4: Acute metabolic complications

Section 4 Acute metabolic complications




Hypoglycaemia



Type 1 diabetes


Hypoglycaemia is the most-feared complication of therapy in insulin-treated patients. Unfortunately, iatrogenic hypoglycaemia is a common and serious hazard of treatment. It has a substantial clinical impact in terms of mortality, morbidity and quality of life. The risk of hypoglycaemia increases as glycaemic control is improved and in intensive insulin therapy it is the principal factor limiting the attainment of lower glycaemic targets.



Iatrogenic hypoglycaemia usually results from a mismatch between:



In the Diabetes Control and Complication Trial, the overall risk of severe hypoglycaemia was increased approximately 3-fold in the intensively treated group. This was observed despite strenuous efforts to exclude patients who were thought to be at high risk of hypoglycaemia. The relation between rate of severe hypoglycaemia and mean glycated haemoglobin (HbA1c) level was inverse and curvilinear. Factors predisposing to severe hypoglycaemia are presented in Table 4.1. However, in a significant proportion of hypoglycaemic episodes, a clear predisposing factor cannot be identified even with very careful scrutiny of the circumstances.


Table 4.1 Risk factors for severe hypoglycaemia








Other causes of hypoglycaemia in insulin-treated patients are presented in Table 4.2. Their effects in individual patients are variable.


Table 4.2 Causes of recurrent hypoglycaemia in insulin-treated patients















Changes in insulin pharmacokinetics

Altered insulin sensitivity

Others


The symptoms and signs of acute hypoglycaemia may be divided into two main categories:



Autonomic (adrenergic) – arising from activation of the sympathoadrenal system (Table 4.3). During hypoglycaemia, the body normally releases adrenaline (epinephrine) and related substances. This serves two purposes:




Neuroglycopenic – resulting from inadequate cerebral glucose delivery (Table 4.3). Specific symptoms vary by age, duration of diabetes, severity of the hypoglycaemia and the speed of the decline. The symptoms in a particular individual may be similar from episode to episode, but are not necessarily so and may be influenced by the speed at which glucose levels are dropping, as well as the previous incidence of hypoglycaemia.


Table 4.3 Autonomic, neuroglycopenic and non-specific symptoms and signs in acute hypoglycaemia















Autonomic (adrenergic)

Neuroglycopenia

Non-specific


Under experimental conditions, adrenergic activation occurs at a higher plasma glucose concentration than the level at which cerebral function becomes impaired (2.7 mmol/L). Thus, the patient is often alerted to the falling plasma glucose concentration by adrenergic activation and is usually able to take corrective action.



Hypoglycaemia and the brain


Cerebral function is critically dependent on an adequate supply of glucose from the circulation. Glucose is transported into the brain across the blood–brain barrier by a facilitative glucose transporter protein, GLUT-1. Studies in humans indicate that the rate of glucose transport into the brain can be modified by changes in plasma glucose levels. In particular, antecedent hypoglycaemia causes upregulation of glucose transport, so that more glucose is transported across the blood–brain barrier during subsequent episodes of hypoglycaemia. This adaptive response has important clinical implications.


Cognitive impairment progresses ultimately to loss of consciousness as plasma glucose falls. Seizures and transient focal neurological deficits may occur.



The most serious consequence of acute hypoglycaemia is cerebral dysfunction with the risk of:



Clinically, hypoglycaemia may be usefully graded as follows:




Hypoglycaemia – counter-regulation


The physiological response to acute hypoglycaemia comprises:






Hypoglycaemia unawareness


Hypoglycaemic unawareness is particularly common in patients:



In addition, certain drugs and alcohol may impair a patient’s perception of these symptoms. β-Blockers are designed to blunt the β-effect of adrenaline and related substances. Hence, if hypoglycaemia occurs in someone who is using this type of drug, he or she may have reduced adrenergic warning symptoms such as tremor and palpitations. β-Blockers may also reduce adrenaline’s effect of stimulating the liver to make glucose, and therefore may lead to the hypoglycaemia being slightly more severe and/or more protracted. β-Blockers are not contraindicated in diabetes, but patients should be aware of these possible problems.


During hypoglycaemia, the body normally releases adrenaline and related substances. The reduction in the β-effect of adrenaline reduces the typical symptoms of hypoglycaemia and blunts liver glycogenolysis and gluconeogenesis. As a result the patient may not be aware that their glucose level is low and the liver produces less glucose.


Attenuation of the adrenaline response is usually due to the glycaemic threshold for the response being shifted to a lower plasma glucose concentration. This can be aggravated by previous episodes of hypoglycaemia.


‘Hypoglycaemia begets hypoglycaemia’ – antecedent hypoglycaemia alters the glycaemic threshold for counter-regulatory hormone secretion – the brain becomes ‘used to’ the low glucose concentration. Clinical studies have shown that intensive insulin therapy leads to symptoms that develop at lower plasma glucose levels. Neuronal glucose transporters increase in number in response to repeated hypoglycaemia. As a result, the hypoglycaemic threshold for the brain to signal adrenaline release falls. Consequently, the patient has less time between the onset of symptoms and the development of severe neuroglycopenia.



Recurrent hypoglycaemia, even if asymptomatic, is therefore a contraindication to intensive insulin therapy in patients with type 1 diabetes. Hypoglycaemic unawareness will sometimes disappear when the frequency of hypoglycaemic episodes has declined, but this is not always the case. With care and expert supervision, this may not necessarily compromise overall glycaemic control as judged by glycated haemoglobin concentrations.



As adrenaline release is a function of the autonomic nervous system, the presence of autonomic neuropathy causes the adrenaline release in response to hypoglycaemia to be lost or blunted. However, it is accepted that classical autonomic neuropathy is not usually responsible for loss of hypoglycaemic awareness.




Nocturnal hypoglycaemia


Hypoglycaemia in type 1 diabetes is particularly common during the night and often goes undetected. Prevention of severe nocturnal hypoglycaemic events remains one of the most challenging goals in the treatment of diabetes. With the prevention of severe hypoglycaemia, it is likely that more people would be able to move toward optimal glycaemic control. Insulin-induced hypoglycaemia is also implicated in occasional sudden death in young patients. Prolonged severe hypoglycaemia, often exacerbated by excessive alcohol consumption, may produce cerebral oedema and permanent brain damage. The risk of hypoglycaemia bars insulin-treated diabetics from certain occupations.



The frequent occurrence of nocturnal hypoglycaemia – which may affect more than 50% of patients and often goes unrecognized – may be an important cause of hypoglycaemia unawareness. In addition, the physiological responses to insulin-induced hypoglycaemia are impaired during stages 3–4 (slow wave) of sleep.


Conventional strategies to minimize nocturnal hypoglycaemia include:




Nocturnal hypoglycaemia often due to poor dietary compliance, and excess alcohol intake has been implicated in the sudden death of some young patients (so-called ‘dead in bed’ syndrome). The cause remains unproven, but catecholamine-mediated falls in plasma potassium concentration leading to cardiac arrhythmias have been implicated.



Treatment of insulin-induced hypoglycaemia




Grade 3–4 hypoglycaemia


Friends, colleagues or relatives may recognize the development of hypoglycaemia before patients themselves. A subtle change in appearance or behaviour may prompt a third party to encourage oral carbohydrate consumption. Unfortunately, cognitive dysfunction may lead to a negative or even hostile response. If the level of consciousness falls, it often becomes hazardous to try forcibly to administer carbohydrate by mouth. Alternatives include:










Recovery from hypoglycaemia may be delayed if:



If the development of cerebral oedema is suspected, computed tomography of the brain should be undertaken and the adjunctive treatment considered: intravenous dexamethasone (4–6 mg 6-hourly) or mannitol. However, evidence for the efficacy of these drugs, or for other measures such as controlled hyperventilation, is poor.




Behavioural problems specific to type 1 diabetes






Type 2 diabetes


Most of the research into hypoglycaemia has looked at hypoglycaemia in the insulin-deficient type 1 diabetic population. The occurrence of hypoglycaemia in the treatment of type 2 diabetes is well recognized, but is more protean in nature, having different risk factors and clinical features according to the nature of the antihyperglycaemic therapy, the extent of the insulin secretory deficit and the duration of diabetes.


The most common cause of hypoglycaemia in type 2 diabetes, resulting in significant physical and psychological morbidity, is iatrogenic, occurring with the use of insulin secretagogues (particularly sulphonylureas) and insulin therapy. These may overwhelm the normal defences that should protect against a significant fall in plasma glucose concentration, primarily by preventing a fall in circulating insulin. Risk of severe hypoglycaemia is further increased by any defects in the other systems for maintaining glucose concentrations. For example, defects in glucagon responses to hypoglycaemia develop in type 2 diabetes along with defects in the other stress responses. Specific therapies may worsen these defects; for example, sulphonylurea therapy sustains intrapancreatic insulin levels during hypoglycaemia, which may further impair glucagon responses.


Risk factors for individual episodes of hypoglycaemia in patients with type 2 diabetes include behavioural, physiological and therapeutic factors. The most common behavioural factor that precipitates individual episodes of severe hypoglycaemia is missed or irregular meals. Other lifestyle factors include alcohol, exercise and incorrect use of glucose-lowering medication (dose/timing).


Therapeutic/physiological factors associated with increased risk include older age, duration of diabetes, presence of co-morbidities, renal impairment, loss of residual insulin secretion, defective counter-regulation and loss of awareness of hypoglycaemia. The use of other medications may also increase risk.


Patient age also affects subjective awareness of hypoglycaemia. In the elderly, neuroglycopenic symptoms specifically related to articulation and coordination, which include unsteadiness, blurred or double vision, lack of coordination and slurred speech, are more common. There are experimental data to show that the adrenergic symptoms of hypoglycaemia decline with increasing age, whereas the tendency for cognitive dysfunction in hypoglycaemia increases.


Time of day is also important – even in the absence of pharmacological therapy, the lowest plasma glucose level of the day is just before the evening meal and unsuspected hypoglycaemia can occur at this time once drug therapy is started. Intensification of treatment targets will increase the risk of severe hypoglycaemia, although this effect will depend on the nature of the treatment used and the degree of insulin deficiency in the patient.


In addition, in type 2 diabetes hypoglycaemia has also been suggested as a private experience that is often not discussed with health-care providers. Hypoglycaemia may be a much greater burden for patients than health professionals are aware. Type 2 patients reported in a recent UK survey that they often received very little information and guidance from health professionals regarding adverse effects of their glucose-lowering regimens.


In patients on lifestyle adjustment and/or insulin-sensitizing treatments, the risk of hypoglycaemia is negligible. Based on patient reporting, the UK Prospective Diabetes Study (UKPDS) 73 showed rates of 0.1% and 0.3% for lifestyle and metformin, respectively, in patients receiving diet alone or monotherapy for 6 years from diagnosis. The recent Diabetes Outcome Progression Trial (ADOPT) reported rates of around 10% in patients on insulin sensitizers (metformin or a thiazolidinedione) over the 5 years of treatment (again all self-reported). Severe episodes were reported in very few patients (0.1%) on either treatment. Patients are more at risk of hypoglycaemia when an insulin sensitizer is combined with insulin or insulin secretagogues.


With the increasing drive for more strict glucose control in type 2 diabetes and new therapies that may carry different risks for hypoglycaemia from established therapies, a review of the risks of hypoglycaemia in type 2 diabetes is appropriate.


Stay updated, free articles. Join our Telegram channel

Mar 10, 2017 | Posted by in ENDOCRINOLOGY | Comments Off on 4: Acute metabolic complications

Full access? Get Clinical Tree

Get Clinical Tree app for offline access