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Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes

Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes
Author:
Adrian Vella, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Jul 21, 2022.

INTRODUCTION — Symptoms of hypoglycemia are nonspecific and may include anxiety, weakness, tremor, perspiration, or palpitations. With marked hypoglycemia, there can be alterations in mental status ranging from confusion to coma. In a person without diabetes who has postprandial sympathoadrenal symptoms, the probability of having a postprandial hypoglycemic disorder is very low if concurrent plasma glucose concentrations are normal, even if the symptoms resolve with eating. Similarly, the presence of a hypoglycemic disorder cannot be diagnosed with confidence solely on the basis of a low plasma glucose concentration postprandially as glucose levels <50 mg/dL (2.8 mmol/L) can be seen in healthy, asymptomatic people. The clinical importance of the evaluation is primarily related to the need to differentiate a true postprandial hypoglycemic disorder from postprandial syndrome.

The evaluation and management of patients with symptoms that resemble those of hypoglycemia and occur predominantly in the postprandial state will be reviewed here. The clinical manifestations of and diagnostic approach to hypoglycemia in general are discussed separately. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)

DEFINITIONS

Postprandial hypoglycemia — Postprandial hypoglycemia describes the timing of hypoglycemia (within four hours after meals) and is not a diagnosis per se. The presence of postprandial hypoglycemia requires an investigation to determine the specific cause of hypoglycemia (table 1). Some disorders can produce both fasting and postprandial hypoglycemia. Disorders that cause hypoglycemia predominantly in the postprandial state include the noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post Roux-en-Y gastric bypass (RYGB) hypoglycemia, and insulin autoimmune hypoglycemia (table 1). (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)

Postprandial syndrome — The term "postprandial syndrome" is used to describe a disorder observed in patients with postprandial symptoms suggestive of hypoglycemia but without concurrent biochemical evidence of hypoglycemia, usually after ingestion of a high carbohydrate meal and with resolution of symptoms after dietary modification [1]. The earlier term "reactive hypoglycemia" to describe this syndrome is no longer used since low glucose levels are not considered to cause the symptoms [2-4].

In the past, patients with symptoms suggestive of increased sympathetic activity (anxiety, weakness, tremor, perspiration, or palpitations) occurring after meals were considered to have functional hyperinsulinism or functional hypoglycemia (ie, an exaggerated physiologic response, but not a disease), as a reaction to the ingestion of food. The diagnosis was based upon reproduction of the patient's hypoglycemia symptoms in association with a blood glucose value of <50 mg/dL (2.8 mmol/L) after an oral glucose tolerance test (OGTT) [5]. However, the OGTT is not a useful test for diagnosing reactive hypoglycemia based on the following observations:

At least 10 percent of healthy, asymptomatic individuals have nadir blood glucose concentrations less than 50 mg/dL (2.8 mmol/L) during a four- to six-hour OGTT [6].

There is often poor correlation between blood glucose concentrations and the occurrence of symptoms during the test [7], and symptoms are poorly reproducible [8].

Many patients with postprandial adrenergic symptoms have similar symptoms after administration of a placebo instead of glucose [6].

Serum cortisol or epinephrine concentrations often do not increase when blood glucose concentrations are low or symptoms are present, suggesting that the fall in blood glucose was not sufficient to activate counterregulation and making it difficult to relate the symptoms to autonomic activation [9,10]. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

In a study in which plasma glucose responses to a mixed meal were compared with those after oral glucose administration, none of the patients who had plasma glucose values less than 50 mg/dL (2.8 mmol/L) after oral glucose had hypoglycemia after a mixed meal or any electroencephalography (EEG) evidence of hypoglycemia [11]. In this and other reports, the patient's typical symptoms occurred during both tests even though there was no hypoglycemia after the mixed meal (figure 1) [1,11,12]. These findings provide especially strong evidence that OGTTs should not be performed as part of the evaluation of patients with symptoms of hypoglycemia in the postprandial period [13].

Few patients who have symptoms suggestive of postprandial hypoglycemia have low blood glucose concentrations at those times, as measured in central laboratories on self-collected capillary specimens [14-16].

Because of the above findings, many experts do not believe that functional hypoglycemia is a true hypoglycemic disorder.

EVALUATION — For patients with postprandial symptoms that resemble those of hypoglycemia, an important goal is to distinguish a true postprandial hypoglycemic disorder from postprandial syndrome.

The presence of a postprandial hypoglycemic disorder cannot be diagnosed solely on the basis of postprandial symptoms (eg, anxiety, weakness, dizziness, tremor, perspiration, or palpitations). Postprandial sympathoadrenal symptoms may be highly suggestive of hypoglycemia, but they cannot be ascribed to hypoglycemia unless the glucose concentration is low (<55 mg/dL [<3 mmol/L]) at the same time, and the symptoms are relieved when glucose levels are raised. This cluster of findings is called Whipple's triad:

Symptoms consistent with hypoglycemia

A low plasma glucose concentration measured with an accurate method

Relief of those symptoms after the plasma glucose level is raised

The purpose of the initial laboratory evaluation is to document Whipple's triad. (See 'Measurement of glucose during spontaneous occurrence of symptoms' below.)

Subsequently, only those patients in whom Whipple's triad is documented require evaluation for a hypoglycemic disorder. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Laboratory testing'.)

Measurement of glucose during spontaneous occurrence of symptoms — For patients with postprandial symptoms that resemble those of hypoglycemia, glucose should be measured during the occurrence of symptoms (algorithm 1).

Self-monitoring of blood glucose – Blood glucose monitoring (BGM) with fingersticks and a glucose meter may be used initially to exclude the presence of hypoglycemia coincident with typical postprandial symptoms. We advise patients to check several fingerstick glucose levels at the time of postprandial symptoms. Glucose values obtained by reflectance meters cannot reliably discriminate a low-normal fasting glucose from a value in the hypoglycemic range. Therefore, the threshold to pursue additional evaluation is set higher than the lower limit of the normal reference range. Continuous glucose monitoring (CGM) systems also have reliability issues in the hypoglycemic range and are therefore prone to error in this range. We generally do not use CGM systems for evaluating symptoms of hypoglycemia in people without diabetes. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Reliability'.)

Fingerstick glucose ≥80 mg/dL (4.4 mmol/L) – If all glucose readings are ≥80 mg/dL at the time of symptoms, hypoglycemia as a cause of the symptoms is excluded.

Fingerstick glucose <80 mg/dL – If any glucose reading is <80 mg/dL at the time of symptoms, hypoglycemia cannot be excluded as a cause of the symptoms. In this setting, measurement of plasma glucose and insulin should be obtained by venipuncture during the spontaneous occurrence of symptoms.

Venipuncture glucose and insulin – For patients in whom hypoglycemia has not been excluded using a glucose meter, the next step in the evaluation is measurement of plasma glucose and insulin simultaneously, obtained by venipuncture during the occurrence of symptoms. Patients can be provided with a laboratory requisition for the blood tests. The glucose should be obtained in a collection tube that contains an inhibitor of glycolysis, and processing should not be delayed.

The testing must be performed during the presence of typical postprandial symptoms. The timing of testing to symptoms may involve spending time in the laboratory (eg, eating a meal and waiting for symptoms to occur).

Venipuncture glucose ≥65 mg/dL (3.6 mmol/L) – If the venipuncture glucose is ≥65 mg/dL at the time of symptoms, hypoglycemia as a cause of the symptoms is very unlikely.

Venipuncture glucose <65 mg/dL – If the venipuncture glucose is <65 mg/dL, hypoglycemia cannot be excluded as a cause of the symptoms. Such patients should be referred to an endocrinologist for provocative testing (generally a mixed meal test) to determine if a hypoglycemic disorder is causing symptoms.

Insulin concentrations in the postprandial period reflect the net result of secretion and clearance. Detectable insulin concentrations at the time of hypoglycemia may reflect either the rate of clearance following the rise in response to nutrient ingestion or the possibility of insulin-induced hypoglycemia. (See 'Mixed meal test' below.)

Mixed meal test — Patients with biochemical evidence of hypoglycemia at the time of hypoglycemia symptoms should have additional testing in the postprandial state, typically during a monitored mixed meal test (algorithm 1). For a mixed meal diagnostic test, the patient consumes a meal of solid composition that usually leads to symptoms and is monitored for the occurrence of symptoms. Patients who have had Roux-en-Y gastric bypass (RYGB) should have a test meal that is appropriate for post-RYGB patients; they should avoid high carbohydrate intake and caloric intake in liquid form [17,18]. (See "Late complications of bariatric surgical operations", section on 'Dumping syndrome' and "Late complications of bariatric surgical operations", section on 'Postprandial hyperinsulinemic hypoglycemia'.)

Venipuncture samples are collected prior to ingestion of the meal and at the time symptoms occur.

Measure:

Plasma glucose

Insulin

Sulfonylureas and meglitinides (with the symptomatic sample only)

After the symptomatic sample is collected, the patient should be given food (eg, approximately 15 g of rapidly available carbohydrate) to determine if symptoms improve when the plasma glucose is raised. Another plasma glucose should be obtained by venipuncture once symptoms improve.

Symptomatic sample:

Glucose ≥65 mg/dL (3.6 mmol/L) – A hypoglycemic disorder is unlikely if a plasma glucose concentration is ≥65 mg/dL at the time of the postprandial symptoms. Evaluate for other causes of postprandial symptoms.

Glucose <65 mg/dL – If glucose is <65 mg/dL during symptoms and symptoms improved when the plasma glucose was raised, a hypoglycemic disorder is likely. A suppressed insulin level (<3 microU/mL [pmol/L]) suggests noninsulin-mediated causes of hypoglycemia (eg, alcohol, medications [other than antihyperglycemic agents], toxins, malnourishment, cortisol deficiency), whereas a nonsuppressed insulin level suggests the possibility of insulin-mediated hypoglycemia (eg, post-bariatric hypoglycemia, factitious hypoglycemia [surreptitious use of insulin, sulfonylureas, or meglitinides], insulinoma). (See 'Determining the cause' below and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Determining the cause of hypoglycemia'.)

Although standards for the interpretation of the mixed meal test have not been established from the study of volunteers with non-insulin-mediated postprandial hypoglycemia, it is reasonable to assume that, in individuals with an intact upper gastrointestinal tract, hypoglycemia should not occur. The interpretation of insulin in the postprandial period is more difficult than in the fasting state as concentrations represent the net sum of secretion and clearance. Insulin has a half-life of approximately 5 minutes. Therefore, elevation in insulin levels in the postprandial period may reflect their rates of clearance following the rise in response to nutrient ingestion. Nevertheless, even discounting the effect of clearance rates, if the hypoglycemia is not insulin mediated, the levels of insulin should be at suppressed levels (<3 microU/mL [pmol/L]). (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Interpretation of data'.)

If symptoms do not occur during the mixed meal test, the patient can be provided with additional laboratory requisitions for glucose and insulin (venipuncture) to be performed at the time of symptoms (see 'Measurement of glucose during spontaneous occurrence of symptoms' above). In post-RYGB patients who have been experiencing symptoms consistent with hypoglycemia but do not develop hypoglycemia during the test, dietary modification (ie, consuming foods similar to those used in the mixed meal test) may be sufficient to alleviate symptoms.

No role for OGTT — An oral glucose tolerance test (OGTT) done in an effort to replicate postprandial symptoms should not be performed (see 'Postprandial syndrome' above). This is true of any evaluation of hypoglycemia because misleading results that do not reflect the usual postprandial state may be obtained. This is especially likely in people after RYGB when rapid emptying and absorption of caloric liquids and appearance of nutrients in the circulation can cause circulatory contraction and a constellation of symptoms often referred to as "dumping syndrome" [17]. Rapid emptying is also true for liquid preparations used for nutritional support; although they contain protein, fat, and carbohydrate, these low-fiber liquids will still empty more rapidly than a solid meal [18]. (See "Late complications of bariatric surgical operations", section on 'Dumping syndrome'.)

DETERMINING THE CAUSE — Postprandial hypoglycemia is a descriptor of the timing of hypoglycemia (within four hours after meals) and is not a diagnosis per se. When biochemical evidence of postprandial hypoglycemia is confirmed, the cause must be determined.

Alimentary hypoglycemia — Postprandial symptoms ascribed to but never confirmed as hypoglycemia have been reported in 5 to 37 percent of patients who have undergone upper gastrointestinal surgery (gastrectomy, gastroenterostomy, or vagotomy and pyloroplasty) [19,20]. These symptoms are of the autonomic type and occur approximately one to two hours after eating. The perturbation of the usual physiology and temporal relationship of gastric emptying, absorption of nutrients in the small intestine and alterations in insulin release after vagotomies and partial vagotomies is thought to be the cause. Alimentary hypoglycemia is less common now that these procedures are performed less frequently.

Post-bariatric surgery — Some patients who have undergone Roux-en-Y gastric bypass (RYGB) as treatment for class 2 or 3 obesity have experienced postprandial hyperinsulinemic hypoglycemia, typically occurring one to three hours after ingestion of a carbohydrate-rich meal [17,21]. This is different than dumping syndrome, which often occurs within 15 to 30 minutes of eating, is not associated with hypoglycemia, and is presumed to be caused by contraction of the plasma volume due to fluid shifts into the gastrointestinal tract [22]. These entities are reviewed in detail elsewhere. (See "Late complications of bariatric surgical operations", section on 'Postprandial hyperinsulinemic hypoglycemia' and "Late complications of bariatric surgical operations", section on 'Dumping syndrome'.)

Factitious hypoglycemia — Persons with factitious hypoglycemia from use of insulin or sulfonylurea can have symptoms at any time and, therefore, from time to time may experience postprandial hypoglycemia. (See "Factitious hypoglycemia".)

Insulin autoimmune hypoglycemia — Insulin autoimmune hypoglycemia due to spontaneous generation of insulin antibodies is a rare cause of postprandial and sometimes fasting hypoglycemia [23]. Insulin secreted in response to a meal binds to the antibody and then (it is proposed) disassociates in an unregulated fashion causing late postprandial hyperinsulinemia and hypoglycemia. In addition to a history of postprandial symptoms, diagnostic clues include evidence of other autoimmune phenomena and very high plasma total insulin concentrations. The finding of circulating antibodies to insulin (and with a high binding capacity for insulin) confirms the diagnosis. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Determining the cause of hypoglycemia'.)

Noninsulinoma pancreatogenous hypoglycemia syndrome — Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is characterized by endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma. Pancreatic specimens from such patients show beta cell hypertrophy, islets with enlarged and hyperchromatic nuclei, and increased periductular islets [24].

The predominant clinical feature of NIPHS is postprandial hypoglycemia, occurring two to four hours after meals. Neuroglycopenic symptoms (including loss of consciousness and generalized seizures) are common. This syndrome is discussed in detail elsewhere. (See "Noninsulinoma pancreatogenous hypoglycemia syndrome".)

Other causes — There are several other causes of true postprandial hypoglycemia (table 1). (In each of these, symptoms are neuroglycopenic rather than sympathoadrenal in type.)

Patients with insulinoma typically have fasting hypoglycemia but may have postprandial symptoms, sometimes exclusively. (See "Insulinoma".)

Postprandial sympathoadrenal symptoms have been reported in patients with insulin resistance or very mild type 2 diabetes mellitus [25]. However, blood glucose concentrations have rarely been measured at the time of spontaneously occurring symptoms in these patients, and this phenomenon thus has yet to be firmly established. The presumed mechanism of early diabetes hypoglycemia would be a supranormal insulin response to a supranormal rise in plasma glucose after glucose ingestion, followed by an excessively rapid response to the insulin.

Ingestion of unripened ackee fruit (containing the toxin hypoglycin) can cause hypoglycemia in children and adults with chronic malnutrition by inhibiting the transport of long-chain fatty acids into mitochondria, leading to decreased fatty-acid oxidation and gluconeogenesis [26].

Postprandial hypoglycemia can occur in children with hereditary fructose intolerance [27].

In rare patients, hypoglycemia can occur after the ingestion of toxic substances. The intake of large amounts (three drinks or more) of ethanol and simple carbohydrate (eg, gin and tonic) [28], but not complex carbohydrates [29], can cause hypoglycemia within three to four hours. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Patients with type 1 diabetes who have undergone whole organ pancreatic transplantation occasionally report typical but mild and usually transitory hypoglycemia postprandially. Biochemical evidence of hypoglycemia in this setting is scant, and symptoms usually resolve within months of transplantation [30].

TREATMENT

Postprandial hypoglycemia – The acute management of postprandial hypoglycemia is similar to the management of hypoglycemia during the treatment of diabetes. Patients with symptomatic hypoglycemia should ingest carbohydrates. Fifteen to 20 grams of oral glucose is typically sufficient. Glucose may be ingested in the form of tablets, juice, milk, other snacks, or a meal. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)

For patients with a bona fide hypoglycemic disorder leading to postprandial hypoglycemia, long-term treatment is directed to the specific cause. (See "Insulinoma" and "Nonislet cell tumor hypoglycemia" and "Noninsulinoma pancreatogenous hypoglycemia syndrome" and "Factitious hypoglycemia" and "Late complications of bariatric surgical operations", section on 'Postprandial hyperinsulinemic hypoglycemia'.)

Postprandial syndrome – For patients with postprandial autonomic symptoms not related to hypoglycemia (ie, postprandial syndrome), frequent (every three hours) small meals or snacks, consuming foods high in fiber, avoiding foods high in sugar, and a regular exercise regimen have been recommended [2,3]. There is little high-quality evidence that any of these dietary changes are beneficial, but clinical experience suggests that many patients will identify a change in eating pattern or meal content that ameliorates their symptoms. If dietary modification is not successful in reducing symptoms, a trial of alpha-glucosidase inhibitors to delay carbohydrate absorption and thereby reduce the insulin response to a meal may be helpful in some patients [31]. However, there are few data to support the efficacy of alpha-glucosidase inhibitors in this context [32-34].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basic topics (see "Patient education: Low blood sugar in people without diabetes (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions

Postprandial hypoglycemia – Postprandial hypoglycemia describes the timing of hypoglycemia (within four hours after meals) and is not a diagnosis per se.

Postprandial syndrome – Postprandial syndrome is used to describe a disorder observed in patients with postprandial symptoms suggestive of hypoglycemia but without concurrent biochemical evidence of hypoglycemia after ingestion of a high carbohydrate meal and with resolution of symptoms after dietary modification. The term "reactive hypoglycemia" is an outmoded term that often is erroneously used to describe postprandial syndrome. (See 'Definitions' above.)

Evaluation – For patients with postprandial symptoms that resemble those of hypoglycemia, the clinical importance of the evaluation is primarily related to the need to distinguish a true postprandial hypoglycemic disorder from postprandial syndrome. (See 'Evaluation' above.)

Measurement of glucose during symptoms – Glucose should be measured during the occurrence of symptoms (algorithm 1). Blood glucose monitoring (BGM) with fingersticks and a glucose meter may be used initially to exclude the presence of hypoglycemia during typical postprandial symptoms. However, glucose values obtained by reflectance meters (or continuous glucose monitoring [CGM] systems) cannot reliably discriminate a low-normal fasting glucose from a value in the hypoglycemic range. Therefore, the threshold to pursue additional evaluation is set higher than the lower limit of the normal reference range. (See 'Measurement of glucose during spontaneous occurrence of symptoms' above.)

-Fingerstick glucose ≥80 mg/dL (4.4 mmol/L) – If all glucose readings are ≥80 mg/dL at the time of symptoms, hypoglycemia as a cause of the symptoms is excluded.

-Fingerstick glucose <80 mg/dL – If any glucose reading is <80 mg/dL at the time of symptoms, hypoglycemia cannot be excluded as a cause of the symptoms. In this setting, measurement of plasma glucose and insulin should be obtained by venipuncture during the spontaneous occurrence of symptoms.

-Venipuncture glucose ≥65 mg/dL (3.6 mmol/L) – If the venipuncture glucose is ≥65 mg/dL at the time of symptoms, hypoglycemia as a cause of the symptoms is very unlikely.

-Venipuncture glucose <65 mg/dL – If the venipuncture glucose is <65 mg/dL, patients should be referred to an endocrinologist for provocative testing (generally a mixed meal test) to evaluate for a hypoglycemic disorder.

Mixed meal test – For a mixed meal diagnostic test, the patient consumes a meal of solid composition that usually leads to symptoms and is then observed for symptoms of hypoglycemia. Patients who have had Roux-en-Y gastric bypass (RYGB) should have a test meal that is appropriate for post-RYGB patients; they should avoid high carbohydrate intake and caloric intake in liquid form. (See 'Mixed meal test' above.)

Venipuncture samples (glucose, insulin) are collected prior to ingestion of the meal and then a sample for glucose, insulin, and a sulfonylurea/meglitinide screen is collected during the occurrence of symptoms (algorithm 1).

-Glucose ≥65 mg/dL (3.6 mmol/L) – A hypoglycemic disorder is unlikely if a plasma glucose concentration is ≥65 mg/dL at the time of the postprandial symptoms. Evaluate for other causes of postprandial symptoms.

-Glucose <65 mg/dL – If glucose is <65 mg/dL during symptoms and symptoms improve when the plasma glucose is raised, a hypoglycemic disorder is likely. A suppressed insulin level (<3 microU/mL [pmol/L]) suggests non-insulin-mediated causes of hypoglycemia (eg, alcohol, medications [other than antihyperglycemic agents], toxins, malnourishment, cortisol deficiency), whereas a nonsuppressed insulin level suggests the possibility of insulin-mediated hypoglycemia (eg, post-bariatric hypoglycemia, factitious hypoglycemia [surreptitious use of insulin, sulfonylureas, or meglitinides], insulinoma).

Determining the cause – When biochemical evidence of postprandial hypoglycemia is confirmed, the cause must be determined. There are several hypoglycemic disorders that cause predominantly postprandial symptoms (table 1). (See 'Determining the cause' above.)

Treatment

Postprandial hypoglycemia – Treatment is directed to the specific cause. (See 'Treatment' above and "Insulinoma" and "Nonislet cell tumor hypoglycemia" and "Noninsulinoma pancreatogenous hypoglycemia syndrome" and "Factitious hypoglycemia".)

Postprandial syndrome – Initial treatment includes dietary and lifestyle changes, Eating frequent (every three hours) small meals or snacks, consuming foods high in fiber, avoiding foods high in sugar, and adding a regular exercise regimen. If dietary modification is not successful in reducing symptoms, a trial of alpha-glucosidase inhibitors to delay carbohydrate absorption and thereby reduce the insulin response to a meal may be helpful in some patients. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to earlier versions of this topic review.

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