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Article Author:
Philip Mathew
Article Editor:
Deepu Thoppil
11/21/2020 2:12:13 PM
For CME on this topic:
Hypoglycemia CME
PubMed Link:


Hypoglycemia is often defined by a plasma glucose concentration below 70 mg/dL; however, signs and symptoms may not occur until plasma glucose concentrations drop below 55 mg/dL. The symptoms of Whipple's triad have been used to describe hypoglycemia since 1938.  For Whipple's triad, the practitioner must first recognize symptoms of hypoglycemia, then obtain low blood glucose, and finally, demonstrate immediate relief of symptoms by the correction of the low blood glucose.  Glucose is the primary metabolic fuel for the brain under physiologic conditions. Unlike other tissues of the body, the brain is very limited in supplying its glucose. Expectedly, the brain requires a steady supply of arterial glucose for adequate metabolic function. Potential complications can arise from an interruption in the glucose supply. As such, protective mechanisms to guard against low serum blood glucose (hypoglycemia) have evolved in the body. 

During fasting states, serum glucose levels are maintained via gluconeogenesis and glycogenolysis in the liver. Gluconeogenesis is the pathway in which glucose is generated from non-carbohydrate sources.  These non-carbohydrate sources could be protein, lipids, pyruvate or lactate. In contrast, glycogenolysis is the breakdown of glycogen into glucose product. Much of glycogenolysis occurs in hepatocytes (liver) and myocytes (muscle).

Hypoglycemia is most often seen in patients suffering from diabetes who are undergoing pharmacologic intervention. Amongst this group, patients with type 1 diabetes are 3 times as likely to experience hypoglycemia as compared to patients with type 2 diabetes when receiving treatment.


In patients who do not have diabetes, hypoglycemia is uncommon, but when it occurs, there are a few major causes of hypoglycemia: pharmacologic, alcohol, critical illness, counter-regulatory hormone deficiencies, and non-islet cell tumors.

Most cases of hypoglycemia occur in diabetic patients who are undergoing therapeutic intervention with meglitinides, sulfonylureas, or insulin. Drugs are the most common cause of hypoglycemia.[1] Metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter 2 inhibitors (SGLT-2), and dipeptidyl peptidase-4 (DPP-4) inhibitor use does not lead to hypoglycemia.

Non-diabetic patients with intact hepatic function will rarely experience fasting hypoglycemia because of preventative counter-regulatory measures. Episode of true hypoglycemia in a non-diabetic patient is likely due to iatrogenic causes such as the surreptitious use of insulin. Other potential causes of hypoglycemia are critical illness, alcohol, cortisol deficiency, or malnourishment.

Alcohol inhibits gluconeogenesis in the body, but does not affect glycogenolysis. Thus, hypoglycemia occurs after several days of alcohol consumption and after glycogen stores are depleted.

In critical illness states, for example, end-stage liver disease, sepsis, starvation, or renal failure, glucose utilization exceeds glucose intake, glycogenolysis and/or gluconeogenesis. The result of this imbalance is hypoglycemia. Counter-regulatory hormone deficiencies can occur as in states of adrenal insufficiency. Hypoglycemia associated with such deficiencies are rare. Non-islet cell tumors may also be a cause of hypoglycemia through increased secretion of insulin-like growth factor 2 (IGF-2).[2] IGF-2 increases glucose utilization, which can lead to hypoglycemia.

Insulinomas are hyperfunctioning islet cell tumors associated with increased insulin secretion. They can be life-threatening and primarily manifest with postprandial hypoglycemia. Although these tumors are rare, MEN1 should be a consideration in the workup of suspected cases.


Hypoglycemia is common with type 1 diabetes, particularly in those patients receiving intensive insulin therapy. Severe hypoglycemic events have been reported to be anywhere between 62 to 320 episodes per 100 patient-years in type 1 diabetes.[3] As opposed to patients who have type I diabetes and require insulin therapy exclusively, patients with type II diabetes experience hypoglycemia relatively less frequently compared to patients with type I diabetes. This can be due, in part, to pharmacotherapies that do not induce hypoglycemia like metformin. The incidence of hypoglycemia in patients with type II diabetes has been reported to be approximately 35 episodes for 100 patient-years.[4] There are no reported disparities in incidents based on gender.


The body has inherent counter-regulatory mechanisms to prevent hypoglycemic episodes. All of these counter-regulatory mechanisms include an interplay of hormones and neural signals to regulate the release of endogenous insulin, to increase hepatic glucose output, and to alter peripheral glucose utilization. Among the counter-regulatory mechanisms, the regulation of insulin production plays a major role.  Decreases in insulin production as a response to low serum glucose is the bodies first line of defense against hypoglycemia. For endogenous glucose production to take place, particularly hepatic glycogenolysis, low insulin levels are necessary. As plasma glucose levels decline, beta cell secretion of insulin also decreases, thus leading to increased hepatic/renal gluconeogenesis and hepatic glycogenolysis. Glycogenolysis maintains serum glucose levels over 8 to 12 hours until glycogen stores are depleted. Over time, hepatic gluconeogenesis contributes more to maintaining euglycemia when required.

The decrease in insulin production occurs while the glucose level is in the low-normal range. This serves as a distinctive feature compared to other counter-regulatory measures. Additional counter-regulatory measures typically occur once the serum glucose levels decrease beyond physiologic range. Among the additional counter-regulatory mechanisms, pancreatic alpha cell secretion of glucagon is the next line of defense against hypoglycemia. Should increased glucagon fail to achieve euglycemia, adrenomedullary epinephrine is secreted [5]. All three counter-regulatory measures occur in the acute stage of hypoglycemia.

The previously mentioned counter-regulatory mechanisms may fail to resolve the hypoglycemia. Further counter-regulatory measures are employed in the form of growth hormone and cortisol. Both the release of growth hormone and cortisol are seen in prolonged hypoglycemic states.

History and Physical

The clinical manifestations of hypoglycemia can be classified as either neuroglycopenic or neurogenic. Neuroglycopenic signs and symptoms are signs and symptoms that result from direct central nervous system (CNS) deprivation of glucose. These include behavioral changes, confusion, fatigue, seizure, coma, and potential death if not immediately corrected. Neurogenic signs and symptoms can either be adrenergic (tremor, palpitations, anxiety) or cholinergic (hunger, diaphoresis, paresthesias). Neurogenic symptoms and signs arise from sympathoadrenal involvement (either norepinephrine or acetylcholine release) in response to perceived hypoglycemia. 

A detailed history is essential in evaluating hypoglycemia. Pertinent issues that should be addressed while taking a patient's history include 

  • A detailed medication history
  • History of alcohol and/or drug use
  • History of psychiatric disorders
  • Personal or family history of diabetes mellitus or multiple endocrine neoplasia syndromes (MEN)
  • Unintentional weight changes
  • Changes in medication
  • Consideration of acute kidney injury or renal failure
  • Symptoms of other hormone deficiencies.
  • It is also important to note the context of the hypoglycemic episode relative to meals or exercise.

There is no agreed-upon lab value that defines hypoglycemia. Hypoglycemia is said to be present when the patient has symptoms consistent with hypoglycemia in addition to a low serum glucose measurement (less than  70 mg/dL). This perspective reflects the idea that hypoglycemia is a clinical presentation coupled with a lab finding of low serum glucose rather than a pure chemistry finding. Typically neurogenic and neuroglycopenic symptoms of hypoglycemia occur at a glucose level of or below 50 to 55 mg/dL, but this threshold can vary from individual to individual.

Patients who have diabetes can present with symptoms of hypoglycemia at relatively higher serum glucose levels. The chronic hyperglycemia alters the "set point" in which neuroglycopenic/neurogenic symptoms become apparent. This phenomenon is referred to as "pseudohypoglycemia" because the serum glucose may be within normal range despite symptom presentation.


As previously mentioned, documentation of Whipple’s triad is a potential indicator of hypoglycemia, and any initial laboratory evaluation should confirm hypoglycemia. Other pertinent labs to consider include insulin, proinsulin, and C-peptide levels during any episode of suspected hypoglycemia. If C-peptide levels are low in the presence of high insulin levels, the patient has received exogenous insulin. The pro-form of insulin created within the body is attached to C peptide. The body then cleaves C peptide from the pro form of the molecule to create active insulin. Elevated C-peptide levels and insulin levels can be seen with secretagogue agents such as sulfonylureas or insulin secretagogues since both classes of agents stimulate endogenous insulin secretion.

Once the use of exogenous insulin administration is ruled out, sources of endogenous hyperinsulinemia need to be considered. Localization is usually performed via abdominal computed tomography (CT) with MRI.

Treatment / Management

Identification of a hypoglycemic patient is critical due to potential adverse effects including coma and/or death. Severe hypoglycemia can be treated with intravenous (IV) dextrose followed by infusion of glucose. For conscious patients able to take oral (PO) medications, readily absorbable carbohydrate sources (such as fruit juice) should be given. For patients unable to take oral agents, a 1-mg intramuscular (IM) injection of glucagon can be administered. Once the patient is more awake, a complex carbohydrate food source should be given to the patient to achieve sustained euglycemia. More frequent blood glucose monitoring should occur to rule out further drops in blood sugar.

Nonpharmacological management of recurrent hypoglycemia involves patient education and lifestyle changes. Some patients are unaware of the serious ramifications of persistent hypoglycemia. As such, patients should be educated on the importance of routine blood glucose monitoring as well as on the identification of the individual's symptoms of hypoglycemia.  If lifestyle changes are not effective in preventing further episodes, then pharmacologic intervention should be modified. Patients should be advised to wear a medical alert bracelet and to carry a glucose source like gel, candy or tablets on their person in case symptoms arise. In the outpatient setting, reviewing blood sugar logs as well as food logs may be helpful in identifying problem areas for the patient.

Glycemic control has been an important aspect of medical management due to the association between glycated hemoglobin levels and cardiovascular events in diabetes mellitus type 2 patients. In the 2008 ACCORD trial, it was determined that intensive therapy (defined as a goal hemoglobin A1C less than 6.0%) did not significantly reduce major cardiovascular events and was associated with increased mortality and risk for hypoglycemia.[6] It should be noted, however, that the intensive therapy group had proportionally more participants using rosiglitazone compared to the standard therapy group (91.2% versus 57.5%), thus possibly contributing to an increased incidence of cardiovascular events in the intensive therapy group.

The 2009 VADT study additionally studied the effect of intensive blood glucose control in a sample of 1791 veterans with poorly controlled diabetes mellitus type 2. More rigid glycemic control did not appear to have a significant effect on cardiovascular outcomes, although it did improve microalbuminuria compared to the standard therapy arm.[7]  The results, however, cannot be extrapolated to females since 97% of the study participants were male. Besides, there was a significant dropout (approximately 15%), limiting statistical power.

Regarding endogenous sources of insulin, insulinomas are often managed surgically. Evidence of an insulinoma should prompt workup or investigative effort into potential multiple endocrine neoplasia (MEN) disorders.

Differential Diagnosis

If hypoglycemia is confirmed, the focus should be on correcting the hypoglycemia and identifying an underlying cause. In the workup of hypoglycemia, history should include medication and dietary adherence, changes in medication, suspicion for acute kidney injury or intentional/unintentional over the administration of medications.


Complications of untreated hypoglycemia can lead to serious neurologic consequences, the most serious being death.


Most cases of hypoglycemia can be managed conservatively. Recurrent episodes of hypoglycemia with no apparent or obvious cause may warrant specialty consultation with an endocrinologist. Consultation with a diabetic educator may also be beneficial for the long-term management of diabetes and hypoglycemia.

Deterrence and Patient Education

Patient education remains a pivotal component in the prevention of hypoglycemic episodes. Focus on preventing hypoglycemia should include patient education on signs and symptoms that constitute hypoglycemia and early recognition of these signs and symptoms.

Pearls and Other Issues

Hypoglycemia in non-diabetic patients is uncommon.  When it does occur, a critical illness, sustained alcohol use, malnutrition, and exogenous medications should be considered. Tumors may be a cause of hypoglycemia but are rare.

Hypoglycemia is relatively common in neonates, particularly in mothers with uncontrolled diabetes. A 2017 study performed in Israel showed that 559 neonates out of 3595 neonates were observed to have a glucose level of less than 47 mg/dL.[8] Gestational glucose intolerance in the mother is usually attributed to the presence of human placental lactogen. Pregnant women with impaired glucose tolerance not responsive to diet or exercise can be started on insulin. Insulin does not cross the placenta although the fetus will be exposed to maternal hyperglycemia. Since the fetal pancreatic islet cells produce insulin starting at 10 weeks gestation, the fetal pancreas is capable of responding to hyperglycemia. Upon delivery, the newborn pancreas continues to secrete insulin although maternal hyperglycemia is withdrawn. Subsequently, the neonate’s glucose will decrease, resulting in an insulin-glucose imbalance and hypoglycemia.

Enhancing Healthcare Team Outcomes

An interprofessional approach to hypoglycemia is recommended.

Adequate measures to minimize hypoglycemic events involve participation and effective communication between the primary care physicians, physician assistant, nurse practitioner, endocrinologists, diabetes educators, pharmacists, diabetic nurses, the patient's family, and the patient. The cornerstone of this management is the patient.

Patient education should address the importance of relatively detailed documentation regarding blood glucose levels, timing, units of insulin administered, and any pertinent notes such as increased/decreased food intake or exercise relative to blood glucose measurements. Such documentation allows a primary care physician or endocrinologist to make appropriate adjustments to diabetic medication therapy to best optimize blood glucose levels. Stability of blood glucose levels can be obtained with consistent dietary and exercise habits in addition to the appropriate timing of insulin therapy to avoid drastic spikes and dips in blood glucose levels. Hospitalized patients with newly diagnosed diabetes can be taught by the nurse diabetic educator insulin administration and self-injections while in the hospital. The educator should coordinate with the clinician managing the case so that appropriate patient education is achieved prior to discharge. Discussions with the patient and pharmacist will help decide the best medications to achieve safe glycemic control. Group education classes and local event planning can help diabetic patients learn and grow their knowledge between themselves as well as others in the household.

Non-adherence to medication or diet are the most common cause of treatment failure. Patients should monitor for signs or symptoms of hypoglycemia and have sources of glucose (for example, hard candy, fruit juice) immediately available. Developing programs to educate healthcare staff has also shown to provide better outcomes. Teaming up with local pharmacies or grocery stores can help some of the barriers often encountered by diabetic patients.

Patients should be advised to have fairly consistent exercise and dietary habits to avoid drastic spikes and dips in hour-to-hour blood glucose measurements.

With an interprofessional approach to hypoglycemia, outcomes will be optimized leading to better patient quality of life. [Level 5]


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