CLINICAL RECOGNITION

Hypoglycemia is frequently seen in patients treated tor diabetes but is uncommon in people who do not have diabetes. Low blood glucose concentrations lead to both adrenergic and neuroglycopenia symptoms (Table 1). Glucose levels below 55 mg/dl cause adrenergic symptoms while glucose levels below 48-50 mg/dL result in neuroglycopenic symptoms. In individuals with frequent hypoglycemia the adrenergic symptoms of hypoglycemia may be blunted. At times hypoglycemia may present with focal neurological deficits that resolve with increasing the glucose levels.

Symptomatic hypoglycemia is diagnosed clinically using Whipple’s triad: symptoms of hypoglycemia, plasma glucose concentration <55 mg/dL (3.0 mmol/L), and resolution of those symptoms after the plasma glucose concentration is raised. Capillary blood glucose measurements and continuous glucose monitors (CGM) should not be used in the diagnosis of hypoglycemia due to poor accuracy when blood glucose levels are low. However, capillary blood glucose levels or CGM may be helpful in understanding the pattern of hypoglycemic episodes and whether there are triggering factors.

DIFFERENTIAL DIAGNOSIS

Hypoglycemia in patients with diabetes is typically the result of treatments that raise insulin levels (insulin administration, sulfonylureas, and meglitinides) thereby lowering plasma glucose levels. In adults not taking glucose-lowering drugs to treat diabetes a variety of disorders should be considered (Table 2). Additionally, a number of drugs may cause hypoglycemia (Table 3). Ingestion of unripe ackee fruit can also cause hypoglycemia. The timing of hypoglycemia (relationship to food ingestion, physical activities, day versus nocturnal time) and severity (frequency, presence of neuroglycopenia, and requiring assistance to treat), are critical in the differential diagnosis. A history of nutritional status, current medication/supplement use, and concurrent multisystem illnesses such as liver, heart, kidney failure, or sepsis, as well as a thorough physical exam and laboratory data, can point to existing primary conditions that predispose to hypoglycemia.

An approach for the evaluation of hypoglycemia in healthy appearing patients is shown in figure 1.

Figure 1.

Evaluation of non-diabetic hypoglycemia in healthy appearing adults. From Endotext chapter entitled “Non-Diabetic Hypoglycemia”.

PATHOPHYSIOLOGY

Glucose is an obligatory fuel for the brain under physiologic conditions. In order to maintain proper brain function, plasma glucose must be maintained within a relatively narrow range. Redundant counter-regulatory mechanisms are in place to prevent or correct hypoglycemia. As glucose levels decline, major defenses include: 1) a decrease in insulin secretion; 2) an increase in glucagon secretion; 3) an increase in epinephrine secretion. Increased cortisol and growth hormone secretion also occur. If these defenses fail, plasma glucose levels will continue to fall. Symptoms, prompting food ingestion, typically develop at a plasma glucose of 55 mg/dl (3.0 mmol/liter). At glucose levels of 55 mg/dl and lower, insulin secretion is normally almost completely suppressed. In longstanding type 1 and type 2 diabetes these counter-regulatory responses to hypoglycemia are impaired. This increases the risk of hypoglycemia and contributes to hypoglycemia unawareness.

DIAGNOSTIC TESTS

To confirm the diagnosis and explore etiology, it is necessary to collect blood samples during hypoglycemia, whether it occurs spontaneously or by provoked testing that can be selected based on clues from the medical history. One should measure plasma glucose, insulin, c-peptide, proinsulin, and beta-hydroxybutyrate concentrations and screen for oral hypoglycemic agents (sulfonylurea and meglitinide drugs) during an episode of spontaneous hypoglycemia. Glucagon, 1 mg IV, should then be administered, with a rise in glucose >25 mg/dl (1.4 mmol/L) suggesting hyperinsulinemic hypoglycemia. The diagnosis of insulinoma is supported if insulin, c-peptide and proinsulin levels are elevated, beta-hydroxybutyrate is <2.7 mmol/l, and sulfonylurea/meglitinide levels are undetectable during the hypoglycemic episode (Table 4).

If testing cannot be performed during a spontaneous episode of hypoglycemia, a 72 h fast or a mixed meal test, performed in a monitored setting, followed by administration of glucagon are the most useful diagnostic strategies.

During a 72 hour fast, patients are allowed no food but can consume non-caloric caffeine-free beverages. Insulin, c-peptide, and glucose samples are obtained at the beginning of the fast and every 4-6 hours. When the plasma glucose falls to <60 mg/dl, specimens should be taken every 1-2 hours under close supervision. Patients should continue activity when they are awake. The fast continues until the plasma glucose falls below 45 mg/dl (2.5 mmol/l) [plasma glucose <55 mg/dl (3.0 mmol/l) is recommended in the Endocrine Society guidelines] and symptoms of neuroglucopenia develop, at which time insulin, glucose, c-peptide, oral insulin secretagogue, proinsulin, and beta-hydroxybutyrate levels are obtained and the fast is terminated. Additional samples for insulin antibodies, anti-insulin receptor antibodies, IGF-1/IGF-2, and plasma cortisol, glucagon, or growth hormone can also be obtained at this time if a non-islet cell tumor,

autoimmune etiology, or hormone deficiency is suspected. Patients are fed at the conclusion of the fast. The results of the fasting test will help to differentiate hypoglycemia mediated by insulin- versus non-insulin factors (Table 4).

For patients with hypoglycemic symptoms several hours after meals, a mixed meal test may be performed. This test has not been well standardized. Patients eat a meal similar to one that provokes their symptoms, or a commercial mixed meal. Samples for plasma glucose, insulin, c-peptide, and proinsulin are collected prior to the meal and every 30 minutes thereafter for 5 hours. If symptoms occur prior to the end of the test then additional samples for the above are collected prior to administration of carbohydrates. If Whipple’s triad is demonstrated, testing for oral hypoglycemic drugs and testing for insulin antibodies should be done. Interpretation of test results is the same as for the 72-hour fast or spontaneous hypoglycemia (Table 4).

In a patient with documented hypoglycemia with laboratory findings consistent with endogenous hyperinsulinism localizing studies should be done to evaluate for insulinoma. These may include computed tomography (CT) or magnetic resonance imaging, transabdominal and endoscopic ultrasonography, and, where available, nuclear medicine scans (Somatostatin receptor scintigraphy SPECT / PET, 18F-DOPA PET, and Glucagon-Like Peptide-1 (Exendin-4) Receptor Imaging SPECT / PET). If the diagnosis remains unclear, selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels can be performed.

TREATMENT

Immediate treatment should be focused on reversing hypoglycemia. If the patient is able to ingest carbohydrates 15-30 grams of glucose should be given every 15 minutes until the hypoglycemia has resolved. If the patient is unable to ingest carbohydrates, or if the hypoglycemic episode is severe then parenteral glucose should be administered. In a healthcare setting intravenous dextrose is used. Twenty-five-gram boluses of 50% dextrose are given until the hypoglycemia has been resolved. If needed, an infusion of 10% or 20% dextrose can be used to sustain euglycemia in patients with recurrent episodes of hypoglycemia. In the outpatient setting, glucagon, given as an intramuscular injection or nasally, may be used to correct hypoglycemia, depending upon the etiology of the hypoglycemia. In patients with recurrent hypoglycemia the availability of ready-to-use glucagon treatments is advantageous. Glucose gel and other forms of oral glucose should be used in impaired patients with caution and only in circumstances where no alternative is available, as they pose an aspiration risk.

Long-term treatment should be tailored to the specific hypoglycemic disorder, taking into account the burden of hypoglycemia on well-being and patient preferences. Offending medications should be discontinued and underlying illnesses treated, whenever possible.

Surgical resection can be curative for insulinomas, and can alleviate hypoglycemia in non-islet cell tumors, even if the malignancy cannot be cured. Partial pancreatectomy can be considered in patients with β-cell disorders. Medical treatment with frequent feedings, α-glucosidase inhibitors, diazoxide, or octreotide can be used if resection is not possible, or as a temporizing measure. New drugs that may be helpful include long-acting somatostatin analogs, mTOR inhibitors, and GLP-1 antagonists. Autoimmune hypoglycemic conditions may be treated with either glucocorticoids or immunosuppressants, but these disorders may be self-limited.

For adults taking insulin or insulin secretagogues for diabetes mellitus risk factors for hypoglycemia, such as advanced age and renal insufficiency, should be considered. The treatment regimen and glycemic goals should be reviewed and adjusted if needed. Patients should be instructed on how to manage hypoglycemia, either by the ingestion of carbohydrates if possible, or by parenteral glucagon or glucose. If the patient has hypoglycemia unawareness, a 2-to 3-week period of strict avoidance of hypoglycemia should be maintained, as hypoglycemia awareness will return in many patients. For individuals with type 1 diabetes and a history of serious hypoglycemia, the use of a personal continuous glucose monitoring device, sensor-augmented insulin pump therapy, or a hybrid closed loop system should be considered.

ACKNOWLEGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

GUIDELINES

1.

Cryer, PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009. [PubMed: 19088155]

2.

McCall AL, Lieb DC, Gianchandani R, MacMaster H, Maynard GA, Murad MH, Seaquist E, Wolfsdorf JI, Wright RF, Wiercioch W. Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2023 Feb 15;108(3):529-562. [PubMed: 36477488]

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