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Causes of Hypoglycemia

Causes of hypoglycemia can broadly be classified as reactive or fasting, insulin-mediated or non-insulin-mediated, and drug-induced or non drug-induced (Merck 2012).

Drug-Induced Hypoglycemia

Iatrogenic (treatment-related) hypoglycemia. Hypoglycemia is most commonly associated with the treatment of diabetes, either with insulin or oral drugs that reduce blood sugar levels (Merck 2006; Cryer 2009). This is known as “iatrogenic hypoglycemia,” meaning it occurs as an adverse effect of treatment. In addition to glucose-lowering drugs, other drugs such as pentamidine (Nebupent®) or quinine may cause hypoglycemia (Merck 2006).

Insulin injections, which are the staple treatment for type 1 diabetes and are also used in type 2 diabetes, contribute to hypoglycemia directly by causing glucose disposal into peripheral tissues such as fat and skeletal muscle.

Several reviews of published studies reveal that attempts to aggressively lower blood glucose levels with intensive insulin therapy are associated with a 2-2.5-fold higher risk of severe hypoglycemia (Bloomfield 2012). One study found that the incidence of severe hypoglycemia was 3-fold higher among type 2 diabetic patients receiving insulin compared to those not receiving insulin (Samann 2012). The severity of this is evidenced by the ACCORD trial, wherein type 2 diabetics assigned to the intensive glucose-lowering treatment group experienced significantly more hypoglycemia and an increase in all-cause mortality (Gerstein 2008). In fact, for the group receiving the intensive treatment approach, the clinical trial was stopped after a 3.4-year follow-up period because the investigators noted a 22% higher all-cause mortality (Riddle 2010).

Another type of drug often used to treat type 2 diabetes, sulfonylureas, are well-known causes of hypoglycemia (Holstein 2010). These drugs work by increasing pancreatic insulin secretion without regards to glucose level. Although the risk of hypoglycemia associated with sulfonylurea drugs is well known, studies suggest that this risk may be underappreciated, especially in patients who are older or have reduced kidney function (Holstein 2010). Metformin, an anti-diabetic drug that works by suppressing gluconeogenesis, is effective at controlling glucose levels in type 2 diabetic patients and has been shown to be far less likely to cause hypoglycemia. In fact, one study involving more than 50 000 subjects showed that the risk for developing hypoglycemia was 179% greater among diabetics receiving sulfonylureas compared to those taking metformin (Bodmer 2008).

Antibiotics. Certain antibiotics are known to cause hypoglycemia. For example, the fluoroquinolone levofloxacin (Levaquin®) enhances insulin secretion by a mechanism similar to sulfonylureas and induces hypoglycemia, which sometimes may be life-threatening (Kelesidis 2009). Hypoglycemia has also been observed after the administration of norfloxacin (Noroxin®), another fluoroquinolone drug (Mishra 2012).

Non Drug-Induced Hypoglycemia

Reactive hypoglycemia. Reactive hypoglycemia occurs after eating, usually 2-5 hours after food intake, and is caused by insulin hypersecretion (McCool 1977; Hofeldt 1989; Altuntas 2005; Meier 2006; Bell 1985). This form of hypoglycemia is also more prevalent in people who have undergone Roux-en-Y gastric bypass surgery; it was reported to occur as a late complication in about 72% of the patients who underwent gastric bypass surgery (Meier 2006; Mingrone 2012). This is thought to occur, at least in part, as a result of nesidioblastosis, excessive function of the cells of the pancreas that produce insulin (Rabiee 2011).

Reactive hypoglycemia may also occur in people who have not had gastric bypass surgery (Mayo Clinic 2012a). In some cases, individuals have symptoms similar to reactive hypoglycemia without the corresponding low blood sugar levels. Nevertheless, these patients often reduce their risk of this condition by avoiding rapidly-absorbed carbohydrates and eating a high-fiber diet with moderate amounts of quality protein and fat (eg, omega-3 fatty acids) (Gaby 2011; Bell 1985). Reactive hypoglycemia is more common in overweight and obese individuals, people that are insulin-resistant as well as those with a family history of type 2 diabetes (Hamdy 2013).

Glucagon deficiency. Glucagon deficiency can cause hypoglycemia, and together with other hormones such as epinephrine, glucagon represents a primary defense against hypoglycemia (Hussain 2005).

One of the challenges in treating iatrogenic hypoglycemia is that in some diabetic patients with more pronounced damage to the pancreas, their glucagon response to hypoglycemia is defective, which can make their hypoglycemic episodes more severe and prolonged (Cryer 1983; Cryer 2009; Taborsky 2012).

Addison’s disease. Cortisol is an anti-inflammatory hormone produced by the adrenal glands that also helps sustain glucose levels. Addison’s disease is a condition of adrenal insufficiency wherein the production of cortisol is impaired (MedlinePlus 2011). Addison’s patients often develop hypoglycemia, among other symptoms (Meyer 2012).  

Fasting-induced hypoglycemia. Fasting-induced hypoglycemia is usually associated with either an insulin-secreting tumor, known as insulinoma, or with genetic mutations. Alternatively, excess alcohol consumption after a period of fasting could also trigger a bout of hypoglycemia. This is because alcohol cannot be excreted from the body as is, but it first needs to be metabolized in the liver (Berg 2002). Alcohol metabolism prevents the production of pyruvate, which is an important building block of gluconeogenesis (Berg 2002; Devenyi 1982; Watford 2006). Alcohol alone does not necessarily cause hypoglycemia, but it does when combined with the additional insult of fasting-induced depletion of liver glycogen reserves. Something similar is seen when fasting and alcohol ingestion are combined with sulfonylureas, drugs which enhance the secretion of insulin. In elderly individuals with type 2 diabetes, even a small amount of alcohol during a short-term fast were shown to lower blood glucose levels. In this case, the effect is compounded by sulfonylureas (Burge 1999).

Polycystic ovary syndrome (PCOS). PCOS is associated with obesity and an exaggerated insulin response, and reactive hypoglycemia is significantly more prevalent in PCOS sufferers than the general population (Kasim-Karakas 2007). 

Congenital/genetic causes. Fasting-induced hypoglycemia is associated with a number of congenital disorders, many of which are diagnosed in childhood and persist in adulthood. Some examples of conditions in this group are glycogen storage or fatty acid metabolism diseases and gluconeogenesis disorders (Douillard 2012). 

Exercise-induced hypoglycemia. Exercise-induced hypoglycemia may be caused by pyruvate-related mutations that result in a massive insulin hypersecretion in response to anaerobic exercise (Meissner 2005). It causes hypoglycemia specifically during anaerobic exercise because pyruvate in the blood is increased by the high intensity activity. Another cause of exercise-induced hypoglycemia is hypoglycemia-associated autonomic failure (HAAF), which may be mediated by an exaggerated endorphin response to exercise.

Other Causes

Additional causes of hypoglycemia include (Toth 2013):

  • Advanced liver or kidney disease
  • Autoimmune disease
  • Sepsis
  • Hypopituitarism