glucagon-secreting α- and somatostatin-secreting δ-cells ( Fig. 26.1 ). Islets are well vascularized to facilitate rapid hormone release and are also innervated by sympathetic and parasympathetic neurons, implying that there is a neurological contribution to pancreatic endocrine regulation.

Physiology

When blood glucose concentrations rise after feeding, insulin is secreted to convert glucose into glycogen ( Fig. 26.2 ) and facilitate cellular uptake, where the glucose is converted to glucose-6-phosphate. By contrast, when glucose levels fall during fasting, concentrations are maintained through secretion of glucagon, which facilitates glucose production from glycogeno­lysis. Other counter-regulatory hormones such as cortisol, growth hormone and epinephrine also contribute to gluconeogenesis through protein degradation and lipolysis. The latter is particularly facilitated by the switching off of insulin release as blood glucose concentrations fall.

Triglycerides are transported in blood by very-low-density lipoproteins to target tissues where lipases promote hydrolysis of triglycerides into glycerol and free fatty acids. Glycerol is then metabolized to rejoin the glycogenolysis and gluconeogenesis pathways. Free fatty acids are transported across the mitochondrial membrane to undergo a process of beta oxidation, which generates two-carbon molecules of acetyl co-A, which can enter the citric acid cycle to ultimately generate ATP.

Important differences exist between young children and adults with respect to blood glucose regulation. The young child is at particular risk from hypoglycaemia due to the relatively large brain size and limited glycogen stores. To compensate, infants in particular are able to generate ketones as an alternative cerebral fuel source more easily than adults.

History

In a child presenting with hyperglycaemia, the following history is important:

• Duration of symptoms such as polyuria, polydipsia, weight loss, lethargy, constipation or blurred vision

• Infection, particularly candidiasis

• Vomiting or abdominal pain might suggest ketoacidosis

• Family history of diabetes of any type or other autoimmune disease.

Examination

Many children with newly diagnosed diabetes will have no abnormal findings on clinical examination. In children with hyperglycaemia and presumed diabetes, the critical need is to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D), as the approach to treatment will be very different for each form:

• Weight loss, dehydration, signs of acidosis such as Kussmaul breathing (deep and tachypnoeic, reflecting the respiratory effort to correct the metabolic acidosis) with sweet (acetone-smelling) breath, depressed consciousness and signs of cerebral oedema suggest type 1 diabetes

• Overweight, hypertension and acanthosis nigricans suggest developing insulin resistance and type 2 diabetes.

Investigations

In hyperglycaemic children, the following investigations need to be considered:

• If there is uncertainty about a diagnosis of diabetes, a random or two hour glucose tolerance test blood glucose of >11.1 mmol/L or fasting blood glucose >7 mmol/L indicates the presence of diabetes; however, in most children with type 1 diabetes, the diagnosis can be determined by clinical features and random blood glucose and no further investigations are required

• The degree of elevation in HbA1c levels, which may indicate the length of prodrome

• The presence of glutamic acid decarboxylase (GAD) antibodies indicates probable autoimmune-mediated T1D

• If a diagnosis of T1D seems likely, screening for other autoimmune disease (hypothyroidism, hyperthyroidism and coeliac disease) is indicated

• There can be uncertainty whether the child has T1D or T2D and a formal oral glucose tolerance test with measurement of high concentrations of insulin and c-peptide on baseline and two hour blood samples along with suppressed sex hormone binding globulin concentrations would indicate the presence of T2D.

Diseases of blood glucose regulation

History

When evaluating a child for hypoglycaemia, attention should be paid to:

• Autonomic symptoms of hypoglycaemia, such as pallor, sweating, tachypnoea in a neonate or anxiety, palpitations and tremor in an older child

• Neuroglycopenic symptoms of jitteriness, apnoea, hypotonia, feeding problems, irritability, abnormal cry, convulsions or coma in a neonate or hunger, abdominal pain, nausea, vomiting, pins and needles, headache, weakness, dizziness, blurred vision, irritability, mental confusion, odd behaviour, fainting, convulsions or coma in an older child

• In a neonate, pregnancy details (e.g. maternal symptoms of diabetes), mode of delivery (breech said to be more common in hypopituitarism), birth weight (hypoglycaemia more common in intrauterine growth restriction or large for gestational age due to maternal diabetes) and the relationship of hypoglycaemia to feeding (i.e. is this a question of inadequate fuel supply or excess fuel requirements as in hyperinsulinism?)

• Access to oral hypoglycaemic medication, which may have been accidentally ingested

• Family history of sudden infant death or consanguinity might suggest an inborn error of metabolism

• Development of symptoms in response to foods containing lactose, fructose or sucrose might suggest galactosaemia or disorders of fructose metabolism.

Examination

Most children with a history of hypoglycaemia will not have any abnormal clinical signs on examination unless actually hypoglycaemic at the time. However, the presence of the following signs may indicate an associated diagnosis:

• Optic atrophy – septo-optic dysplasia

• Cranial midline defects, short stature, microgenitalia – hypopituitarism

• Increased skin or buccal pigmentation, hypotension – Addison's disease

• Underweight or signs of malnutrition – accelerated starvation

• Tall stature, excess weight – hyperinsulinism

• Abnormal ear-lobe creases, macroglossia, umbilical hernia, hemihypertrophy – Beckwith–Wiedemann syndrome

• Hepatosplenomegaly – glycogen storage disorder.

Investigations

The aim of investigations is to establish the severity of hypoglycaemia and to evaluate the counter-regulatory responses and intermediary metabolite pathways by obtaining a blood sample before instituting treatment of the hypoglycaemic episode for measurement of:

• Glucose to confirm severity of hypoglycaemia

• Urea and electrolytes for evidence of adrenal insufficiency

• Bicarbonate or pH, as acidosis might imply adrenal failure or an inborn error of metabolism

• Liver function tests, as may be abnormal in primary liver disease, sepsis, glycogen storage disease, galactosaemia, fatty acid oxidation defects and hereditary fructose intolerance

• Ammonia, may be elevated in a number of inborn errors of metabolism and some forms of hyperinsulinism

• Insulin and c-peptide, should normally be suppressed

• Cortisol, ACTH and growth hormone should normally be elevated, implying an appropriate stress response

• Free fatty acids and β-hydroxybutyrate, if elevated in proportion imply appropriate lipolysis

• Acylcarnitine will be abnormal in some fatty acid oxidation defects

• Lactate will be elevated in metabolic liver disease, glycogen storage disorder and sepsis

• Alanine, if low suggests ‘accelerated starvation’ (see below)

• After glucose has been administered to correct the hypoglycaemia, the next urine sample should be collected to measure the presence of ketones, reducing sugars, dicarboxylic acids, glycine conjugates, carnitine derivatives, and amino and organic acids to screen for inborn errors of metabolism and a toxicology screen.

Treatment

Treatment depends on aetiology. Hypoglycaemia may be broadly subdivided into two groups:

• 1.

  Causes associated with reduced glucose availability arise due to defects in the counter-regulatory response including limited supplies of glucose precursors. These include:

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    Being born with intrauterine growth restriction

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    Prematurity

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    Hypopituitarism

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    Adrenal insufficiency

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    Growth hormone deficiency

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    Hypothyroidism

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    Glucagon deficiency

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    Accelerated starvation (ketotic hypoglycaemia)

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    Inborn errors of metabolism

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    Drugs such as alcohol, aspirin and beta blockers

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    Liver dysfunction

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    Congenital heart disease.

  Investigation of hypoglycaemia frequently fails to demonstrate any underlying abnormality. Accelerated starvation is an example of this. It can only be diagnosed once other endocrine and metabolic causes are excluded, and is of unknown aetiology. It is characterized by demonstration of a normal endocrine counter-regulatory response with raised fatty acid and ketone responses. It is more common in boys than girls and in those who were born small for gestational age or who have a thin physique; it usually resolves by puberty. Treatment of this group of causes involves avoidance of prolonged fasting, particularly during intercurrent illness, administration of complex carbohydrates such as cornstarch at bedtime to provide a prolonged glucose response to feeding and intravenous dextrose as required to reverse acute hypoglycaemia.

• 2.

  Alternatively, hypoglycaemia may occur in the context of increased glucose consumption due to:

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    Congenital hyperinsulinism

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    Transient neonatal hyperinsulinism

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    Being an infant of a diabetic mother

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    Insulinoma

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    Beckwith–Wiedemann syndrome

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    Rhesus haemolytic disease

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    Perinatal asphyxia

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    Malaria.

  Markedly excessive glucose requirements (e.g. in excess of 12 mg/kg body weight/hour) to avoid hypoglycaemia suggest underlying hyperinsulinism. Congenital hyperinsulinism may occur in relation to several genetic defects affecting the regulation of insulin release. The most commonly identified are those of genes encoding the sulphonylurea receptor (ABCC8) and associated potassium inward rectifying channel (KCNJ11). Affected children are at increased risk of hypoglycaemia-induced brain damage as the hyperinsulinism suppresses not only glucose but also ketone body production, which is an alternative cerebral fuel source. Some respond to diazoxide and chlorothiazide treatment, diazoxide exerting its effect through actions on the potassium channel by inducing hyperpolarization, decreased calcium influx and reduced insulin secretion. If these fail, then a somatostatin analogue may be used to exert a direct receptor-mediated inhibition of insulin release. Scientific advances in our understanding of the genetics and new imaging techniques such as [ ¹⁸ F]DOPA positron emission tomography scanning allow, in persistent cases, distinguishing focal from diffuse pancreatic disease, the former being curable by surgical excision with minimal morbidity.

Embryology

The thyroid develops from four weeks' gestation from an outpouching of the floor of the pharynx (the precursor of T4-producing follicular cells) and bilateral protrusions of the fourth pharyngeal pouches (which give rise to calcitonin-secreting cells). The thyroid descends along the thyroglossal tract, which then regresses, though remnants may come to form thyro­glossal cysts. Failure of descent results in an ectopic thyroid gland, a common form of congenital hypothyroidism. The process of thyroid development is regulated by a number of transcription factors (including PAX-8, FOXE-1 and NKX2.1).