Diabetes Mellitus and Disorders of Glucose Homeostasis

Key Concepts

The diagnosis of diabetes can be determined by one or more of four methods—random plasma glucose level above 200 mg/dL, fasting plasma glucose concentration above 126 mg/dL, 2-hour, 75-g post-load oral glucose tolerance test (OGTT) > 200 mg/dL, or HbA _1c value above 6.5%.
Diabetic ketoacidosis (DKA) is diagnosed by the presence of hyperglycemia, anion gap metabolic acidosis, and elevated ketoacid levels.
The essential treatment of DKA includes administration of insulin, correction of dehydration, correction of potassium level, correction of acidosis, and treatment of the underlying cause.
The use of sodium bicarbonate to correct acidosis in DKA has not demonstrated any benefit and may be associated with worse outcomes.
A hyperglycemic hyperosmolar state is usually seen in older adults with multiple comorbid conditions and is distinguished from DKA by the absence of ketoacidosis. In addition to fluid resuscitation and correction of hyperglycemia, treatment should address the underlying cause of the state, which includes infection, myocardial infarction, and cerebrovascular accident.
Diabetic peripheral neuropathy is common and has multiple treatment options, including gabapentin, pregabalin, and duloxetine.
Diabetic foot ulcers and other diabetic soft-tissue infections (e.g., gas gangrene, Fournier’s gangrene) are frequently polymicrobial and require broad-spectrum antibiotic therapy covering gram-positives, gram-negatives, and anaerobes.
Hypoglycemia may be associated with significant morbidity and mortality. When the diagnosis is suggested and, if possible, confirmed by laboratory evaluation, therapy should be initiated immediately.
Hypoglycemia caused by sulfonylurea oral hypoglycemic agents may be prolonged. Patients should be observed for an extended period or hospitalized.

Diabetes Mellitus

Diabetes Mellitus Foundations

Background and Importance

Diabetes mellitus is the most common endocrine disease. It comprises a heterogeneous group of hyperglycemic disorders characterized by a high serum glucose concentration and disturbances of carbohydrate and lipid metabolism. Acute complications include hypoglycemia and hyperglycemia, diabetic ketoacidosis (DKA), and hyperglycemic hyperosmolar state (HHS). Long-term complications affect multiple organ systems through involvement of the microvasculature and include retinopathy, nephropathy, neuropathy, and angiopathy. As a result, complications such as coronary and cerebral vascular disease, blindness, chronic kidney disease, complicated infections, and amputations occur with a much higher incidence in patients with diabetes than in patients without. Diabetes is ranked as one of the five major chronic diseases that account for a significant proportion of our health care spending. Several trials have shown to varying degrees that tight glucose control can reduce the risk of death and severe microvascular complications. Patients with diabetes mellitus incur emergency department (ED) costs three times higher than those of nondiabetic patients and are admitted to the hospital four times more often. ^,

Epidemiology

The most recent data (2015) estimate that some 30 million people, or 9.4% of all Americans and 13% of adults older than 20 years have diabetes. The incidence of diabetes in those younger than 20 approaches as high as 45/100,000 by the teenage years. The type of diabetes depends on age; most of those younger than 10 years have type 1, whereas type 2 predominates among the 10- to 19-year-olds. Additionally, 33% of the total US population is thought to have prediabetes.

Type 1 is less common than type 2. The peak age at onset of type 1 diabetes is 10 to 14 years, and approximately 1 of every 600 schoolchildren has this disease. In the United States, the prevalence of type 1 is approximately 0.26% by the age of 20 years, and the lifetime prevalence approaches 0.4%. The annual incidence among persons from birth to 16 years of age in the United States is 12 to 14 per 1 million population. The incidence is age-dependent, increasing from near-absence during infancy to a peak occurrence at puberty and another small peak at midlife. ^,

The morbidity of diabetes is related primarily to its vascular complications. A mortality rate of 36.8% has been attributed to cardiovascular causes, 17.5% to cerebrovascular causes, 15.5% to diabetic comas, and 12.5% to renal failure.

Anatomy, Physiology, and Pathophysiology

Normal Physiology

Because plasma glucose is the predominant metabolic fuel used by the central nervous system (CNS), maintenance of the plasma glucose concentration is critical to survival. The CNS cannot synthesize glucose, store more than a few minutes’ supply, or concentrate glucose from the circulation. Brief hypoglycemia can cause profound CNS dysfunction, and prolonged severe hypoglycemia may cause cellular death. Glucose regulatory systems have evolved to prevent and correct hypoglycemia.

The plasma glucose concentration is normally maintained within a relatively narrow range, between 60 and 150 mg/dL, despite wide variations in glucose levels after meals and exercise. Glucose is derived from three sources—intestinal absorption from the diet, the breakdown of glycogen (glycogenolysis), and the formation of glucose from precursors (gluconeogenesis), including lactate, pyruvate, amino acids, and glycerol. After glucose ingestion, the plasma glucose concentration increases as a result of glucose absorption. Endogenous glucose production is suppressed, and the plasma glucose level rapidly declines in response to insulin to a level below the baseline.

Insulin

Insulin receptors on the beta cells of the pancreas sense elevations in the blood glucose concentration and trigger insulin release. For incompletely understood reasons, glucose taken orally results in more insulin release than parenteral glucose. Certain amino acids induce insulin release and even cause hypoglycemia in some patients. Sulfonylurea oral hypoglycemic agents work, in part, by stimulating the release of insulin from the pancreas.

The number of receptors determines the sensitivity of the specific tissue to circulating insulin. The number and sensitivity of receptors are also the primary factors affecting the long-term efficacy of the sulfonylurea oral hypoglycemic agents. Receptor sites are increased in glucocorticoid deficiency and may be relatively decreased in obese patients.

Under normal circumstances, insulin is rapidly degraded through the liver and kidneys. The half-life of insulin is 3 to 10 minutes. Whereas insulin is the major anabolic hormone implicated in diabetes, glucagon is the major catabolic hormone in disorders of glucose homeostasis.

Although most tissues have the enzyme systems required to synthesize and hydrolyze glycogen, only the liver and kidneys have glucose-6-phosphatase , the enzyme necessary to release glucose into the circulation. The liver is essentially the sole source of endogenous glucose production. Renal gluconeogenesis and glucose release contribute substantially to the systemic glucose pool only during prolonged starvation.

Glucose Regulatory Mechanisms

Maintenance of the normal plasma glucose concentration requires precise matching of glucose use with endogenous glucose production and dietary glucose intake. The regulatory mechanisms that maintain systemic glucose balance involve hormonal, neurohumoral, and autoregulatory factors. Glucose regulatory hormones include insulin, glucagon, epinephrine, cortisol, and growth hormone. Insulin is the main glucose-lowering hormone. Insulin suppresses endogenous glucose production and stimulates glucose use. Insulin is secreted from the beta cells of the pancreatic islets into the hepatic portal circulation and has important actions on the liver and peripheral tissues. Insulin stimulates glucose uptake and storage, and it is used by other insulin-sensitive tissues, such as fat and muscle.

Counterregulatory hormones include glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. When glucose is not transported intracellularly because of a lack of food intake or lack of insulin, the body perceives a fasting state and releases glucagon, attempting to provide the glucose necessary for brain function. Glucagon is released in response to hypoglycemia as well as to stress, trauma, infection, exercise, and starvation. It increases hepatic glucose production within minutes, although transiently.

Epinephrine both stimulates hepatic glucose production and limits glucose use through direct and indirect actions mediated by α-adrenergic and β-adrenergic mechanisms. Epinephrine also acts directly to increase hepatic glycogenolysis and gluconeogenesis. It acts within minutes and produces a transient increase in glucose production but continues to support glucose production at approximately basal levels thereafter. Norepinephrine exerts hyperglycemic actions by mechanisms similar to those of epinephrine, except that norepinephrine is released from axon terminals of sympathetic postganglionic neurons.

Cortisol is released in response to stress, and it increases blood glucose by both increasing hepatic gluconeogenesis and inhibiting skeletal muscle uptake of glucose. These mechanisms contribute to the hyperglycemia seen during physiologic stress or illness.

Pathophysiology

Type 1 diabetes results from a chronic autoimmune process that usually exists in a preclinical state for years. The classic manifestations of type 1 diabetes—hyperglycemia and ketoacidosis—occur late in the disease, an overt sign of beta-cell destruction. The most striking feature of long-standing type 1 diabetes is the nearly total lack of insulin-secreting beta cells and insulin, with the preservation of glucagon-secreting alpha cells, somatostatin-secreting delta cells, and pancreatic polypeptide–secreting cells.

Although the exact cause of diabetes remains unclear, research has provided some clues. Studies of the pathogenesis of diabetes mellitus have demonstrated that the cause of the disordered glucose homeostasis varies from individual to individual. This cause may determine the presentation in each patient. Individual patients are currently not studied for the source of their disease, except on an experimental basis. The goals of ongoing research are to identify who is susceptible to the development of diabetes, prevent diabetic emergencies and sequelae, and prevent expression of the disease.

Types of Diabetes

The American Diabetes Association (ADA) defines four major types of diabetes mellitus: type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and diabetes due to secondary disease processes or drugs. ^, Additionally, the diagnostic criteria of prediabetes was established for patients with glucose levels above the normal fasting range of 110 mg/dL but less than 126 mg/dL; this category has received much attention for the targeting of focused interventions to reduce progression to diabetes mellitus. The 1997 National Diabetes Data Group discontinued the use of the terms insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus because they were confusing and clinically inaccurate. The most recent update to the standards of care for diabetes was published in January 2021. The diagnostic criteria for the diagnosis of diabetes were changed in 2010 from the previous standards of elevated fasting glucose concentration and an abnormal result on the 2-hour oral glucose tolerance test (OGTT) to use of the hemoglobin A _1c (HbA _1c ) value as the preferred confirmatory test. A HbA _1c value above 6.5% is diagnostic of diabetes. However, the fasting plasma glucose concentration and 2-hour OGTT are still considered valid screening tests for diabetes, as is the presence of a random glucose measurement of more than 200 mg/dL in a non-fasting patient with symptoms of diabetes. Use of the fasting plasma glucose concentration may help identify patients at risk for diabetes when the glucose concentration is elevated but does not meet the threshold for the diagnosis of diabetes.

Type 1 Diabetes Mellitus

Type 1 diabetes is characterized by an abrupt failure of insulin production with a tendency to ketosis, even in the basal state. Parenteral insulin is required to sustain life. From 85% to 90% of patients with type 1 diabetes demonstrate evidence of one or more autoantibodies implicated in the cell-mediated autoimmune destruction of the beta cells of the pancreas. The autoimmune destruction has multiple genetic predispositions and may be related to undefined environmental insults.

Type 2 Diabetes Mellitus

Patients with type 2 diabetes may remain asymptomatic for long periods and show low, normal, or elevated levels of insulin. Ketosis is rare in type 2 disease. Patients frequently have hypertriglyceridemia and a high incidence of obesity. No association exists with viral infections, islet cell autoantibodies, or human leukocyte antigen (HLA) expression. Hyperinsulinemia may be related to peripheral tissue resistance to insulin because of defects in the insulin receptor. Defects in muscle glycogen synthesis have an important role in insulin resistance.

Gestational Diabetes

Gestational diabetes mellitus is characterized by an abnormal OGTT result that occurs during pregnancy and reverts to normal during the postpartum period or remains abnormal. The clinical pathogenesis is thought to be similar to that of type 2. The clinical presentation is usually nonketotic hyperglycemia during pregnancy. Screening is performed around the 24th to 28th week with a 75-g oral glucose load in a woman with no prior history of diabetes.

Diabetes of Other Causes

Myriad causes of diabetes have been identified, including chronic pancreatitis, cystic fibrosis, genetic defects in the beta cell or in insulin receptors, and chemical-induced (e.g., Vacor; statins; chemotherapeutic, antipsychotic, or antiretroviral medications). The management of diabetes due to these conditions is cause-specific and depends on whether the underlying pathophysiologic process more closely resembles type 1 or 2 diabetes.

Prediabetes

Impaired glucose tolerance (IGT) has been replaced by the term prediabetes to identify individuals at high risk for the development of diabetes. The pathogenesis of prediabetes is thought to be related to insulin resistance. This group is composed of persons whose plasma glucose levels are between normal and diabetic; they are at increased risk for diabetes and cardiovascular disease. Prediabetes encompasses patients with both impaired fasting glucose (110 to 125 mg/dL) or IGT (level of 140 to 199 mg/dL after a 75 g oral glucose load). Presentations of prediabetes include nonketotic hyperglycemia, insulin resistance, hyperinsulinism, and often obesity. Prediabetes is not associated with the same degree of complications of diabetes mellitus, and many of these patients have normal glucose tolerance. However, each year, about 1% to 5% of patients with prediabetes will develop diabetes mellitus.

Diabetes Mellitus Clinical Features

Type 1

The patient with type 1 diabetes is usually lean, younger than 40 years at diagnosis, and prone to ketosis. Plasma insulin levels are absent to low; plasma glucagon levels are high but suppressible with insulin, and patients require insulin therapy to treat their symptoms. The onset of symptoms may be abrupt, with polydipsia, polyuria, polyphagia, and weight loss developing rapidly. In some cases, the disease is heralded by ketoacidosis. Myriad problems related to type 1 diabetes may prompt an ED visit, including acute metabolic complications, such as DKA, and late complications, such as cardiovascular or circulatory abnormalities, retinopathy, nephropathy, neuropathy, foot ulcers, severe infections, and various skin lesions.

Type 2

The patient with type 2 diabetes is usually middle-aged or older and overweight, with normal to high insulin levels. Insulin levels are lower than would be predicted for glucose levels, however, leading to a relative insulin deficiency. Type 2 patients demonstrate impaired insulin function related to poor insulin production, failure of insulin to reach the site of action, or failure of an end-organ response to insulin. Although most adult patients with type 2 are obese, 20% are not.

Symptoms in type 2 diabetes tend to begin more gradually than in type 1. The diagnosis of type 2 is often made by the discovery of an elevated blood glucose level on routine laboratory examination. Hyperglycemia may be controlled by dietary therapy, oral hypoglycemic agents, or insulin administration. Decompensation of the disease usually leads to HHS rather than to ketoacidosis.

Diabetes Mellitus Differential Diagnosis

The differential diagnosis for diabetes includes hyperglycemia due to physiologic stress, catecholamine release, or certain toxins. Calcium channel blocker overdose has been known to cause insulin resistance and thus present with both significant hyperglycemia and metabolic acidosis. The rodenticide PNU (vacor), which destroys the pancreatic islet cells, can induce a diabetes-like state. Patients with prediabetes may exhibit frank hyperglycemia with a large carbohydrate load or physiologic stress.

Diabetes Mellitus Diagnostic Testing

Serum Glucose Level

The diagnosis of diabetes can be established in one or more of four ways—random plasma glucose level above 200 mg/dL, fasting plasma glucose concentration above 126 mg/dL, 2-hour, 75-g post-load OGTT higher than 200 mg/dL, or HbA _1c value above 6.5%. In the absence of hyperglycemia with metabolic decompensation, these criteria should be confirmed by repeated testing on a different day. Confirmation can be made by the same test or two different tests (e.g., fasting plasma glucose and HbA _1c ). A fasting value above 150 mg/dL is likely to distinguish diabetic from nondiabetic patients more accurately. Formal OGTTs are unnecessary except during pregnancy or in patients who are thought to have diabetes, but who do not meet the criteria for a particular classification. The World Health Organization and ADA have provided protocols for performing the OGTT.

Glycosylated Hemoglobin

Measurement of glycosylated hemoglobin (HbA _1c ) is one of the most important ways to assess the level of glucose control. An elevated serum glucose level binds progressively and irreversibly to the amino-terminal valine of the hemoglobin β chain. The HbA _1c measurement provides insight into the quality of glycemic control over time. Given the long half-life of red blood cells, the percentage of HbA _1c is an index of glucose concentration of the preceding 6 to 8 weeks, with normal values approximately 4% to 6% of total hemoglobin, depending on the assay used. Levels in patients with poorly controlled disease may reach 10% to 12%. The ADA has recommended at least biannual measurements of HbA _1c for the follow-up of all types of diabetes. The ADA currently sets an HbA _1c value of less than 7% as a treatment goal. Different medical societies have advocated for patient-specific A _1c goals, particularly in the elderly, who are more prone to adverse effects from hypoglycemia resulting from attempts at tight glucose control. ^, For functionally independent older adults, the HbA _1c goal is 7% to 7.5%, and 7% to 8% is recommended for functionally dependent, frail patients, or patients with dementia.

Urine Glucose Level

Urine glucose measurement methods are of two types, reagent tests and dipstick tests. The reagent tests (e.g., Clinitest) are copper reduction tests. The reagent tests are rarely used because they are difficult to perform, and the test material is toxic for ingestion or dermal exposure. Dipstick tests generally use glucose oxidase, which may also be affected by different substances. Dipsticks are inexpensive and convenient but may vary in their sensitivity and strength of reaction to a given concentration of glucose. Dipstick interpretation can vary significantly, depending on the observer and type of lighting. Both falsely high and falsely low urine glucose readings can also occur. With the plus system, 1+, 2+, 3+, and 4+ have different implications about urine glucose concentrations, depending on the brand of the dipstick. The use of reflectance colorimeters to read dipsticks increases accuracy.

Urine Ketone Level

Urine ketone dipsticks use the nitroprusside reaction, which test for acetoacetate but does not measure β-hydroxybutyrate. Although the usual ratio of acetoacetate to β-hydroxybutyrate in DKA is 1:2.8, it may be as high as 1:30, and in which case, the urine dipstick does not reflect the true level of ketosis. When ketones are in the form of β-hydroxybutyrate, the urine ketone dipstick may infrequently yield a negative reaction in patients with significant ketosis.

Dipstick Blood Glucose Level

Dipsticks for testing the blood glucose level are clearly more accurate than urine dipsticks as a means of monitoring blood glucose concentration, but they also may be inaccurate. Hematocrits below 30% or above 55% cause inaccurately high or low readings, respectively, and a number of the strips specifically disclaim accuracy when used for neonates. The sensitivity of dipsticks to a variety of factors varies with the particular brand. The largest errors are in the hyperglycemic range. Dipstick readings rarely err more than 30 mg/dL when the actual concentration is below 90 mg/dL. Although specific glucose concentrations may not be accurately represented, blood glucose dipsticks are useful for estimating the general range of the glucose value. Reflectance meters increase the accuracy of the dipstick blood glucose level determination. The use of glucometers has supplanted the use of dipsticks in most clinical settings and tends to be fairly accurate, except, again, at the extremes of glucose levels (<30 or >600 mg/dL). If maximum accuracy is desired, a laboratory blood glucose level should be determined.

Diabetes Mellitus Management

Management of Hyperglycemia

Patients often present to the ED with typical diabetic symptoms, such as polyuria, polydipsia, and polyphagia. Many have serum glucose concentrations above 200 mg/dL but are not ketotic. Patients with newly diagnosed hyperglycemia with normal electrolyte values may be treated with intravenous (IV) hydration alone or with insulin, often reducing the glucose concentration to 150 mg/dL. In reliable patients whose initial glucose concentration is greater than 400 mg/dL, initiation of oral hypoglycemic therapy may be appropriate, with lifestyle modification and coordination with a clinician who will provide longitudinal care. An HbA _1c value should be obtained before initiation of therapy to confirm a diagnosis of diabetes and to establish a baseline.

Detailed descriptions of oral hypoglycemics are provided below, but considerations for ED initiation in acute hyperglycemia are listed here. Initial therapy for type 2 diabetes generally includes metformin at a dose of 500 mg daily or twice daily depending on immediate or extended-release formulation. The extended-release formulation may be better tolerated in terms of GI side effects. Sulfonylurea therapy may be considered as well, with glyburide (2.5 to 5 mg once daily) or glipizide (5 mg once daily). Patients with kidney disease may have complications from the use of a sulfonylurea or metformin and will likely need insulin therapy with or without a glucagon-like peptide-1 receptor agonist. Patients with heart failure or less severe renal disease might benefit from a sodium/glucose cotransporter-2 inhibitor (SGLT-2). Recent studies have shown a mortality benefit to canagliflozin and empagliflozin. If possible, diabetic testing supplies should be given and patients should be taught how to test blood glucose prior to discharge. No target blood glucose level needs to be achieved for safe discharge; observational studies showed no difference in short-term outcomes whether a specific glucose target was achieved or not. Follow-up should be stressed and warning signs of hypoglycemia discussed.

Management of Diabetes Mellitus

Although emergency clinicians do not routinely provide longitudinal care for diabetic patients, these patients frequently present to the ED, and it is helpful to understand fundamental management principles of this important disease. The basic concepts of the diabetic diet remain unchanged, although many studies emphasize foods and medications that alter glucose absorption. Various high-fiber diets have improved glycemic control. The number of supplements or low–glycemic index snacks has risen in the last decade . Exercise continues to be a cornerstone of diabetes management, although care must be taken to balance it with appropriate calorie intake and medication use.

Oral Hypoglycemic Agents

Goals of diabetic management include lowering the hemoglobin A _1c to less than 7% and maintenance of the fasting blood sugar level to within 90 to 130 mg/dL. When started on monotherapy, after 3 years, approximately 50% of patients need a second drug. There have been an increasing number of oral agents for hyperglycemia available in recent years. ( Table 115.1 ) Some of these have serious side effects, requiring the emergency clinician to be familiar with these drugs. If these effects are expected to be prolonged, the patient may require observation. Categories of oral agents may be divided into those that increase the insulin supply, including sulfonylureas, secretagogues, and insulin itself. Medications that decrease insulin resistance include the biguanides and thiazolidinediones; drugs that reduce the rate of glucose absorption include α-glucosidase inhibitors. Metformin is generally used as the first-line agent for oral therapy. If the goal of lower HbA _1c levels is not achieved, the addition of a sulfonylurea or pioglitazone should be considered.

TABLE 115.1

Common Oral Diabetic Medications

Medication	Function	Details
Biguanides (metformin)	Decrease hepatic glycogenolysis	500–1000 mg daily or bid
Sulfonylureas (glipizide, glimepiride)	Stimulate pancreatic insulin release	2.5–5 mg daily or bid
Thiazolidinediones (pioglitazone, rosiglitazone)	Insulin sensitizers, decrease hepatic gluconeogenesis	Increased risk of adverse cardiac events
Meglitinides (repaglinide, nateglinide)	Stimulate postprandial insulin release	Take with meals only
Dipeptidyl peptidase 4 inhibitors (sitagliptin)	Decrease insulin degradation and gluconeogenesis	Once daily; can be found in multiple combination medications
α-Glucosidase inhibitors (acarbose, miglitol)	Delay breakdown of carbohydrates in the intestines	Major side effect is diarrhea

Biguanides

The ADA and European Association for the Study of Diabetes have recommended lifestyle changes, including weight control, at the time of diabetes diagnosis. Metformin (a biguanide) is the initial drug of choice because it does not induce weight gain, has low cost and good tolerability, and does not induce hypoglycemia. However, it lowers blood glucose by only about 100 mg/dL and lowers HbA _1c by approximately 1.5%. Newly diagnosed diabetics frequently require additional agents to control their serum glucose and to lower their HbA1c levels.

Metformin is renally excreted and should not be used with a glomerular filtration rate (GFR) < 30. The Food and Drug Administration (FDA) also recommends not starting metformin in patients with a GFR of 30 to 45, though increased rates of adverse events were not noted in this group. Metabolic and lactic acidosis are a concern with biguanides. Historically, holding metformin after IV contrast and rechecking renal function before restarting has been advocated. However, evidence has failed to show the necessity of this approach for most patients. Patients with existing kidney disease, or those with dehydration or hypoperfusion, should probably have metformin held after IV contrast. There is no clear evidence to support holding metformin routinely for all patients. Metformin must be used with caution in patients with hypoxemia, pregnancy, heart failure, liver compromise, and alcohol abuse. These patients may be at increased risk for developing lactic acidosis, associated with a 50% mortality rate.

Sulfonylureas

Developed in the 1940s, sulfonylureas have historically been a mainstay of oral diabetes treatment. These drugs increase insulin secretion by interacting with potassium channels in the beta cell membrane. This class of drugs is especially useful for patients with early-onset, type 2 diabetes mellitus, and fasting blood glucose levels less than 300 mg/dL. This class of drugs is contraindicated in patients with a known allergy to sulfa agents. Examples of sulfonylureas include glipizide (Glucotrol, Glucotrol XL), glimepiride (Amaryl), gliclazide (Diamicron), chlorpropamide (Diabinese), and glyburide (DiaBeta, Glynase PresTab, Micronase). The risk of hypoglycemia is greater in older adults and in those with impaired renal and hepatic function. This class of medication is also associated with weight gain. They generally lower the glucose level by 20%, and HbA _1c levels by 1% to 2%. Glipizide is shorter acting and therefore less likely than the other sulfonylureas to induce prolonged hypoglycemia. However, for all sulfonylureas, there have been several case reports of delayed onset of hypoglycemia from 12 to 21 hours after ingestion, leading to general recommendations to observe the patient for a 24-hour period. In addition to providing glucose, hypoglycemia due to sulfonylureas may be treated with octreotide, although the data supporting this recommendation is limited.

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