Whipple triad is defined as symptomatic hypoglycemia, biochemically confirmed hypoglycemia (plasma glucose <55 mg/dl), and reversal of hypoglycemic symptomatology after correction of hypoglycemia.
Introduction
The classic Whipple triad was first described by Allen Oldfather Whipple in a paper titled “the surgical therapy of hyperinsulinism” in 1938. Neuroglycopenic symptoms of hypoglycemia include confusion, unusual behavior, seizures and visual changes. The sympathoadrenal symptoms of hypoglycemia are tremulousness, diaphoresis and palpitations.
What are the elements of Whipple’s triad?
The triad described in patients with true hypoglycemia is termed the Whipple triad and is primarily composed of (1) hypoglycemia symptoms, (2) hypoglycemia (blood glucose levels < 55 mg / dL), and (3) relief of symptoms after ingesting glucose).
Working definitions of hypoglycemia
Severe hypoglycemia : Symptoms of hypoglycemia requiring assistance from another person (in the form of a glucose load, glucagon or other resuscitative actions).
Symptomatic hypoglycemia : Typical symptoms of hypoglycemia with a measured plasma glucose of less than 70mg/dl (3.9 mmol/l).
Asymptomatic hypoglycemia : Measured plasma glucose of less than 70mg/dl (3.9mmol/l) in the absence of the typical symptoms of hypoglycemia.
Relative hypoglycemia : Typical symptoms of hypoglycemia with a measured plasma glucose greater than 70mg/dl (3.9 mmol/l)
The Clinical Problem of Hypoglycemia in Diabetes
Hypoglycemia is a critical challenge in diabetes management, particularly when caused by treatment itself, known as iatrogenic hypoglycemia. While achieving optimal glycemic control is essential for reducing complications, hypoglycemia remains a major barrier, particularly in individuals treated with insulin or insulin secretagogues.
Glycemic Control and Its Importance
Glycemic control plays a crucial role in managing diabetes. Maintaining near-normal blood glucose levels helps reduce microvascular complications such as retinopathy, nephropathy, and neuropathy in both type 1 (T1DM) and type 2 diabetes (T2DM). Studies also suggest that early glycemic control may lower the risk of macrovascular complications, emphasizing the need for safe, long-term normoglycemia to optimize patient outcomes.
Iatrogenic Hypoglycemia: The Limiting Factor
Despite the benefits of glycemic control, iatrogenic hypoglycemia often limits its achievement. Typically caused by insulin or insulin secretagogues, hypoglycemia is a recurrent problem for most individuals with T1DM and many with advanced T2DM. It can lead to a vicious cycle of recurrent episodes, impair defenses against future glucose drops, and sometimes result in fatal outcomes. This challenge underscores the difficulty of maintaining euglycemia while minimizing hypoglycemia’s risks.
Hypoglycemia in Type 1 and Type 2 Diabetes
In T1DM, nearly all individuals experience hypoglycemia, including frequent asymptomatic episodes that undermine the body’s defenses against future events. On average, these patients experience two symptomatic episodes weekly and one severe episode annually, which can result in functional brain impairment or, in extreme cases, death. Hypoglycemia may also cause cardiac arrhythmias, increase blood clotting, and exacerbate cardiovascular risks, contributing to mortality rates of up to 10% in some populations.
In T2DM, hypoglycemia is less frequent but still significant due to the larger number of affected individuals. As T2DM progresses and insulin therapy becomes necessary, the incidence of hypoglycemia increases, approaching levels seen in T1DM. While insulin sensitizers like metformin and GLP-1 receptor agonists rarely cause hypoglycemia on their own, they may increase risk when combined with insulin or insulin secretagogues.
Defining and Classifying Hypoglycemia
The American Diabetes Association and International Hypoglycemia Study Group classify hypoglycemia into three levels:
- Level 1 (Hypoglycemia Alert): Blood glucose ≤70 mg/dL (3.9 mmol/L), requiring immediate carbohydrate intake or medication adjustment.
- Level 2 (Clinically Significant): Blood glucose <54 mg/dL (3.0 mmol/L), indicating serious hypoglycemia.
- Level 3 (Severe Hypoglycemia): Associated with severe cognitive impairment, requiring external assistance for recovery.
Complications of Hypoglycemia
Severe hypoglycemia is associated with increased mortality, particularly in individuals undergoing aggressive glucose-lowering therapies. It can cause cardiovascular complications such as myocardial ischemia, arrhythmias, and pro-coagulant states, along with oxidative stress and inflammation. Hypoglycemia is also linked to cognitive decline, particularly in older individuals with T2DM, though this association is less pronounced in younger T1DM patients. Beyond physiological effects, hypoglycemia significantly impacts quality of life, leading to anxiety, depression, and fear of future episodes.
Glucose Counterregulation and Its Impairment in Diabetes
In healthy individuals, the body has several defenses against falling blood glucose levels, including reduced insulin secretion, increased glucagon and epinephrine release, and behavioral responses such as carbohydrate intake. However, in diabetes, these defenses are often impaired. In T1DM, β-cell failure leads to a loss of insulin and glucagon regulation. Additionally, the epinephrine response may be blunted, causing hypoglycemia unawareness and increasing the risk of recurrent episodes.
Risk Factors for Hypoglycemia
Risk factors include excessive insulin dosing, missed meals, increased glucose utilization (e.g., after exercise), or reduced glucose production (e.g., due to alcohol consumption or liver dysfunction). Another critical factor is Hypoglycemia-Associated Autonomic Failure (HAAF), a condition in which recurrent hypoglycemia diminishes the body’s ability to counteract low blood sugar levels, creating a cycle of recurring events.
Preventing Hypoglycemia in Diabetes
Preventing hypoglycemia involves several steps:
- Acknowledge the Problem: Healthcare providers should regularly discuss hypoglycemia risks with patients and review glucose monitoring data.
- Evaluate Risk Factors: Both conventional factors, such as insulin dosing, and HAAF-specific risks should be assessed.
- Apply Intensive Glycemic Therapy: Individualized treatment plans, including modern insulin regimens and glucose-monitoring technologies, can help balance glycemic goals with hypoglycemia prevention.
Structured patient education is essential, teaching individuals to recognize symptoms, adjust their treatment, and respond effectively to hypoglycemia. Short-term avoidance of hypoglycemia may also help restore awareness in patients with hypoglycemia unawareness.
Treating Hypoglycemia
Most mild to moderate hypoglycemic episodes can be self-treated with fast-acting carbohydrates, such as glucose tablets or juice, followed by a meal or snack to maintain stable glucose levels. Severe hypoglycemia requires external assistance, often with glucagon injections or intravenous glucose in medical settings. Recent advances, such as nasal glucagon and long-lasting glucagon formulations, provide more accessible treatment options.
Pathophysiology
The brain needs glucose as fuel under normal physiological conditions. For the proper functioning of the brain, plasma glucose should remain in an essentially normal range. Several counterregulatory measures to prevent or treat hypoglycemia are at play under normal conditions.
The main protections against hypoglycemia are: 1) Decrease in insulin secretions, 2) Increased glucagon levels 3) Increased epinephrine production and finally an 4) increase in cortisol. In case of failure of such measures, the plasma glucose level is likely to decrease further.
Physiological responses to hypoglycemia
Under normal physiological conditions, there is a balance between glucose utilization and glucose production. When glucose utilization exceeds glucose production, hypoglycemia occurs.
Glucose utilization can be attributed largely to the brain, obligatory glycolytic tissues such as the renal medulla, red blood cells and skeletal muscle. Conversely, the sources of glucose production include oral carbohydrate intake, kidney and the liver. The physiological responses to hypoglycemia can be grouped into four critical stages.
- Stage I : A decrease in insulin production by beta cells of the pancreas.
- Stage II : An increase in glucagon production by alpha cells of the pancreas
- Stage III : An increase in epinephrine production by the adrenal cortex just when glucose declines below the physiological range
- Stage IV : An increase in cortisol and growth hormone production after a period of sustained hypoglycemia.
It is worth noting that behavioral responses to hypoglycemia (extreme hunger) typically occur at a plasma glucose concentration at or below the 55mg/dl (3.0 mmol/l) threshold.
A significant reduction in insulin production occurs at this threshold (Stage I). Plasma insulin levels fall below 3u/ml (18 pmol/L), C-peptide below 0.6ng/ml (0.2 nmol/liter) and proinsulin levels below 5.0 pmol/L.
Causes of hypoglycemia in adults
Medications
- Insulin
- Insulin secretagogues (sulfonylureas, meglitinides)
- Alcohol
- Quinine
- Artesunate/artemisinin/artemether (anti-malarial agents)
Acute critical illness
- Organ failure (hepatic, cardiac or renal)
- Severe septicemia
Loss of counter-regulatory hormone production
- Cortisol (adrenal insufficiency)
- Glucagon and epinephrine (type 1 diabetes mellitus)
Endogenous hyperinsulinemia
- Insulinoma
- Nesidioblastosis also known as functional beta cell disorders. These include post gastric bypass hypoglycemia and noninsulinoma pancreatogenous hypoglycemia.
- Autoimmune insulin-mediated hypoglycemia (antibody to insulin or the insulin receptor)
- Insulin secretagogue
Exogenous insulin
- Malicious intent of patients, accidental or surreptitious exposure.
Diagnosis of hyperinsulinemic hypoglycemia
All of the following criteria should be fulfilled prior to the diagnosis of hyperinsulinemic hypoglycemia.
- Fulfillment of Whipple’s triad
- Elevated plasma insulin level of (> 3 μU/ml) and C-peptide (> 0.6 ng/ml)
- Negative sulfonylurea screen
Whipple triad versus the Warburg effect
| Whipple triad | Warburg effect |
| A diagnosis of true hypoglycemia with a plasma glucose <55mg/dl, hypoglycemic symptoms compatible with neuroglycopenia that are ameliorated by a carbohydrate load or glucagon. | A diagnosis of spontaneous asymptomatic hypoglycemia in nondiabetic patients which occurs as a result of avid glucose consumption by a solid tumor. The reliance of the brain on lactate (produced through the fermentation of glucose) results in an absence of the classic symptoms of hypoglycemia. |
References
- Liberti, Maria V, and Jason W Locasale. “The Warburg Effect: How Does it Benefit Cancer Cells?.” Trends in biochemical sciences vol. 41,3 (2016): 211-218.
- Goyal I, Ogbuah C, Chaudhuri A, Quinn T, Sharma R. Confirmed Hypoglycemia Without Whipple Triad: A Rare Case of Hyper-Warburgism. J Endocr Soc. 2020 Nov 21;5(1):bvaa182.
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