Continuing Education Activity

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 the Whipple triad, the practitioner must first recognize hypoglycemia symptoms, obtain low blood glucose, and finally, demonstrate immediate relief of symptoms by the correction of the low blood glucose after treatment. This activity reviews the evaluation and management of hypoglycemia and highlights the interprofessional team's role in educating patients with this condition about follow up care.

Objectives:

• Describe the pathophysiology of hypoglycemia.
• Explain the diagnostic approach on how to determine that a patient has hypoglycemia.
• Review the management options available for hypoglycemia treatment.
• Summarize the importance of interprofessional team strategies for improving care coordination and communication to aid in prompt diagnosis of hypoglycemia and improving outcomes in patients diagnosed with the condition.

Introduction

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 with glucose treatment. 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 stored into glucose products. Much of glycogenolysis occurs in hepatocytes (liver) and myocytes (muscle).

Hypoglycemia is most often seen in patients who have diabetes that undergoing pharmacologic intervention. Among this group, patients with type 1 diabetes are three times as likely to experience hypoglycemia than patients with type 2 diabetes when receiving treatment.

Etiology

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[1].

Most hypoglycemia cases occur in patients with diabetes who are undergoing therapeutic intervention with meglitinides, sulfonylureas, or insulin. Drugs are the most common cause of hypoglycemia.[2] 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 very infrequently will lead to hypoglycemia.Non-diabetic patients with intact hepatic function will rarely experience fasting hypoglycemia because of preventative counter-regulatory measures. An episode of true hypoglycemia in a non-diabetic patient might be due to iatrogenic causes such as surreptitious insulin use. 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.

For example, in critical illness states, end-stage liver disease, sepsis, starvation, or renal failure, glucose utilization exceeds glucose intake, glycogenolysis, and/or gluconeogenesis. The result of this imbalance is potentially the reason why hypoglycemia may occur. Counter-regulatory hormone deficiencies can occur as in states of adrenal insufficiency. Hypoglycemia associated with such deficiencies is rare. Non-islet cell tumors may also cause hypoglycemia through increased secretion of insulin-like growth factor 2 (IGF-2).[3] 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 fasting morning hypoglycemia. Although these tumors are rare, they should be a consideration in the workup of suspected cases.[4]

Epidemiology

Hypoglycemia is common with type 1 diabetes, particularly in those patients receiving intensive insulin therapy. Severe hypoglycemic events have reportedly been anywhere between 62 to 320 episodes per 100 patient-years in type 1 diabetes.[5] As opposed to patients who have type 1 diabetes and require insulin therapy exclusively, patients with type 2 diabetes experience hypoglycemia relatively less frequently compared to patients with type 1 diabetes. This can be, in part, due to pharmacotherapies that do not induce hypoglycemia like metformin. The incidence of hypoglycemia in patients with type 2 diabetes has been reportedly approximately 35 episodes for 100 patient-years.[6] There are no reported disparities in incidents based on gender.

Pathophysiology

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.  Decrease in insulin production as a response to low serum glucose isn't the body's 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, 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 the 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.[7] All three counter-regulatory measures occur in the acute stage of hypoglycemia.

On occasions the previously mentioned counter-regulatory mechanisms may fail to resolve the hypoglycemia. At this point, 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 state.

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 (including tremors, palpitations, anxiety) or cholinergic (including 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 different hormone deficiencies.
• Timing 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"[8] because the serum glucose may be within normal range despite symptom presentation.

Evaluation

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 cleaves C-peptide from the pro-form of the molecule to create active insulin. Elevated C-peptide levels together with 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) or 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, glucagon should be administered. Glucagon can be given intramusularly, or intranasally with the newest available formulations.[9][10] Once the patient is more awake, a complex carbohydrate food source should be given 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 or necklace and to also carry a glucose source like gel, candy, or tablets on their purse in case symptoms arise. In the outpatient setting, reviewing blood sugar logs and food logs may help identify 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.[11] However, it should be noted 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.[12] However, the results 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 the underlying cause. In the workup of hypoglycemia, history should include medication and dietary adherence, medication changes, suspicion for acute kidney injury, or intentional/unintentional weight changes, especially weight loss.

Prognosis

Severe insulin reactions may be proven fatal, so it is essential to contact EMS immediately when an individual is disoriented or unconscious. The patients with diabetes should also reach out to their clinicians if they begin to experience frequent hypoglycemic episodes, as they may need to have adjustments made to their medication regimen, meal plans, or even their exercise/activity regimen. Non-diabetic individuals who show signs or symptoms of hypoglycemia should contact their clinician to further evaluate their situation. Severe or prolonged hypoglycemia can be life-threatening, and in patients with diabetes, there is a correlation with increased mortality. In non-diabetic individuals experiencing reactive hypoglycemia, the prognosis is good.

Complications

Complications of untreated hypoglycemia can lead to serious neurologic consequences, like seizures, brain damage and even death.

Consultations

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. Patients may also need counseling on meal plans and exercise to manage their condition better.

Pearls and Other Issues

Hypoglycemia in non-diabetic patients is uncommon. When it does occur, a critical illness[13], sustained alcohol use[14], malnutrition, and exogenous medications should be considered. Tumors may be a cause of hypoglycemia but are rare.[15]

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 live births were observed to have a glucose level of less than 47 mg/dL.[16] 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 should 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 interprofessional measures to minimize hypoglycemic events involve participation and effective communication between the primary care physicians, physician assistants, nurse practitioners, endocrinologists, diabetes educators, pharmacists, specialty-trained diabetes nurses, the patient's family, nutritionists and/or dieticians, 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 level relative to blood glucose measurements. Such documentation allows a primary care physician or an endocrinologist to make appropriate adjustments to diabetic medication therapy for optimizing 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 or dips in blood glucose levels. Hospitalized patients with newly diagnosed diabetes can be taught by the nurse diabetic educator how to do the insulin administration and self-injections while in the hospital. The educator should collaborate with the clinician managing the case so that appropriate patient education is achieved before 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 patients with diabetes to learn and grow their knowledge among themselves and other members of the household.

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

Patients should be advised to have fairly consistent exercise and dietary habits to avoid drastic changes 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]