Hypoglycaemia, a too low blood glucose, may result as a consequence of glucose lowering therapy in patients with type 1 and type 2 diabetes. The most important provokers are insulin therapy and sulfonylurea derivatives. Hypoglycaemia can be divided in mild (self-treated by the affected individual) and severe hypoglycaemia (treatment assistance from a third party necessary). In many patients with (early) type 2 diabetes, hypoglycaemia is a rare event, but in those with type 1 diabetes or long-standing type 2 diabetes the frequency of hypoglycaemia remains high, despite attempts to lower the risk of hypoglycaemia in clinical practice. While mild hypoglycaemia carries no long-term risk, severe hypoglycaemia is associated with some serious health risks, particularly in vulnerable groups such as children and elderly. However, in all patients with diabetes, hypoglycaemia can have a major impact on their quality of life.

Defining hypoglycaemia

When trying to discuss, count or compare rates of hypoglycaemia, one should first agree on the definition of hypoglycaemia. The first person to try and define hypoglycaemia was the surgeon Whipple, who put down three criteria needed to establish hypoglycaemia. This so-called Whipple's triad states that hypoglycaemia is only present when:

  1. There is a low blood glucose level
  2. There are symptoms consistent with hypoglycaemia
  3. Symptoms rapidly disappear upon the administration of glucose

While seemingly simple and elegant, on closer inspection these criteria are not as clear as one might wish. Firstly, there is debate about what constitutes a low blood glucose level, with glucose cut-off levels varying between 2.8 mmol/L and 3.9 mmol/L. Secondly, the symptoms of hypoglycaemia are manifold and most are unspecific, i.e. they may occur for other reasons as well. Moreover, not all patients will experience symptoms when having low glucose levels; this is particularly true for those suffering from hypoglycaemia the most. Finally, this definition does not give any indication of the severity of the hypoglycaemic event experienced which may range from unnoticeable through annoying to disabling and even lethal.

Symptoms of hypoglycaemia

While symptoms may vary between individuals, within one patient the symptoms are often remarkably consistent. Two broad categories of symptoms can be discerned:

  • Autonomic symptoms are the result of sympathetic neural activation, which also stimulates the release of counterregulatory hormones, including adrenaline. These effects occur in synchrony, but are not causally related, although adrenaline may augment the magnitude of (some of) the symptom responses. In fact, adrenaline infusion in the absence of hypoglycaemia has very little impact on symptom generation, whereas hypoglycaemic awareness can be completely normal in the absence of adrenaline responses, such as after bilateral adrenalectomy [1]or in patients with complete adrenomedullary failure (e.g. congenital adrenal hyperplasia)[2]. Classical symptoms include palpitations, sweating and trembling.
  • Neuroglycopenic symptoms hallmark the brain dysfunction that results from insufficient fuel. These include visual disturbances, concentrations disorders and character changes (e.g. moodiness).

Classification of hypoglycaemia

Hypoglycaemia can be subdivided along various lines:

  • The first subdivision is between mild hypoglycaemia, which can be self-treated by the patient, and severe hypoglycaemia, which is defined by the need for assistance from another person (third-party assistance) or the need for medical assistance. It must be noted that the term mild is deceptive, as patients may seriously suffer from hypoglycaemia; for this reason some people prefer the term non-severe hypoglycaemia.
  • Hypoglycaemia can also be classified as symptomatic hypoglycaemia or asymptomatic hypoglycaemia.
  • Finally, a division between biochemically confirmed hypoglycaemia and unconfirmed hypoglycaemia can be made. The latter can be caused by a failure to test, and therefore does not exclude hypoglycaemia (in fact, many cases of severe hypoglycaemia remain unconfirmed because the focus of those giving assistance is on treating rather than diagnosing hypoglycaemia). When the patient suffers from symptoms consistent with hypoglycaemia despite a glucose level that is in the normoglycaemic range this is sometimes called relative hypoglycaemia.

Epidemiology of hypoglycaemia

While some patients never experience any hypoglycaemia, others will suffer from frequent hypoglycaemia and/or repeated severe hypoglycaemia. Individual circumstances , such as medication adherence and exercise levels, can highly affect hypoglycaemia risk and in studies it is frequently found that the majority of episodes occurs in a small minority of patients. However, some broad generalisations can be made about the epidemiology of hypoglycaemia. Those with type 1 diabetes, who use intensive insulin therapy regimens, have a far higher risk for hypoglycaemia than those with type 2 diabetes; some of the therapies used in type 2 diabetes, such as metformin, carry no risk for hypoglycaemia at all.


  1. ^ DeRosa MA, Cryer PE: Hypoglycemia and the sympathoadrenal neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. Am J Physiol Endocrinol Metab 2004;E32-41

  2. ^ Engwerda et al.: Hormonal counter-regulatory failure and severe hypoglycemia in a patient with type 1 diabetes and congenital adrenal hyperplasia. Diabetic Hypoglycemia October 2012; 5(3):9-12.


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