Of the two clinical categories, fasting hypoglycemia is by far the more straightforward. The two chief mechanisms are insulin excess (either absolute or relative) and effects of carbohydrate deprivation. Conditions acting through these mechanisms are the following:

1. The most well-known etiology of insulin excess is the beta-cell insulin-producing pancreatic islet cell tumor (insulinoma). About 80% of these tumors are single adenomas, about 10% are multiple adenomas, and about 10% are carcinomas. About 10% of patients with insulinoma also have the MEN type II syndrome (Chapter 33), and of these patients, about 80% have multiple insulinomas. Although insulinomas typically are associated with fasting hypoglycemia, one study reported that nearly 50% of their insulinoma patients developed symptoms less than 6 hours postprandially, which would clinically suggest a postprandial (reactive) etiology.
2. Overdose of insulin in a diabetic person. Since the patient may be found in coma without any history available, insulin overdose must be a major consideration in any emergency room comatose patient.
3. Hypoglycemia may be associated with deficiency of hormones that normally counteract the hypoglycemic effect of insulin. This group includes pituitary insufficiency (deficiency of growth hormone and cortisol) and adrenal insufficiency (cortisol). Glucagon and thyroxine also have a hyperglycemic effect, but hypoglycemia due to a deficiency of these hormones is rare.
4. Prolonged carbohydrate deprivation, even when total calories are relatively adequate, has been reported to predispose to hypoglycemia. Occasionally patients with severe liver disease develop hypoglycemia, but this is uncommon.
5. Certain nonpancreatic tumors have occasionally been reported to cause hypoglycemia, presumably either by glucose utilization or by production of an insulin-like substance. The great majority have been neoplasms of large size described as fibrosarcomas or spindle cell sarcomas, usually located in the abdomen (in one study, about two thirds occurred in the abdomen and one third occurred in the thorax). Hepatoma is next most frequent.
6. Alcoholic hypoglycemia may occur in either chronic alcoholics or occasional drinkers. Malnutrition, chronic or temporary, is an important predisposing factor. In those persons who develop hypoglycemia, fasting for 12-24 hours precedes alcohol intake. Symptoms may occur immediately but most often follow 6-34 hours later. Therefore, alcohol-related hypoglycemia is most often a fasting type but occasionally may appear to be reactive.

Laboratory tests

The major consideration in these patients is to discover a pancreatic islet cell tumor or eliminate its possibility. Diagnosis of islet cell tumor is important since the condition is surgically correctable, but accurate diagnosis is a necessity to avoid unnecessary operation.

Whipple’s triad. Whipple’s triad remains the basic screening procedure for insulinoma:

1. Symptoms compatible with hypoglycemia while fasting.
2. A FBG level of 10 mg/100 ml (0.55 mmol/L) or more below FBG normal lower limits at some time. This is most reliable when the specimen is obtained while the patient is having symptoms.
3. Relief of symptoms by glucose.
4. In addition, most endocrinologists would require an elevated serum insulin value during the hypoglycemia.

Plasma (or serum) insulin/glucose ratio. In functioning insulinomas, one would expect serum insulin levels to be elevated. In some patients with serum glucose within glucose reference range, serum insulin may be elevated not only with insulinoma but also with Cushing’s syndrome, chronic renal failure, growth hormone overproduction, cortisol-type steroids, obesity, and estrogen therapy. On the other hand, about 10% (range, 0%-20%) of patients with insulinoma have been reported to show serum insulin levels in the upper 75% of insulin reference range during hypoglycemia. However, some of these patients with apparently normal insulin levels can be shown to have insulin values that are disproportionately high in relation to the glucose value. Therefore, some investigators consider the ratio of immunoreactive insulin to glucose (IRI/G ratio) to be more sensitive and reliable than blood levels or either glucose alone or insulin alone. Normally, the IRI/G ratio should be less than 0.3 (the immunoreactive insulin is measured in microunits per milliliter, the glucose in milligrams per 100 ml). The ratio is abnormal if it is greater than 0.3 in nonobese persons and greater than 0.3 in obese persons with serum glucose values less than 60mg/100 ml. Hyperinsulinism due to insulinoma results in serum insulin levels inappropriately high in relation to the low serum glucose values. In some institutions a G/IRI ratio is used instead of an IRI/G ratio.

Amended insulin/glucose ratio for diagnosis of insulinoma. Some investigators have proposed variants of the IRI/G ratio to increase sensitivity or specificity for insulinoma. The most commonly used variant is the “amended ratio” of Turner, whose formula is:

Serum insulin level x 100 / Serum glucose – 30 mg/100 ml

when serum insulin is reported in µU/ml and serum glucose in mg/100 ml. A ratio over 50 suggests insulinoma, while a ratio less than 50 is evidence against insulinoma. The serum levels of glucose and insulin are obtained after fasting, which may have to be long-term. The amended IRI/G ratio is reported to be a little more sensitive than the standard IRI/G ratio in some reports, but in other reports there were 20%-35% false negative or nondiagnostic results in patients with insulinoma.

Prolonged fasting. A considerable number of patients do not display symptoms or laboratory evidence of insulinoma after overnight fasting. When this occurs, the most useful procedure is prolonged fasting for a time period up to 72 hours long, with periodic insulin plus glucose measurements, or such measurements if symptoms develop. After an overnight fast, approximately 50% of insulinomas are revealed by the FBG level alone and about 66% by the IRI/G ratio. After a 48-hour fast, the blood glucose value uncovers about 66% of tumors and the IRI/G ratio about 85%. In 72 hours, the blood glucose level alone detects about 70% of patients and the IRI/G ratio is abnormal in more than 95%. In the Mayo Clinic series, Whipple’s triad appeared within 24 hours in 71% of insulinoma patients, within 36 hours in 79%, within 48 hours in 92%, and within 72 hours in 98%. Serum insulin assay alone reveals about the same percentage of patients with elevated values as the blood glucose level does with low values.

Tolbutamide tolerance test. Tolbutamide (Orinase) is a sulfonylurea drug that has the ability to stimulate insulin production from pancreatic islet cells. The drug has been used to treat diabetics who produce insulin but not in sufficient quantity. In the tolbutamide test, a special water-soluble form of tolbutamide (not the therapeutic oral form) is given intravenously. In normal persons there is a prompt fall in blood glucose levels to a minimum at 30-45 minutes, followed by a return to normal values between 1.5 and 3 hours. In patients with insulinoma the fall in the blood glucose level is greater than that of most normal persons, declining to 40%-65% of baseline, whereas normal persons usually do not fall as low as 50% of baseline [Mayo Clinic recent criteria report sensitivity and specificity of 95% when the average of the 120-, 150-, and 180-minute plasma glucose specimens is less than 55 mg/100 ml (3.05 mmol/L) in lean persons and 62 mg/100 ml (3.44 mmol/L) in obese persons].

Since there is occasional overlap between normal persons and those with insulinoma, of greater significance is the fact that hypoglycemia from insulinoma persists for more than 3 hours, whereas in most normal individuals the blood glucose level has returned to fasting values by 3 hours. In a few normal individuals and in those with functional hypoglycemia, values return to at least 80% of FBG levels by 3 hours. Adrenal insufficiency also returns to at least 80% of FBG levels by 3 hours, although the initial decrease may be as great as that for insulinoma. Some patients with severe liver disease have curves similar to those of insulin-producing tumor. However, this is not frequent and usually is not a real diagnostic problem. The tolbutamide test is definitely more sensitive than the OGTT for the diagnosis of islet cell tumor but has the disadvantage that the characteristic responses of diabetic or alimentary hypoglycemia to the OGTT cannot be demonstrated.

The major drawback to the tolbutamide test is the necessity in some patients to stop the test prematurely because of severe hypoglycemic symptoms. Patients must be closely watched during the test. Sensitivity of the test for insulinoma seems to be approximately 80%-85% using the extended 3-hour time period (literature range, 75%-97%). A major advantage of the test is the short time required to obtain an answer. The tolbutamide test is usually not performed if the FBG value is already in the hypoglycemic range.

Proinsulin. Insulin is derived from a precursor called proinsulin, which is synthesized in the pancreas, is metabolically inactive, and is larger in size (“big insulin”). Proinsulin consists of an alpha and a beta chain connected by an area called “connecting peptide” (C-peptide). Proinsulin is enzymatically cleaved within beta cells into equal quantities of insulin and C-peptide. Radioimmunoassay measurement of insulin includes both proinsulin and regular insulin. Normally, about 5%-15% of immunoreactive insulin (that substance measured by immunoassay) is proinsulin. In many (but not all) patients with insulinomas, the amount of circulating proinsulin is increased relative to total insulin. In diabetics with insulin deficiency who are being treated with insulin, the proinsulin fraction of the individual’s own immunoreactive insulin values may be increased. Measurement of proinsulin necessitates special procedures such as Sephadex column chromatography and is not widely available. Sensitivity of proinsulin assay for detection of insulinoma is reported to be about 80%.

Serum connecting peptide (C-peptide) measurement. As noted previously, C-peptide is a by-product of insulin production. Although it is released in quantities equal to insulin, serum C-peptide levels do not exactly parallel those of insulin, due to differences in serum half-life and catabolic rate. Nevertheless, C-peptide values correlate well with insulin values in terms of the position of each in relation to its own normal range (i.e., if one is decreased, the other likewise is decreased). Therefore, C-peptide can be used as an indicator of insulin secretion.

Some insulin is derived from animal pancreas (synthetic human insulin is available but not yet exclusively used). Use of this foreign substance may lead to antiinsulin antibody production. Pork insulin is less antigenic than beef insulin. Insulin antibodies falsely increase insulin assay values in most commercial kits (although in a few systems the values are decreased instead). C-peptide assay kits do not react with animal-origin insulin and therefore reflect only actual patient insulin production without being affected by the presence of insulin antibodies.

C-peptide assay has been used in several ways: (1) most commonly, to detect or prove factitious (self-medication) insulin-induced hypoglycemia, (2) to detect insulinoma in diabetic patients requiring insulin therapy, (3) to evaluate pancreatectomy status, and (4) to evaluate insulin reserve or production in diabetics who have taken or are taking insulin.

Occasionally patients become hypoglycemic by self-administration of insulin. Since insulin assay cannot differentiate between exogenous insulin and that produced by insulinoma, C-peptide assay should be performed on the same specimen that showed elevated insulin levels. In hyperinsulinism from islet cell tumor, C-peptide levels are elevated; in that due to exogenous (self-administered) insulin, C-peptide levels are low. Another cause of low C-peptide levels is a type I diabetic who cannot produce insulin; but the insulin assay value would be low. An elevation of the C-peptide level classically suggests insulinoma but may also be seen after taking oral hypoglycemic agents (since these agents stimulate the production of insulin).

Connecting peptide assay has been used after pancreatectomy to evaluate the possibility of residual pancreatic islet tissue.

Some investigators have used C-peptide assay in diabetics previously treated with insulin to see how much insulin production is possible. Those who have substantial capability for insulin production are treated differently from those who do not. This method can help diagnose the syndrome of peripheral insulin resistance. Also, if the diabetic patient has significant capability for insulin production, frequent and severe episodes of diabetic ketoacidosis may suggest some factor other than insulin deficiency. There is still controversy over criteria dividing type I and type II diabetics based on insulin or C-peptide assay and what therapeutic changes, if any, should be made based on the amount of insulin production using insulin or C-peptide information.

Other tests. The 5-hour OGTT after overnight fasting was widely used in the past for detection of insulinoma. Patients characteristically had a low or low-normal FBG level and a normal sharp rise after glucose administration (the peak remaining within normal OGTT limits), then a slower fall to hypoglycemic levels that did not rapidly return to the reference range. However, the OGTT has been virtually abandoned for diagnosis of insulinoma because a considerable minority of insulinomas are reported to demonstrate a flat curve or sometimes even a diabetic-type curve, or the curve may be normal. The 5-hour OGTT, however, is sometimes used in patients with the postprandial type of hypoglycemia. Leucine and glucagon provocative tests for insulinoma have been reported. However, these are rarely used since they are somewhat less sensitive than tolbutamide and substantially less sensitive than the IRI/G ratio after prolonged fasting.

Current status of tests for insulinoma

At present, most investigators use Whipple’s triad and prolonged fasting (with insulin assay or the IRI/G ratio) as the primary screening tests for insulinoma, with the tolbutamide test available in equivocal or problem cases. The differential diagnosis of decreased glucose and elevated insulin includes insulinoma, factitious hypoglycemia, and antiinsulin antibodies. Insulinoma has increased C-peptide levels and the other two have normal or decreased C-peptide levels.