Glucose Intolerance 

Updated: Jul 08, 2020
Author: Samuel T Olatunbosun, MD, FACP, FACE; Chief Editor: George T Griffing, MD 

Overview

Background

Glucose intolerance is an umbrella term for a group of metabolic conditions that result in higher than normal blood glucose levels. Both the World Health Organization (WHO) and the American Diabetes Association (ADA) have released classification systems and diagnostic criteria for diabetes mellitus (DM) and allied categories of glucose intolerance.[1, 2, 3, 4]  Although similiar, there are a number of variances in recommendations which may result in differences in an individual’s classification. 

The major categories of the disorders of glycemia or glucose tolerance are as follows:

  • Type 1 diabetes mellitus (DM) (due to autoimmune B-cell destruction, usually leading to absolute insulin deficiency)

  • Type 2 diabetes mellitus (due to a progressive loss of B-cell insulin secretion frequently on the background of insulin resistance)

  • Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)[5]

  • Specific types of diabetes due to other causes (such as neonatal diabetes and maturity-onset diabetes of the young, diseases of the exocrine pancreas, and drug- or chemical-induced diabetes)

  • Impaired glucose tolerance (IGT: prediabetes/intermediate hyperglycemia)

  • Impaired fasting glucose (IFG: prediabetes/intermediate hyperglycemia)

Conditions secondarily associated with glucose intolerance also occur. Etiologic types and stages of the major disorders of glucose intolerance are shown in the image below.

Glucose intolerance. Etiologic types and stages of Glucose intolerance. Etiologic types and stages of the major disorders of glucose tolerance are displayed.

In most cases, the diagnosis of a type of diabetes or glucose intolerance is based on the patient’s condition at the time, but not all patients have a set of symptoms that fit readily into a particular class (see Presentation).

When hyperglycemia is present, its severity may change in time, depending on the underlying process. Choosing an appropriate management approach to any disorders of glucose intolerance necessitates a strong understanding of the mechanisms involved in the disease process.[6, 7]  (See Treatment and Medication.)

Pathophysiology

Heterogeneity occurs in most glucose intolerance disorders, including diabetes mellitus syndromes.

Type 1 diabetes mellitus

Type 1 diabetes mellitus is characterized by absolute insulin deficiency. In type 1A, a cellular-mediated autoimmune destruction of beta cells of the pancreas occurs. The disease process is initiated by an environmental factor—that is, an infectious or noninfectious agent in genetically susceptible individuals.

Some genes in the histocompatibility leukocyte antigen (HLA) system are thought to be crucial. A stress-induced epinephrine release, which inhibits insulin release (with resultant hyperglycemia), sometimes occurs and may be followed by a transient asymptomatic period known as "the honeymoon." Lasting weeks to months, the honeymoon precedes the onset of overt, permanent diabetes.

Amylin, a beta-cell hormone that is normally cosecreted with insulin in response to meals, is also completely deficient in persons with type 1 diabetes mellitus. Amylin exhibits several glucoregulatory effects that complement those of insulin in postprandial glucose regulation. Idiopathic forms of type 1 diabetes also occur, without evidence of autoimmunity or HLA association; this subset is termed type 1B diabetes.

The underlying pathophysiology of beta cell demise or dysfunction is currently more understood in type 1 diabetes than in type 2 diabetes. The rate of progression in type 1 diabetes is dependent on the age at first detection of antibody, number of antibodies, antibody specificity, and antibody titer.[1, 8]  Three distinct stages of type 1 diabetes have been recognized.[1, 8]  Both stages 1 and 2 are characterized by autoimmunity and a presymptomatic status; although there is still normoglycemia in stage 1, dysglycemia (impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) is present in stage 2. Stage 3 is characterized by new-onset symptomatic hyperglycemia.[1, 8]

Type 2 diabetes mellitus

In a state of health, normoglycemia is maintained by fine hormonal regulation of peripheral glucose uptake and hepatic production. Type 2 diabetes mellitus results from a defect in insulin secretion and an impairment of insulin action in hepatic and peripheral tissues, especially muscle tissue and adipocytes.[9]  A postreceptor defect is also present, causing resistance to the stimulatory effect of insulin on glucose use. As a result, a relative insulin deficiency develops, unlike the absolute deficiency found in patients with type 1 diabetes. The specific etiologic factors are not known, but genetic input is much stronger in type 2 diabetes than in the type 1 form.[10]

Impaired glucose tolerance (IGT) is a transitional state from normoglycemia to frank diabetes, but patients with impaired glucose tolerance exhibit considerable heterogeneity. Type 2 diabetes, or glucose intolerance, is part of a dysmetabolic syndrome (syndrome X) that includes insulin resistance, hyperinsulinemia, obesity, hypertension, and dyslipidemia. Current knowledge suggests that the development of glucose intolerance or diabetes is initiated by insulin resistance and worsened by the compensatory hyperinsulinemia. Insulin resistance is not only predictive for type 2 diabetes and associated with myriad metabolic derangements in fasting conditions, but nondiabetic insulin-resistant individuals are subjected to a similar adverse postprandial metabolic setting and cardiometabolic risk as those with type 2 diabetes.[11]  In addition, the prevalence of hypertension rises with exacerbation of stages of impaired glucose metabolism; however, only in the early stages of impaired insulin metabolism do hyperglycemia and hyperinsulinemia appear to be significant contributors to the presence of hypertension.[12]

The paths to beta-cell dysfunction or demise are less well defined in type 1 diabetes. The progression to type 2 diabetes is influenced by genetics and environmental or acquired factors, such as a sedentary lifestyle and dietary habits that promote obesity. Most patients with type 2 diabetes are obese, and obesity is associated with insulin resistance. Insulin resistance is not only predictive for type 2 diabetes and associated with myriad metabolic derangements in fasting conditions, but nondiabetic insulin-resistant individuals are subjected to a similar adverse postprandial metabolic setting and cardiometabolic risk as those with type 2 diabetes.[11]  Central adiposity is more important than increased generalized fat distribution. In patients with frank diabetes, glucose toxicity and lipotoxicity may further impair insulin secretion by the beta cells. [13]  [14]  [15]  [16] Moreover, "in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain, and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes."[17]

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) was previously described as any degree of glucose intolerance in which onset or first recognition occurs during pregnancy.[5]  The definition was limited by imprecision. Women diagnosed with diabetes in the first trimester are now classified as having type diabetes. GDM is diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes. Insulin requirements are increased during pregnancy because of the presence of insulin antagonists, such as human placental lactogen or chorionic somatomammotropin, and cortisol; these promote lipolysis and decrease glucose use.

Another factor in increased insulin requirements during pregnancy is the production of insulinase by the placenta. Various genetic defects of the beta cell, insulin action, diseases of the exocrine pancreas, endocrinopathies, drugs, chemical agents, infections, immune disorders, and genetic syndromes can cause variable degrees of glucose intolerance, including diabetes.

To see complete information on Diabetes Mellitus and Pregnancy, please go to the main article by clicking here.

Other specific types of diabetes mellitus

These are specific types of diabetes due to other causes, which include monogenic diabetes syndromes, diseases of the exocrine pancreas, and drug- or chemical induced diabetes.  Various genetic defects of the beta cell, insulin action, diseases of the exocrine pancreas, endocrinopathies, drugs, chemical agents, infections, immune disorders, and genetic syndromes can cause variable degrees of glucose intolerance, including diabetes.

Varying forms of glucose intolerance

Glucose intolerance may be present in many patients with cirrhosis due to decreased hepatic glucose uptake and glycogen synthesis. Other underlying mechanisms include hepatic and peripheral resistance to insulin and serum hormonal abnormalities. Abnormal glucose homeostasis may also occur in uremia, as a result of increased peripheral resistance to the action of insulin.

The gastrointestinal tract plays a significant role in glucose tolerance.[18]  With food ingestion, incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are synthesized and secreted by specialized gut cells. Oral glucose administration results in a higher insulin secretory response than does intravenous glucose administration; this difference is due in part to incretin hormones.

The significance of incretin hormones has been noted as a result of efforts to develop agents that may improve glycemic control in patients with type 2 diabetes through new mechanisms.[19]  These strategies include inhibition of dipeptidyl peptidase IV (DPP-4), the major enzyme responsible for degrading incretin hormones in vivo, and the use of GLP-1 agonists.[20]  Incretin hormones also significantly affect the differentiation, mitogenesis, and survival of beta cells.

Pathologic defects observed in type 2 diabetes mellitus and sometimes in impaired glucose tolerance include postprandial hyperglucagonemia, dysregulation of gastric emptying, and loss of incretin effect.

Postprandial hyperglycemia in diabetes and impaired glucose tolerance (IGT) is related to a lower rate of glucose disposal, whereas insulin secretion and action, as well as postprandial turnover, are essentially normal in individuals with isolated IGT.[21]

Etiology

Genetic defects of beta-cell function include the following:

  • Mutation on chromosome 12, the hepatocyte nuclear factor (HNF-1) alpha -MODY3

  • Mutation on chromosome 7p, the glucokinase gene -MODY2

  • Mutation on chromosome 20, HNF-4 alpha -MODY1

  • Point mutations in mitochondrial DNA

Defects in insulin action include the following:

  • Structure and function of insulin receptor: postreceptor signal transduction pathways

  • Type A insulin resistance

  • Leprechaunism

  • Rabson-Mendenhall syndrome

  • Lipoatrophic diabetes

Diseases of the exocrine pancreas include the following:

  • Pancreatitis

  • Trauma

  • Infection

  • Pancreatectomy

  • Pancreatic cancer

  • Cystic fibrosis

  • Hemochromatosis

  • Fibrocalculous pancreatopathy

(Note that the malnutrition-related diabetes has been eliminated from the above list, as evidence is lacking on protein deficiency as a direct cause of diabetes, and fibrocalculous pancreatopathy has been reclassified as a disease of the exocrine pancreas.)

Endocrine diseases associated with excess production of insulin antagonists include the following:

  • Acromegaly

  • Cushing syndrome

  • Glucagonoma

  • Pheochromocytoma

  • Hyperthyroidism

  • Somatostatinoma

  • Aldosteronoma

Drugs or chemical agents with adverse effects on glucose tolerance include the following:

  • Thiazides

  • Diazoxide

  • Glucocorticoids

  • Calcineurin inhibitors, such as cyclosporine and tacrolimus

  • Oral contraceptives

  • Beta-adrenergic agonists

  • Nicotinic acid

  • Thyroid hormone

  • Pentamidine

  • Alpha interferon

  • Atypical antipsychotics, especially clozapine and olanzapine

  • Antiretroviral drugs

  • Vacor

Infections associated with beta-cell destruction include the following:

  • Rubella

  • Coxsackievirus B

  • Mumps

  • Cytomegalovirus

  • Adenovirus

Genetic syndromes that predispose an individual to impaired glucose tolerance include the following:

  • Down syndrome

  • Klinefelter syndrome

  • Turner syndrome

  • Wolfram syndrome

  • Friedreich ataxia

Pregnancy can be associated with gestational diabetes mellitus, and the risk of diabetes increases with parity.

Obesity is a powerful determinant of glucose intolerance in the general population and develops through the interaction of genetics and acquired factors such as physical inactivity and dietary habits.

Immune-mediated causes of impaired glucose tolerance include stiff person syndrome and anti-insulin receptor abnormalities. Other causes of glucose intolerance are liver disease (as in cirrhosis) and renal failure.

Epidemiology

United States statistics

Approximately 29 million people in the United States (9.3%) have diabetes, with 1.7 million new cases diagnosed in adults each year. The CDC estimates 25% of individuals with diabestes are undiagnosed. Eighty-six million adults aged 20 years and older have prediabetes.[22]  

Type 1 diabetes, which usually occurs in children and adolescents, accounts for 5-10% of diabetes cases. Approximately 1 out of every 400-500 children and adolescents in the United States has type 1 diabetes.

Type 2 diabetes, which most commonly occurs in middle age, is the predominant form of clinical disease, constituting 90-95% of cases. This type of diabetes is reaching epidemic proportions. Minority populations, especially American Indians, Hispanic persons, African Americans, and Asian Americans are at particularly high risk.

Gestational diabetes develops in approximately 4% of pregnancies in the United States. The prevalence is 1-14%, depending on the population studied and the diagnostic criteria.

International statistics

The global prevalence of diabetes has nearly doubled since 1980, rising from 4.7% to 8.5% in the adult population, and results in an estimated 1.5 million deaths each year.  Higher-than-optimal blood glucose levels caused an additional 2.2 million deaths, by increasing the risks of cardiovascular and other diseases. Forty-three percent of these 3.7 million deaths occur before the age of 70 years.[23]  

Race characteristics

In the United States, African Americans, Hispanic persons, and Native Americans are about twice as likely to have diagnosed diabetes as non-Hispanic white adults. The percentage of US adults with prediabetes is similar for whites (35%), African Americans (39%), and Hispanics (38%).[22]

Whites have the highest rates of type 1 diabetes, especially those of northern European descent. Type 2 diabetes is more prevalent in ethnic minorities. The disease is unknown or rare among certain ethnic groups (eg, Japanese, Chinese, African). Type 1B diabetes is more common in patients of Asian or African origin.

Sex characteristics

In the World Health Organization’s global data, the prevalence ratio of diabetes for men and women varies markedly, with no consistent trend; however, impaired glucose tolerance is more common in women than in men. The relative difference in frequency between the sexes is probably related to the presence of underlying factors such as pregnancy and obesity, rather than to a sex-specific genetic tendency.[24]

Age characteristics

Type 1 diabetes occurs most commonly in children and adolescents but may occur in individuals of any age. Type 2 diabetes typically begins in middle life or later, usually after age 30 years; its prevalence rises with age. Maturity-onset diabetes of youth can be expressed in childhood or in early adolescence. In the United States, 208,000 people younger than 20 years have either type 1 or type 2 diabetes.[22]

Prognosis

Several studies have demonstrated a relationship between high plasma glucose distributions and the risk for cardiovascular disease and increased mortality, even within the normoglycemic range.[25, 26, 27, 28, 29, 30]

Diabetes is the sixth leading cause of death by disease worldwide and the seventh leading cause of death in the United States. Those with impaired glucose tolerance have a propensity for acute metabolic complications. IGT is a leading cause of end-stage renal disease and of blindness. Individuals with this condition also are at higher risk for neuropathy and gangrene.

Gestational diabetes

Gestational diabetes mellitus brings an increased risk for fetal and neonatal morbidity and mortality, as well as obstetric complications. There is an associated increased risk for obesity in offspring, as well as for glucose intolerance and type 2 diabetes.[29, 30, 31]

For gestational diabetes mellitus, reclassification is performed at 6-12 weeks postpartum. In most patients with gestational DM, glucose tolerance becomes normal after delivery. The lifetime risk for IGT and diabetes is increased substantially in these women, however.

Impaired glucose tolerance

IGT is a major risk factor for diabetes, with 20-50% of affected persons progressing to diabetes within 10 years. Approximately one third revert to normal glucose tolerance, while others persistently demonstrate IGT, as determined by using the oral glucose tolerance test.[32, 33, 34, 35]

Baseline plasma glucose is the most consistent predictor of progression to diabetes. Individuals who progress to diabetes tend to have rates of cardiovascular risk factors that are intermediate between persons with normal glucose tolerance and those with diabetes. They are at an increased risk of macrovascular complications (eg, coronary disease, gangrene, stroke). Progression to diabetes is not clearly associated with microvascular complications (eg, nephropathy, retinopathy, neuropathy). However, microvascular complications have been found in certain individuals with IGT.[36, 37]

Impaired fasting glucose is not associated with the same risk level as IGT, and the risk of cardiovascular disease is much lower in those with impaired fasting glucose.

Patient Education

It is important to educate patients on the disease, including treatment, monitoring, complications, and primary and secondary preventive measures. In addition, family members should be educated on various related issues, including the management of hypoglycemia.

For patient education resources, see Diabetes Center, as well as Diabetes (Type 1 and Type 2), How Is Glucose Tolerance Testing Used to Diagnose Diabetes?, Hypoglycemia (Low Blood Sugar), Diabetic Ketoacidosis, and Diabetic Eye Disease. See also the Medscape Drugs and Diseases articles Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus.

 

Presentation

History

There are varying and similar presentations between patients with type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, prediabetes, and glucose intolerance.

Type 1 diabetes mellitus

The warning symptoms of type 1 diabetes include polyuria, polydipsia, and polyphagia due to hyperglycemia. Patients may present with the unexplained weight loss and easy fatigability that result from reduced glucose use and increased catabolism.

Irritability, drowsiness, and loss of consciousness may occur, especially as ketoacidosis develops. The temporal profile is consequent to progression of the metabolic derangement, which is characterized by dehydration, electrolyte abnormalities, osmolality, and acid-base disturbances. After presentation with ketoacidosis, a patient may briefly revert to normoglycemia without requiring therapy (ie, the honeymoon remission).

Type 2 diabetes mellitus

Patients with type 2 diabetes may have any of the symptoms described under type 1 diabetes, but often these persons are asymptomatic. Hyperosmolar nonketotic coma, which may complicate type 2 diabetes mellitus, is characterized by severe dehydration secondary to osmotic diuresis from hyperglycemia. Ketoacidosis, although uncommon, may also occur in type 2 diabetes.

For more information, see Hyperosmolar Coma.

Antecedent history in patients with type 2 diabetes includes frequent or recurrent infections, poor wound healing, blurring of vision, and numbness or tingling sensations in the extremities.

Gestational diabetes mellitus

Gestational diabetes is typically detected during routine screening of pregnant women for glucose intolerance. Any degree of glucose intolerance with onset or recognition during gestation places a patient in the category of gestational diabetes mellitus.[38, 39, 40]

Prediabetes

The categories of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have been officially termed prediabetes, because they are risk factors for future diabetes and for cardiovascular disease.[41, 42]  However, the World Health Organization (WHO) recommends the term intermediate hyperglycemia, noting that prediabetes does not  always progress to diabetes as the term implies and the focus on diabetes may divert attention from the significantly increased cardiovascular risk.[3]  

Most cases of IGT and IFG are diagnosed when the presence of one or more cardiovascular risk factors necessitates the need to screen for a disorder of glucose tolerance.

Patients with impaired glucose homeostasis are generally asymptomatic. Features of related risk factors for cardiovascular disease may be present, even with a mild degree of hyperglycemia. They include a history of hypertension, obesity, dyslipidemia, and/or macrovascular disease, such as stroke, coronary disease, or peripheral vascular disease.

Glucose intolerance

Diagnosis of glucose intolerance may coincide with various patient conditions that may be complicated by glucose intolerance, such as liver cirrhosis, end-stage renal disease, and some rare genetic disorders.

Physical Examination

Overt hyperglycemia that has progressed to diabetes, if left untreated, may result in signs of dehydration. Hypotension and other features of hemodynamic decompensation occur with worsening hyperglycemia. Other clinical features, such as Kussmaul respiration and altered level of consciousness due to metabolic derangement, are commonly observed during acute deterioration. Evidence of a precipitating factor, such as fever from an infectious process, may be present and should always be sought.

In routine evaluation of patients with glucose intolerance, weight, height, waist, and hip measurements are recommended. The aim is to determine the body mass index (BMI), the risk level, and the presence of truncal obesity. In type 2 diabetes, 60-90% of patients are obese. A patient may have central adiposity in spite of a normal BMI. Skin-fold thickness measurement may also be useful in determining regional fat distribution, although it is not often accurate or reproducible.

Peripheral stigmata of lipid abnormalities and atherosclerosis, such as premature arcus cornealis, xanthelasma, eruptive (skin) xanthomata, tendon xanthomata, and lipemia retinalis, may be found in some patients.

Blood pressure measurement is important, because hypertension is a frequent component of the dysmetabolic syndrome. Hypertension is 1.5 to 2 times more common in individuals with diabetes than in matched individuals without diabetes. Approximately 40% of individuals with hypertension have impaired glucose tolerance.

A thorough evaluation of the various systems and organs is pertinent. An eye examination is important; ocular manifestations, such as pupillary abnormalities, cataract, refractory errors, retinopathy, and other changes, may be found in patients with diabetes. These manifestations result mainly from chronic, uncontrolled hyperglycemia.

A neurologic examination is also necessary, because muscle wasting, sensory abnormalities, and other features of neuropathy are characteristic of many patients with diabetes who have chronic complications.

Related diseases

Specific phenotypic characteristics are found in certain conditions, especially the genetic syndromes.

In addition to glucose intolerance, patients with type A insulin resistance (absent or dysfunctional insulin receptor) may have certain clinical features such as (1) acanthosis nigricans, which is hyperpigmentation and skin thickening of flexural areas, or (2) features of hyperandrogenism, some variants of which may be characterized by thin or muscular body habitus or acral enlargement (pseudoacromegaly).

Due to autoantibodies to the insulin receptor, this resistance commonly manifests as symptomatic diabetes mellitus; ketoacidosis is unusual. Other genetic syndromes associated with insulin resistance include leprechaunism (abnormal facies, growth retardation) and lipodystrophic states (diverse phenotypic manifestations).

Other patients may have physical findings that are characteristic of certain internal organ diseases, in which glucose intolerance is only part of the spectrum of metabolic derangement that complicates these conditions. In cirrhosis, the liver may be normal, enlarged, or shrunken, depending on the disease stage. Other clinical features of portal hypertension and liver cell failure are often present. In cases of uremia, the various systemic changes, with the wide range of external manifestations that occur in the late phases of renal failure, are generally evident.

 

DDx

Diagnostic Considerations

Genetic defects of beta-cell function include the following:

  • Mutation on chromosome 12, the hepatocyte nuclear factor (HNF-1) alpha -MODY3

  • Mutation on chromosome 7p, the glucokinase gene -MODY2

  • Mutation on chromosome 20, HNF-4 alpha -MODY1

  • Point mutations in mitochondrial DNA

Defects in insulin action include the following:

  • Structure and function of insulin receptor: postreceptor signal transduction pathways

  • Type A insulin resistance

  • Leprechaunism

  • Rabson-Mendenhall syndrome

  • Lipoatrophic diabetes

Diseases of the exocrine pancreas include the following:

  • Pancreatitis

  • Trauma

  • Infection

  • Pancreatectomy

  • Pancreatic cancer

  • Cystic fibrosis

  • Hemochromatosis

  • Fibrocalculous pancreatopathy

Endocrine diseases associated with excess production of insulin antagonists include the following:

  • Acromegaly

  • Cushing syndrome

  • Glucagonoma

  • Pheochromocytoma

  • Hyperthyroidism

  • Somatostatinoma

  • Aldosteronoma

Drugs or chemical agents with adverse effects on glucose tolerance include the following:

  • Thiazides

  • Diazoxide

  • Glucocorticoids

  • Calcineurin inhibitors, such as cyclosporine and tacrolimus

  • Oral contraceptives

  • Beta-adrenergic agonists

  • Nicotinic acid

  • Thyroid hormone

  • Pentamidine

  • Alpha interferon

  • Atypical antipsychotics, especially clozapine and olanzapine

  • Antiretroviral drugs

  • Vacor

Infections associated with beta-cell destruction include the following:

  • Rubella

  • Coxsackievirus B

  • Mumps

  • Cytomegalovirus

  • Adenovirus

Genetic syndromes that predispose an individual to impaired glucose tolerance include the following:

  • Down syndrome

  • Klinefelter syndrome

  • Turner syndrome

  • Wolfram syndrome

  • Friedreich ataxia

Pregnancy can be associated with gestational diabetes mellitus, and the risk of diabetes increases with parity.

Immune-mediated causes of impaired glucose tolerance include stiff person syndrome and anti-insulin receptor abnormalities. Other causes of glucose intolerance are liver disease (as in cirrhosis) and renal failure.

Differential Diagnoses

 

Workup

Approach Considerations

ADA Diagnostic Criteria

According to the 2019 American Diabetic Association (ADA) guidelines, the following diagnostic criteria are required for the three stages of type 1 diabetes[4] :

  • Stage 1: multiple autoantibodies; no impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
  • Stage 2: multiple autoantibodies; dysglycemia (IFG and/or IGT); fasting plasma glucose (FPG) of 100-125 mg/dL (5.6-6.9 mmol/L); 2-hour  plasma glucose (PG) of 140-199 mg/dL (7.8-11.0 mmol/L); HBA1C of 5.7%-6.4% (39-47 mmol/mol) or ≥10% increase in HBA1C
  • Stage 3: clinical symptoms; diabetes by standard criteria
  • Use plasma glucose rather than HBA1C to diagnose the acute onset of type 1 diabetes in those with hyperglycemia symptoms
  • The persistence of two or more autoantibodies predicts clinical diabetes and may indicate intervention is needed in the setting of a clinical trial

One of the following criteria must be met for a diagnosis of diabetes[4] :

  • FPG ≥126 mg/dL (7.0 mmol/L), OR 
  • 2-hour PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT), OR
  • HBA1C ≥6.5% (48 mmol/mol), OR
  • Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

To avoid misdiagnosis or missed diagnosis, perform HBAIC testing with  a method that is certified by the NGSP and standardized to the Diabetes Control and Complications Trial (DCCT) assay.[4]

In the presence of marked discordance between measured and plasma glucose levels of HBA1C, consider the possibility of HBA1C assay interference from hemoglobin variants (ie, hemoglobinopathies), and consider use of an assay without interference or plasma glucose criteria to diagnose diabetes.[4]  Use only plasma glucose criteria to diagnose diabetes in the setting of conditions associated with an altered relationship between HBA1C and glycemia (eg, sickle cell disease, second and third pregnancy trimesters and the postpartum period, glucose-6-phosphate dehydrogenase deficiency, infection with human immunodeficiency virus, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy).[4]

If unequivocal hyperglycemia is absent, the diagnosis requires two abnormal test results from the same sample or in two separate test samples.[4]

A diagnosis of prediabetes is made if one of the following criteria are met[1] :

  • IFG: FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) 
  • IGT: OGTT 2-hour PG 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) 
  • HBA1C 5.7−6.4% (39−47 mmol/mol)

The ADA notes that for all three tests, risk extends below the lower limit of the range and becomes greater at the higher end of the range.

WHO Diagnostic Criteria

The World Health Organization diagnostic criteria for diabetes and impaired glucose tolerance are as follows[3] :

  • Diabetes: FPG ≥126 mg/dL (7.0 mmol/L) OR OGTT 2-hour PG ≥200 mg/dL (11.1 mmol/L)
  • Impaired fasting glucose (IFG):  FPG 110 mg/dL to 125mg/dL (6.1 to 6.9mmol/L) AND OGTT 2-hour PG < 140mg/dL (< 7.8mmol/L) 
  • Impaired glucose tolerance (IGT): FPG < 126 mg/dL (< 7.0 mmol/L) AND OGTT 2-hour PG 140mg/dl to 200mg/dl (≥7.8 and < 11.1mmol/L) 

Gestational Diabetes

The ADA has recommended the use of either the one- or two-step approach at 24–28 weeks of gestation in pregnant women not previously known to have diabetes.[1, 4] The one-step approach involves performing a 75-g OGTT, with plasma glucose measurement when the patient is fasting and at 1 and 2 hours in this group of gravida at 24-28 weeks' gestation. Optimally, perform the OGTT in the morning after an overnight fast of at least 8 hours. The diagnosis of GDM is made when any of the following is met or exceeded[1, 4] :

  • Fasting: 92 mg/dL (5.1 mmol/L) 
  • 1 hour: 180 mg/dL (10.0 mmol/L) 
  • 2 hour: 153 mg/dL (8.5 mmol/L)

The two-step approach is a 1-hour (nonfasting) plasma glucose measurement after a 50-g oral glucose load in women at 24-48 weeks' gestation who were not previously diagnosed with diabetes. If the plasma glucose level after 1 hours is ≥130 mg/dL, 135 mg/dL, or 140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L, respectively), perform a fasting 100-g OGTT.

The diagnosis of GDM is made if at least two of the following four plasma glucose levels (measured during OGTT) are met or exceeded[1] : 

  • Fasting: 95 mg/dL (5.3 mmol/L)
  • 1 hour: 180 mg/dL (10.0 mmol/L) 
  • 2 hour: 155 mg/dL (8.6 mmol/L) 
  • 3 hour: 140 mg/dL (7.8 mmol/L) 

This two-step approach is favored by the American Congress of Obstetricians and Gynecologists (ACOG) with the recommendation of either 135 mg/dL (7.5 mmol/L) or 140 mg/dL (7.8 mmol/L).[43]

Women with risk factors for type 2 diabetes are to be screened during the first prenatal visit, using standard diagnostic criteria; if positive, patients should receive a diagnosis of overt, not gestational, diabetes mellitus. Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years.[1, 4]

Glucose Testing

Plasma glucose (PG) measurement is used as a screening test and for confirmation of a previously detected abnormality of glucose tolerance.

Fasting Plasma Glucose (FPG)

Fasting plasma glucose studies are the preferred diagnostic test of the American Diabetes Association (ADA). The ADA diagnostic criteria, which emphasize fasting plasma glucose, facilitate the screening of individuals with undiagnosed diabetes; the criteria help to identify fewer people with diabetes than does OGTT, however.

Oral Glucose Tolerance Test (OGTT)

The standard oral glucose tolerance test (OGTT) involves measurement of plasma glucose concentration 2 hours after a 75-g oral glucose load. It is seldom used as a confirmatory test in the diagnosis of diabetes, but it may be helpful in situations where fasting or random glucose results are equivocal. It is required for diagnosing impaired glucose tolerance (IGT), though it is increasingly reserved for research purposes.

A provisional diagnosis of diabetes must be confirmed on a subsequent day by any of three methods: fasting, casual, and OGTT.

A1C Testing

The ADA has approved the use of the glycated hemoglobin  as an additional tool for the diagnosis of diabetes, based on HBA1C equal to or greater than 6.5%, with 5.7-6.4% categorized as prediabetes.[1] However, the WHO does not recognize HbA1C aa a diagnostic test for diabetes or IFG or IGT[3]  HBA1C testing alone may not always be sufficient in detecting presence of glucose intolerance and primarily serves as an index of the severity of hyperglycemia throughout the 6-8 weeks that precede the measurement.[44]  Obtaining at least fasting plasma glucose levels along with HBA1C measurement is probably prudent when screening an individual for glucose intolerance. The HBA1C is highly specific as evidence of chronic hyperglycemia. It is a predictor of chronic complications.[45]

Laboratory Studies

Workup for the diagnosis of glucose intolerance include plasma glucose level, oral glucose tolerance testing, other screening tests, urinalysis, complete blood count, lipid profile, liver function testing, and measurement of serum electrolytes, BUN, creatinine, uric acid, and blood gases.

Urinalysis is important because ketonuria and massive glycosuria are indicators of acute decompensation. Significant proteinuria may be present in patients with diabetic nephropathy. Abnormalities of specific gravity and pH can be found in patients with uremia. Urine microalbumin is a marker of early renal impairment and endothelial dysfunction.

A complete blood cell count is obtained, because an increased white blood cell count is common during acute infection. Ketoacidosis also is a cause of leukocytosis.

A lipid profile is necessary to detect an increased triglyceride level, often a reflection of poor glycemic control that may normalize on attainment of euglycemia. Other lipid abnormalities, such as increased total cholesterol and low-density lipoprotein levels, are commonly found.

Liver function tests assessing baseline liver function are used to exclude hepatic disease prior to commencing certain antihyperglycemic agents (eg, biguanides, thiazolidinediones). Periodic measurements are required during treatment with thiazolidinediones. Liver cirrhosis is a cause of glucose intolerance.

Serum electrolytes, BUN, creatinine, uric acid, and blood gases are evaluated, because during acute decompensation, metabolic derangement from loss of water, sodium, potassium, and other electrolytes, as well as anion gap and osmolality abnormalities, are very common. Normal renal and hepatic function must be confirmed before therapy is started with some oral antidiabetic agents.

A C-peptide profile is needed, because an undetectable plasma level indicates type 1 diabetes (in the absence of hypoglycemia). C-peptide profiling may also be helpful in deciding treatment in some cases of type 2 diabetes. It is not routinely used in clinical practice.

Increased levels of plasma plasminogen activator inhibitor type 1, a marker of impaired fibrinolysis, are frequently found in patients with glucose intolerance and are a correlate of insulin resistance syndrome.[46, 47]  An increased plasma homocysteine level is a risk factor for atherosclerosis. The homocysteine level should therefore be measured in selected patients.

Electrocardiography and Other Cardiac Workup

Perform ECG and other tests, depending on the patient's cardiovascular risk profile. Features of left ventricular hypertrophy and/or cardiomegaly are common in patients with hypertension. Low-risk patients may have normal test results, whereas with appropriate cardiac testing, patients with significant cardiovascular disease may show evidence of ischemia.

 

Treatment

Approach Considerations

Routine evaluation in an ambulatory setting is feasible for most patients. Patients with acute decompensation due to glucose intolerance or any related disorders may require inpatient care. A major goal in the management of glucose intolerance is glycemic control.

Of note is the novel treatment with DPP-4–resistant GLP-1 receptor agonists, such as exenatide and liraglutide, which are incretin mimetics, as well as with the DPP-4 inhibitors sitagliptin and vildagliptin.[48, 49, 50] Exenatide may be effective in preventing steroid-induced glucose intolerance through suppression.[51]

Both strategies have been successful in clinical studies. Liraglutide was approved by the FDA in January 2010 for monotherapy, as a second-line treatment and in combination with oral agents. The mechanisms of action of incretin mimetics include stimulation of insulin secretion in response to nutrient intake, inhibition of glucagon secretion, delay of gastric emptying, and induction of early satiety. Other benefits include preservation of beta cell mass and improvement of secretory function. The advantages of the DPP-IV inhibitors include oral availability, good tolerability, and weight neutrality.

Amylin has several glucoregulatory effects that complement those of insulin in postprandial glucose regulation; thus, mealtime amylin administration may be adjunctive to mealtime insulin replacement and may facilitate improvement of postprandial and overall glycemic control in patients with type 1 or type 2 diabetes. Naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties, however; pramlintide acetate contains an amylin analogue without those limitations.[52, 53, 54, 55, 56]

All patients with type 1 diabetes are insulin-dependent. Treatment of severe hyperglycemia during acute decompensation in a patient with type 2 diabetes may reverse the state of glucose toxicity, further improving secretory function of beta cells in the pancreas. Type 2 diabetes can be treated effectively with oral hypoglycemic drugs, with or without the addition of insulin. The natural history of type 2 diabetes is that of progressive beta-cell deterioration, secondary failure of oral agents, and the subsequent need for insulin therapy.

Gestational diabetes mellitus is treated with insulin and/or with lifestyle change. Oral agents are contraindicated in pregnancy.

With regard to the management of impaired glucose tolerance, the current approach is aggressive lifestyle modification. The results of the Diabetes Prevention Program showed that metformin therapy and intensive lifestyle intervention reduced the risk of developing type 1 and type 2 diabetes by 31% and 58%, respectively, compared with placebo in individuals with impaired glucose tolerance.[57] The Study to Prevent Non-Insulin–Dependent Diabetes Mellitus Trial demonstrated a 25% relative risk reduction in the development of diabetes, and an associated reduction in hypertension (34%) and cardiovascular events (49%).[58]

Orlistat may be beneficial in the context of obesity.[59]

Medical nutritional therapy should be guided by the American Dietetic Association recommendations and individualized by weight and height, level of physical activity, and requirements for calories and nutrients.[60]  A high level of physical activity is desirable, as appropriate to the patient's ability and general health. Most patients benefit from carefully planned exercise programs tailored to individual needs.[61]

Long-term monitoring of affected patients includes ensuring medication compliance, identifying adverse effects, blood glucose and HbA1c monitoring, dietary consultations and measures, and exercise management.

For more information, see Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2.

Lifestyle Modification

Intensive lifestyle modification has been shown to effectively delay or prevent diabetes in a cost-effective manner.[59, 62, 63] Nonpharmacologic therapy and lifestyle modification include the following:

  • Diet 

  • Exercise

  • Counseling related to smoking cessation and alcohol intake

  • Reversing drug-related, iatrogenic causation of glucose intolerance

  • Substituting or adding agents that do not adversely affect glucose tolerance; reducing dosage of offending drugs

2018 USDHHS physical activity guidelines

The guidelines on physical activity were released in November 2018 by the Physical Activity Guidelines Advisory Committee of the US Department of Health and Human Services (USDHHS).[64, 65]

Age- and condition-related recommendations

Children aged 3-5 years: Should be physically active throughout the day to enhance growth and development.

Children aged 6-17 years: Sixty minutes or more of moderate-to-vigorous physical activity per day.

Adults: At least 150-300 minutes per week of moderate-intensity aerobic physical activity, OR 75-150 minutes per week of vigorous-intensity aerobic physical activity, OR an equivalent combination of moderate- and vigorous-intensity aerobic activity; muscle-strengthening activities should be performed on two or more days per week.

Older adults: Multicomponent physical activity to include balance training, aerobic activity, and muscle-strengthening activity.

Pregnant and postpartum women: At least 150 minutes of moderate-intensity aerobic activity weekly.

Adults with chronic conditions or disabilities who are able: Follow key guidelines and perform both aerobic and muscle-strengthening activities.

Sleep, daily functioning, and mental health

Strong evidence demonstrates that moderate-to-vigorous physical activity improves sleep quality by decreasing the time it takes to fall asleep; it can also increase deep-sleep time and decrease daytime sleepiness.

Single episodes of physical activity promote improvements in executive function, to include organization of daily activities and future planning. Cognition (ie, memory, processing speed, attention, academic performance) also can be improved with physical exercise.

Regular physical activity reduces the risk of clinical depression, as well as reducing depressive symptoms and symptoms of anxiety.

Strong evidence demonstrates regular physical activity improves perceived quality of life.

Risk of diseases and conditions

Regular physical activity minimizes excessive weight gain, helps maintain weight within a healthy range, improves bone health, and prevents obesity, even in children as young as 3-5 years.

In pregnant women, physical activity helps reduce excessive weight gain in pregnancy and helps reduce the risk of developing gestational diabetes and postpartum depression.

Regular physical activity has been shown to improve cognitive function and to reduce the risk of dementia; falls and fall-related injuries; and cancers of the breast, esophagus, colon, bladder, lung, endometrium, kidney, and stomach. It also helps retard the progression of osteoarthritis, type 2 diabetes, and hypertension.

Promotion of physical activity

School- and community-based programs can be effective.

Environmental and policy changes should improve access to physical activity and support of physical activity behavior.

Information and technology should be used to promote physical activity, to include activity monitors (eg, wearable devices), smartphone apps, computer-tailored printed material, and Internet-based programs for self-monitoring, message delivery, and support.

Pharmacologic Therapy

Pharmacologic therapy may be required in the following situations:[66]

  • Fasting glucose more than 126 mg/dL, postprandial glucose more than 160 mg/dL, or glycosylated hemoglobin (HbA1c) more than 7%

  • Hyperglycemia (a significant risk factor in development of vascular complications)

In addition to lifestyle counseling, metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with a body mass index (BMI) above 35 kg/m2, those younger than 60 years, women with prior gestational diabetes, and/or those with rising HBA1C despite lifestyle intervention.[4]

Note that long-term metformin use may be associated with biochemical vitamin B12 deficiency; thus, consider periodic measurement of vitamin B12 levels in patients receiving metformin, particularly those with anemia or peripheral neuropathy.[4]

Bariatric Surgery

Bariatric surgery should be considered in a patient with type 2 diabetes who has a BMI of more than 35 kg/m2, especially if glycemic control with lifestyle and pharmacotherapy is difficult.[1]  Surgically induced weight loss may result in improvements in insulin sensitivity and beta-cell function, as well as changes in gut hormones.[67, 68] Better diabetic control or complete resolution of the disease (64-93%) is the end result.

A bariatric procedure is not currently recommended in the management of IGT or IFG; however, glucose intolerance resolved in 99-100% of cases of patients who underwent bariatric surgery for a comorbid state that required such an intervention (eg, class 3 obesity).

Long-term support and medical monitoring are still important after a bariatric procedure. Various complications, including postprandial hyperinsulinemic hypoglycemia, have been reported following gastric bypass surgery.

 

Guidelines

Guidelines Summary

ADA Screening Guidelines

Type 1 diabetes

The 2019 American Diabetes Association (ADA) guidelines notes that screening with an autoantibodies panel for type 1 diabetes risk is currently recommended only in the setting of a research trial or in first-degree relatives of a proband with type 1 diabetes.[4]

Type 2 diabetes

Equally appropriate tests for prediabetes and type 2 diabetes are fasting plasma glucose (FPG), 2-hour plasma glucose (PG) during a 75-g oral glucose tolerance test (GTT), and HBA1C.[4]

Consider risk-based screening for prediabetes and/or type 2 diabetes after the onset of puberty or after age 10 years (whichever occurs earlier) in overweight or obese children and adolescents (body mass index [BMI] ≥85th percentile or ≥95th percentile, respectively) and those with additional risk factors for diabetes.[4]

In asymptomatic adults, consider screening tests for prediabetes and type 2 diabetes mellitus with an informal assessment of risk factors or validate tools.[4] Consider screening tests for prediabetes and/or type 2 diabetes in asymptomatic adults of any age who are overweight or obese (BMI ≥25 kg/m2 (≥23 kg/m2 for Asian Americans) and have one or more additional risk factors,[4] including the following[1] :

  • Physical inactivity

  • First-degree relative with diabetes

  • High-risk ethnic background (eg, African American, Latino, Native American, Asian American, Pacific Islander)

  • Women who were diagnosed with gestational diabetes mellitus

  • Hypertension of 140/90 mm Hg and greater or on therapy for hypertension

  • High-density lipoprotein cholesterol (HDL-C) level below 35 mg/dL (0.90 mmol/L) and/or triglyceride level above 250 mg/dL (2.82 mmol/L)

  • Women with polycystic ovarian syndrome (PCOS)[69, 70, 71]

  • HBA1C ≥5.7% [39 mmol/mol], impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) on previous testing

  • Other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans)

  • History of cardiovascular disease

All individuals should be tested beginning at age 45 years.[4]  If test results are normal, it is reasonable to repeat testing at a minimum of 3-year intervals. Consider more testing more frequently depending on the initial results and risk status.

Test annually patients with prediabetes (HBAIC ≥5.7% [39 mmol/mol], IGT, or IFG). Women previously diagnosed with gestational diabetes should have lifelong testing at a minimum of every 3 years.[4]

Novel CV Risk Reduction Therapies in T2D and CVD

The American College of Cardiology released expert consensus decision pathways on the use of two major new classes of diabetes drugs—sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs)—for cardiovascular (CV) risk reduction in patients with type 2 diabetes (TD2) and atherosclerotic CV disease (ASCVD) in November 2018.[72, 73] The main focus of management is in the outpatient ambulatory setting.

The SGLT2 inhibitors appear to reduce major adverse CV events (MACE) and the risk of heart failure (HF) but increase the risk for genital mycotic infections, whereas GLP-1RAs offer reductions in MACE but are associated with transient nausea and vomiting. Both classes of agents have benefits in reducing blood pressure and weight, and they have a low risk for hypoglycemia.

For CV risk reduction, initiate agents with demonstrated CV benefit from either drug class at the lowest doses; no uptitration is necessary for SGLT2 inhibitors, whereas the GLP-1RAs should be slowly uptitrated (to avoid nausea) to the maximal tolerated dose.

At the initiation of an SGLT2 inhibitor or a GLP-1RA agent, clinicians should avoid hypoglycemia in patients by monitoring those with A1C levels near or below target, particularly when patients' existing diabetes therapies include sulfonylureas, glinides, or insulin.

In addition to reducing MACE and CV death, SGLT2 inhibitors are also suitable for preventing hospitalization for HF.

Empagliflozin is the preferred SGLT2 inhibitor based on the available evidence and overall benefit-risk balance.

Liraglutide should be the preferred agent among the GLP-1RAs for CV event risk reduction.

Two SGLT2 inhibitors (ie, canagliflozin, ertugliflozin) appear to be associated with an increased risk of amputation. It is unclear whether or not this is a class effect; therefore, clinicians should closely monitor patients on these agents who have a history of amputation, peripheral arterial disease, neuropathy, or diabetic foot ulcers.

Patients with T2D and clinical ASCVD on metformin therapy (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1RA with proven CV benefit added to their treatment regimen. For patients not on background metformin therapy, practitioners may use their clinical judgment to prescribe an SGLT2 inhibitor or GLP-1RA for CV risk reduction.

It appears reasonable to concomitantly use an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit if clinically indicated, although such combination therapy has not been studied for CVD risk reduction.

 

Medication

Medication Summary

Oral antidiabetic agents can be classified into functional categories, as follows[50, 74, 75, 76, 77, 78, 79, 80, 81, 82] :

  • Secretagogues (eg, sulfonylureas, meglitinides), which stimulate insulin release

  • Insulin sensitizers (eg, biguanides, thiazolidinediones), which reduce insulin resistance

  • Medications that slow the digestive/absorptive process (eg, alpha-glucosidase inhibitors)

  • Incretin-based therapies: Dipeptidyl peptidase 4 (DPP-4) inhibitors (eg, sitagliptin), which inhibit DPP-4, the enzyme that inactivates incretin hormones glucagon-like peptide 1 (GLP-1) and glucose‐dependent insulinotropic polypepide (GIP).[48, 49]  More recently, a GLPRA (GLP-1 receptor agonist) has become available as an oral agent.

  • Selective sodium-glucose transporter-2 (SGLT2) inhibitors (eg, canagliflozin) block reabsorption of glucose in the kidney

  • Centrally acting dopamine agonist (bromocriptine), presumably via increase in central (hypothalamic) dopaminergic tone

Sulfonylureas

Class Summary

Sulfonylureas stimulate insulin release from pancreatic beta cells. These agents include chlorpropamide and tolbutamide (first-generation), as well as glipizide, glyburide, and glimepiride (second-generation), are secretagogues (ie, medications that stimulate insulin secretion).

Glipizide (Glucotrol, Glucotrol XL)

Glipizide is a second-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.

Glyburide (Glynase)

Glyburide is a second-generation sulfonylurea and is more potent and exhibits fewer drug interactions than first-generation agents.

Glimepiride (Amaryl)

Glimepiride is a third-generation sulfonylurea that may cause more physiologic insulin release than some of the older agents.

Chlorpropamide (Diabinese, Glucamide)

Chlorpropamide is a first-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells. It is the longest-acting sulfonylurea, present in blood longer than 24 hour in many patients, and longer in patients with renal insufficiency.

Tolbutamide

First-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.

Meglitinide derivatives

Class Summary

These agents stimulate insulin secretion from pancreatic cells, lowering blood glucose levels.

Repaglinide (Prandin)

Repaglinide is a meglitinide analogue, a secretagogue that acts on the pancreas to stimulate the release of insulin.

Nateglinide (Starlix)

Nateglinide is an analogue of D-phenylalanine. It mimics endogenous insulin patterns, restores early insulin secretion, and controls mealtime glucose surges.

Biguanides

Class Summary

These agents improve peripheral glucose uptake and utilization.

Metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)

Metformin reduces insulin resistance (ie, metformin is an insulin sensitizer). Hepatic glucose output is decreased; peripheral insulin-stimulated uptake is increased.

Thiazolidinediones

Class Summary

These agents stimulate peripheral use of glucose as stimulated by insulin. Rosiglitazone and pioglitazone are commonly used.

Following the online publication of a meta-analysis, the Food and Drug Administration on May 21, 2007, issued an alert to patients and health care professionals stating that rosiglitazone can potentially cause an increased risk of myocardial infarction and heart-related deaths. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity.

The drug is highly selective and is a potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.

As of September 2010, the FDA is requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.

For more information, see FDA’s Safety Alert on Avandia. The meta-analysis published online, entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (theheart.org from WebMD), including the following articles: Rosiglitazone increases MI and CV death in meta-analysis and The rosiglitazone aftermath: legitimate concerns or hype?

Rosiglitazone (Avandia)

Available only through a restricted access program. Rosiglitazone sensitizes target cells' response to insulin and has an effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue.

Pioglitazone (Actos)

Pioglitazone improves target cell response to insulin and increases insulin-dependent glucose use in skeletal muscle and adipose tissue.

Alpha-glucosidase inhibitors

Class Summary

These agents include acarbose and miglitol, medications that slow the digestive and absorptive process, preventing postprandial glucose surges.

Acarbose (Precose)

Acarbose slows digestive and absorptive processes. It delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. Acarbose inhibits the metabolism of sucrose to glucose and fructose.

Miglitol (Glyset)

Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.

Rapid-acting insulins

Class Summary

Rapid-acting insulins have a short duration of action and are appropriate before meals or when blood glucose levels exceed target levels and correction doses are needed. These agents are associated with less hypoglycemia than regular insulin.

Insulin aspart (NovoLog)

Insulin aspart has a short onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin aspart is FDA approved for use in insulin pumps.

Insulin glulisine (Apidra)

Insulin glulisine has a rapid onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin glulisine is FDA approved for use in insulin pumps.

Insulin lispro (Humalog)

Insulin lispro has a rapid onset of action of 5-15 minutes and a short duration of action of 4 hours.

Insulin inhaled (Afrezza)

Inhaled human insulin is identical, in structure, to that of native human insulin. It is absorbed into carrier particles which dissolve within the lungs after inhalation. This leads to rapid absorption of insulin in the systemic circulation. Inhaled insulin is an ultra-rapid acting insulin.

Short-acting insulins

Class Summary

Short-acting insulins are commonly used when a slower onset of action or greater duration of action is desired.

Regular insulin (Humulin R, Novolin R)

Regular insulin has a rapid onset of action of 0.5-1 hours and duration of action of 4-6 hours. The peak effects are seen within 2-4 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) and 30% regular human insulin (ie, Novolin 70/30, Humulin 70/30) are also available.

Intermediate-acting insulins

Class Summary

Intermediate-acting insulins have a slow onset of action and a longer duration of action. These agents are commonly combined with faster-acting insulins to maximize the benefits of a single injection.

Insulin NPH (Humulin N, Novolin N)

Insulin NPH has an onset of action of 3-4 hours and duration of action of 16-24 hours. The peak effect of insulin NPH occurs within 8-14 hours.

Long-acting insulins

Class Summary

These insulins provide a longer duration of action, and, when combined with rapid- or short-acting insulins, they provide better glucose control.

Insulin detemir (Levemir)

Insulin detemir is indicated for once- or twice-daily dosing for patients with type 1 or 2 diabetes mellitus. The duration of action is up to 24 hours, resulting from slow systemic absorption of detemir from the injection site.

Insulin Glargine (Lantus)

Insulin glargine has an onset of action of 4-8 hours and duration of action of 24 hours. Peak effects occur within 16-18 hours.

Premixed Insulins

Class Summary

Premixed insulins are used in the treatment of type 1 or 2 diabetes mellitus. These combinations combine rapid- and long-acting insulins.

Insulin aspart protamine/insulin aspart (NovoLog 50/50, NovoLog 70/30)

The insulin aspart protamine/insulin aspart combination includes a rapid-onset insulin, insulin aspart, and intermediate-acting insulin, insulin aspart protamine. Insulin aspart is absorbed more rapidly than regular human insulin, and insulin aspart protamine has a prolonged absorption profile after injection.

Insulin lispro protamine/insulin lispro (Humalog 50/50, Humalog 75/25)

The insulin lispro protamine/insulin lispro combination includes a rapid-onset insulin, insulin lispro, and insulin lispro protamine, which has a prolonged duration of action.

Glucagon-like Peptide-1 (glp-1) Receptor Agonists

Class Summary

This new class broadens the armamentarium of antidiabetic medications. Exenatide and liraglutide are dipeptidyl peptidase 4 (DPP-4)–resistant glucagonlike peptide-1 (GLP-1) receptor agonists or analogues. As incretin mimetics, they enhance insulin secretion, suppress glucagon secretion, and slow gastric emptying. Exenatide has been approved by the FDA as adjunctive therapy in patients who have not achieved adequate control with metformin or sulfonylurea; exenatide has been available since June 2005, and a new, long-acting, once-weekly subcutaneous injection (Bydureon) was approved by the FDA in January 2012. Liraglutide was approved by the FDA in January 2010. This agent is administered daily.

In the DURATION-5 (Diabetes therapy Utilization: Researching changes in A1C, weight and other factors Through Intervention with exenatide ONce weekly) study, the exenatide once-weekly formulation was found to provide significantly greater improvement in glycemic control than the twice-daily preparation. Additionally, less nausea was observed with the once-weekly exenatide formulation compared with the twice-daily preparation.[83]

There are currently other weekly injectable GLPRA (GLP-1 receptor agonists) (eg, dulaglutide, semaglutide). Semaglutide is available as an oral formulation (Rybelsus), approved by the FDA in 2019, the first in the class that does not need to be injected.

Lixisenatide is another injectable GLPRA. It is administered daily.

Recommendations for the use of GLPRAs have been strengthened by increasing evidence of their efficacy and cardiovascular outcome.

Exenatide injectable solution/suspension (Byetta, Bydureon)

Exenatide is a 39-amino acid incretin mimetic peptide derived from Gila monster hormone exendin-4. It is structurally similar to glucagonlike peptide-1 (GLP-1). It enhances glucose-mediated insulin secretion in the beta cell, decreases the pathologic hypersecretion of glucagon in the alpha cell, slows gastric emptying, and induces satiety. It also improves postprandial hyperglycemia without a significant risk of hypoglycemia, producing moderate weight loss. Improvement in islet cell function has been demonstrated by increased proinsulin-to-insulin ratio.

The suspension form of exenatide allows once-weekly dosing by SC administration. Clinical trials observed a statistically significant improvement in HBA1c levels and fasting plasma glucose levels with the long-acting exenatide once-weekly SC injection compared with the twice-daily SC injection. The suspension is supplied as a pre-filled disposable single-dose autoinjector or cartons of four single-dose trays (includes one vial containing 2mg exenatide, one prefilled syringe containing diluent, one vial connector, and two custom needles specific to this delivery system).

Liraglutide (Victoza, Saxenda)

Liraglutide is an incretin mimetic agent that elicits glucagonlike peptide-1 (GLP-1) receptor agonist activity. It activates GLP-1 receptor by stimulating G-protein in pancreatic beta cells. It also increases intracellular cyclic AMP, leading to insulin release in the presence of elevated glucose concentrations.

Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has not been studied in combination with insulin.

Amylinomimetic agents

Class Summary

Pramlintide is an amylinomimetic agent that modulates gastric emptying, prevents postprandial increases in plasma glucagon, and promotes satiety, leading to decreased caloric intake and potential weight loss.[52, 53, 54, 55, 56, 84]

Although naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties (eg, poor solubility; self-aggregation; formation of b-pleated sheets, amyloid fibrils, amyloid plaques), the selective substitution of the amino acid proline for Ala25, Ser28, and Ser29 addresses the suboptimal physicochemical properties of human amylin while preserving the important metabolic actions. Pramlintide acetate injection, which contains this amylin analogue, is a sterile, clear, colorless, aqueous solution that also contains mannitol for isotonicity and the preservative m-cresol.

Pramlintide (SymlinPen)

Pramlintide is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreas beta cells. Pramlintide slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. It is indicated to treat type 1 or type 2 diabetes in combination with insulin.

Pramlintide is administered before meals in patients who have not achieved desired glucose control despite optimal insulin therapy. The drug helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1c levels) compared with insulin alone. Reductions in insulin use and body weight are also observed.

Dipeptidyl Peptidase-IV Inhibitors

Class Summary

The DPP-4 inhibitors are oral agents that inactivate the major enzyme responsible for degrading incretin hormones in vivo.

Sitagliptin (Januvia)

Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. Sitagliptin increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for diabetes type 2 as monotherapy or in combination with metformin or with a peroxisome proliferator-activated receptor gamma agonist (eg, thiazolidinediones).

Saxagliptin (Onglyza)

Saxagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Sodium-glucose Cotransporter 2 Inhibitors

Class Summary

SGLT2 inhibitors block the reabsorption of glucose in the kidney through an increased glucose excretion by lowering the renal threshold.

Canagliflozin (Invokana)

Canagliflozin reduces plasma glucose concentrations by increasing urinary excretion of glucose.

Dopamine Agonists

Class Summary

The exact mechanism is unclear. The dopamine receptor agonist is considered to increase CNS dopamine receptor activity to positively affect neuroendocrine metabolic control.

Bromocriptine (Cycloset)

Bromocriptine quick-release formulation (Cycloset) is the only bromocriptine product indicated for type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. It is thought to increase dopamine receptor activity in the central nervous system, thereby positively affecting neuroendocrine metabolic control.

Antidiabetics, Glucagon-like Peptide-1 Agonists

Semaglutide (Rybelsus, Ozempic)

Semaglutide is a GLP-1 receptor agonist that is available in an oral form (Rybelsus) and as an injectable (Ozempic). It is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.

 

Questions & Answers

Overview

What is glucose intolerance?

What is the pathophysiology of gestational diabetes mellitus (GDM)?

What is the pathophysiology of glucose intolerance disorders?

What is the pathophysiology of type 1 diabetes mellitus (DM)?

What is the pathophysiology of type 2 diabetes mellitus (DM)?

What causes specific types of diabetes other than DM and GDM?

What is the pathophysiology of glucose intolerance?

What causes glucose intolerance?

What is the prevalence of glucose intolerance disorders in the US?

What is the global prevalence of glucose intolerance disorders?

What are the racial predilections of glucose intolerance disorders?

What are the sexual predilections of glucose intolerance disorders?

Which age groups have the highest prevalence of glucose intolerance?

What is the prognosis of glucose intolerance disorders?

What is the prognosis of gestational diabetes?

What is the prognosis of impaired glucose tolerance?

What is included in the patient education about glucose intolerance disorders?

Presentation

Which clinical history findings are characteristic of type 1 diabetes mellitus (DM)?

Which clinical history findings are characteristic of type 2 diabetes mellitus (DM)?

Which clinical history findings are characteristic of gestational diabetes mellitus (GDM)?

Which clinical history findings are characteristic of prediabetes?

Which clinical history findings are characteristic of glucose intolerance?

Which physical findings are characteristic of glucose intolerance disorders?

Which physical findings are characteristic of genetic syndromes associated with glucose intolerance?

Which physical findings are characteristic of systemic disorders associated with glucose intolerance?

DDX

Which conditions are included in the differential diagnoses of glucose intolerance?

What are the differential diagnoses for Glucose Intolerance?

Workup

What are the ADA diagnostic criteria for type 1 diabetes mellitus (DM)?

What are the ADA diagnostic criteria for prediabetes?

What are the WHO diagnostic criteria for diabetes and impaired glucose tolerance?

What are the ADA diagnostic criteria for gestational diabetes mellitus (GDM)?

What are the indications for plasma glucose (PG) measurement?

What is the role of fasting plasma glucose (FPG) studies in the workup of glucose intolerance disorders?

What is the role of oral glucose tolerance test (OGTT) in the workup of glucose intolerance disorders?

What is the role of A1C testing in the workup of glucose intolerance disorders?

What is the role of lab tests in the workup of glucose intolerance disorders?

What is the role of cardiac testing in the workup of glucose intolerance disorders?

Treatment

How are glucose intolerance disorders treated?

Which lifestyle modifications are used in the treatment of glucose intolerance disorders?

What are the USDHHS guidelines on physical activity for the prevention of glucose intolerance disorders?

What is the role of medications in the treatment of glucose intolerance disorders?

What is the role of bariatric surgery in the treatment of glucose intolerance disorders?

Guidelines

What are the ADA screening guidelines for glucose intolerance disorders?

What is the role of sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in the treatment of glucose intolerance disorders?

Medications

Which medications are used in the treatment of glucose intolerance disorders?

Which medications in the drug class Dopamine Agonists are used in the treatment of Glucose Intolerance?

Which medications in the drug class Sodium-glucose Cotransporter 2 Inhibitors are used in the treatment of Glucose Intolerance?

Which medications in the drug class Dipeptidyl Peptidase-IV Inhibitors are used in the treatment of Glucose Intolerance?

Which medications in the drug class Amylinomimetic agents are used in the treatment of Glucose Intolerance?

Which medications in the drug class Glucagon-like Peptide-1 (glp-1) Receptor Agonists are used in the treatment of Glucose Intolerance?

Which medications in the drug class Premixed Insulins are used in the treatment of Glucose Intolerance?

Which medications in the drug class Long-acting insulins are used in the treatment of Glucose Intolerance?

Which medications in the drug class Intermediate-acting insulins are used in the treatment of Glucose Intolerance?

Which medications in the drug class Short-acting insulins are used in the treatment of Glucose Intolerance?

Which medications in the drug class Rapid-acting insulins are used in the treatment of Glucose Intolerance?

Which medications in the drug class Alpha-glucosidase inhibitors are used in the treatment of Glucose Intolerance?

Which medications in the drug class Thiazolidinediones are used in the treatment of Glucose Intolerance?

Which medications in the drug class Biguanides are used in the treatment of Glucose Intolerance?

Which medications in the drug class Meglitinide derivatives are used in the treatment of Glucose Intolerance?

Which medications in the drug class Sulfonylureas are used in the treatment of Glucose Intolerance?

Which medications in the drug class Antidiabetics, Glucagon-like Peptide-1 Agonists are used in the treatment of Glucose Intolerance?