eMedicine Specialties > Endocrinology > Diabetes Mellitus

Glucose Intolerance

Author: Samuel T Olatunbosun, MD, FACP, Chief, Internal Medicine, 56th Medical Group, Luke Air Force Base
Coauthor(s): Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP, Professor of Medicine, Program Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center
Contributor Information and Disclosures

Updated: Aug 5, 2009

Introduction

Background

Several distinct disorders of glucose tolerance exist. The most widely used classification of diabetes mellitus and allied categories of glucose intolerance is that recommended by the World Health Organization (WHO) in 1985. However, the American Diabetes Association (ADA) has proposed a system based on disease etiology instead of on type of pharmacologic treatment.1

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

  • Type 1 diabetes mellitus
  • Type 2 diabetes mellitus
  • Other specific types of diabetes
  • Gestational diabetes mellitus (GDM)2
  • Impaired glucose tolerance (IGT)
  • Impaired fasting glucose

Conditions secondarily associated with glucose intolerance also occur.

The diagnosis of a type of diabetes or glucose intolerance in a patient is usually based on the circumstances at the time of diagnosis; however, not all patients easily fit into a particular class. When hyperglycemia is present, its severity may change over time, depending on the nature of the underlying process. An appropriate management approach to any of the disorders of glucose intolerance depends on a good understanding of the mechanisms involved in the disease process.3,4

Pathophysiology

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

Type 1 diabetes

Type 1 diabetes 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 of the 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. 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.

In health, normoglycemia is maintained by fine hormonal regulation of peripheral glucose uptake and hepatic production.

Type 2 diabetes
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.5 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.

Impaired glucose tolerance is a transitional state from normoglycemia to frank diabetes; however, 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 is worsened by the compensatory hyperinsulinemia.

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. Central adiposity is more important than is increased generalized fat distribution. In patients with frank diabetes, glucose toxicity and lipotoxicity may further impair insulin secretion by the beta cells.6

Other forms of glucose intolerance

Gestational diabetes mellitus is described as any degree of glucose intolerance in which onset or first recognition occurs during pregnancy.2 Insulin requirements are increased during pregnancy. This is because of the presence of insulin antagonists, such as human placental lactogen or chorionic somatomammotropin, and cortisol, which 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. 

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.

Causes of glucose intolerance

The gastrointestinal tract plays a significant role in glucose tolerance. Upon 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 lately as a result of efforts to develop new agents that may improve glycemic control in patients with type 2 diabetes through mechanisms that are not currently available. These strategies include the inhibition of dipeptidyl peptidase IV (DPP-4), the major enzyme responsible for degrading incretin hormones in vivo, and the use of GLP-1 agonists.7 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 lower rate of glucose disposal, whereas insulin secretion and action, as well as postprandial turnover, are essentially normal in individuals with isolated IGT.8

Frequency

United States

  • Approximately 19.3 million (9.3%) people in the United States have diabetes. Nearly 6 million of these cases are undiagnosed.9,10
  • Impaired glucose tolerance (IGT), considered to be the most common form of glucose intolerance in the United States, is present in 11% of the general population. Prevalence of impaired fasting glucose is 6.9% (13.4 million Americans).10 According to the ADA, however, a review of previous data using a new diagnostic criterion for impaired fasting glucose revised the statistics to 41 million Americans in the 2 categories combined, with 16 million Americans in the IGT category alone.
  • Type 1 diabetes, which usually occurs in children and adolescents, accounts for 5-10% of diabetes cases. Approximately 1 per 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 diabetes cases. This type of diabetes is reaching epidemic proportions. Minority populations, especially American Indians, Hispanic persons, and African 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 used.

International

  • The lowest prevalence rates of diabetes (<1%) are found among certain African and Chinese populations and in rural populations of the Mapuche Indians of Chile. 
  • The highest prevalence rates of type 2 diabetes among patients older than 30 years are found in the Pima Indians of Arizona and in the Nauran people of the Pacific island of Nauru. The prevalence rates of these populations are 50%11 and 35%, respectively. The risk in other populations is classified as ranging from low to high-medium. 
  • The overall range for impaired glucose tolerance (IGT; 1-25%) is considerable, although not as wide as for diabetes (0-50%). IGT is rare in Mapuche Indians but is common in many other population groups. Generally, residents of developing nations and migrant or ethnic minorities in industrialized countries are at higher risk for diabetes and for IGT. 
  • The highest rates of type 1 diabetes occur in whites, especially in those of northern European descent. The disease is unknown or rare in certain ethnic groups (eg, Japanese, Chinese, African). 
  • The incidence and prevalence rates of many specific types of diabetes or glucose intolerance, such as the genetic syndromes, are presently unknown in general populations.

Mortality/Morbidity

Several studies demonstrate a relationship between high plasma glucose distributions and the risk for cardiovascular disease and for increased mortality, even within the normoglycemic range. The total annual economic cost (direct and indirect) of diabetes in the United States is at least $132 billion. The overall cost of all categories of glucose tolerance and related cardiovascular risk factors surpasses this estimate. The relationship of morbidity and mortality to glucose tolerance disorders is as follows:

  • Diabetes
    • Sixth leading cause of death by disease 
    • Seventh leading cause of death in the United States 
    • Propensity for acute metabolic complications 
    • Leading cause of end-stage renal disease 
    • Leading cause of blindness 
    • Much higher risk for heart disease 
    • Higher risk for stroke 
    • High risk for neuropathy 
    • High risk for gangrene 
  • Gestational diabetes mellitus
    • Increased risk for fetal and neonatal morbidity and mortality
    • Obstetric complications
    • Increased risk for obesity in offspring, glucose intolerance, and type 2 diabetes 
  • Impaired glucose tolerance (IGT)
    • Major risk factor for diabetes, with 20-50% of persons with IGT progressing to diabetes within 10 years
    • Baseline plasma glucose is the most consistent predictor of progression to diabetes
    • Rates of cardiovascular risk factors that are intermediate between persons with normal glucose tolerance and those with diabetes
    • Increased risk of macrovascular complications (eg, coronary artery disease, gangrene, stroke)
    • Not clearly associated with microvascular complications (eg, nephropathy, retinopathy, neuropathy) 
  • Impaired fasting glucose
    • Not associated with the same risk level as IGT
    • Risk of cardiovascular disease much lower in impaired fasting glucose

Race

  • Native Americans and certain Pacific island populations have the highest risk for glucose intolerance.
  • African Americans and Hispanics have higher rates of glucose intolerance than do non-Hispanic whites.
  • Type 2 diabetes is more prevalent in ethnic minorities, while type 1 diabetes occurs with higher frequencies in whites, especially in white persons of northern European descent.
  • Type 1B diabetes is more common in patients of Asian or African origin.

Sex

  • In the WHO global data, the prevalence ratio of diabetes between 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.

Age

  • 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; the prevalence rises with age.
  • Maturity-onset diabetes of youth (MODY) can be expressed in childhood or in early adolescence.

Clinical

History

  • Type 1 diabetes
    • The warning symptoms of type 1 diabetes include polyuria, polydipsia, and polyphagia due to hyperglycemia.
    • Patients may present with 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
    • 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.
    • 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 - This 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.
  • Prediabetes - The categories of impaired glucose tolerance (IGT) and impaired fasting glucose have been officially termed prediabetes, because they are risk factors for future diabetes and for cardiovascular disease.12,13
    • 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, of obesity, of dyslipidemia, and of macrovascular disease, such as stroke, coronary disease, or peripheral vascular disease.
    • In most cases of IGT and impaired fasting glucose, the presence of 1 or more cardiovascular risk factors actually triggers a screening test for disorders of glucose tolerance.
  • Glucose intolerance - Diagnosis of glucose intolerance may also be coincidental in patients with various conditions that may be complicated with glucose intolerance. These conditions include liver cirrhosis, end-stage renal disease, and some rare genetic disorders.

Physical

  • Acute presentation
    • 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.
  • Routine evaluation
    • 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 the 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 1.5-2 times more common in individuals with diabetes than in matched individuals without diabetes. Approximately 40% of individuals with hypertension have impaired glucose tolerance.
  • Thorough evaluation - A thorough evaluation of the various systems and organs is pertinent.
    • Eye examination is important, because ocular manifestations, such as pupillary abnormalities, cataract, refractory errors, retinopathy, and other changes, may be found in some patients with diabetes. These manifestations result mainly from chronic, uncontrolled hyperglycemia.
    • 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.
    • Type A insulin resistance - 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, of which some variants may be characterized by thin or muscular body habitus or acral enlargement (pseudoacromegaly).
    • Type B insulin resistance - 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).
    • Internal organ diseases - 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 stage of the disease. 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.

Causes

  • Genetic defects of beta-cell function
    • 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
    • Others
  • Defects in insulin action
    • Structure and function of insulin receptor - Postreceptor signal transduction pathways
    • Type A insulin resistance
    • Leprechaunism
    • Rabson-Mendenhall syndrome
    • Lipoatrophic diabetes
    • Others
  • Diseases of the exocrine pancreas - Note that the category malnutrition-related diabetes has been eliminated from the list below because of lack of evidence of the association of protein deficiency with direct causation of diabetes, while fibrocalculous pancreatopathy has been reclassified as a disease of the exocrine pancreas
  • Endocrine diseases associated with excess production of insulin antagonists
  • Drugs or chemical agents with adverse effects
    • Thiazides
    • Diazoxide
    • Glucocorticoids
    • Oral contraceptives
    • Beta-adrenergic agonists
    • Nicotinic acid
    • Thyroid hormone
    • Pentamidine
    • Alpha interferon
    • Atypical antipsychotics, especially clozapine and olanzapine
    • Antiretroviral drugs
    • Vacor
    • Others 
  • Infections associated with beta-cell destruction
  • Immune-mediated causes
    • Stiff person syndrome
    • Anti-insulin receptor abnormalities 
  • Genetic syndromes
  • Pregnancy
  • Obesity
    • Powerful determinant of glucose intolerance in general population
    • Interaction of genetics and acquired factors, such as physical inactivity and dietary habits
  • Other causes of glucose intolerance

More on Glucose Intolerance

Overview: Glucose Intolerance
Differential Diagnoses & Workup: Glucose Intolerance
Treatment & Medication: Glucose Intolerance
Follow-up: Glucose Intolerance
Multimedia: Glucose Intolerance
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

glucose intolerance, abnormal glucose tolerance, abnormal glucose homeostasis, disorders of glucose tolerance, disorders of glycemia, glucose tolerance, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, GDM, impaired glucose tolerance, IGT, impaired fasting glucose, IFG, insulin resistance, hyperglycemia, normoglycemia, ketoacidosis, dysmetabolic syndrome, central adiposity, pancreas, pancreatic function, hypoglycemia, pancreatic beta cells

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Contributor Information and Disclosures

Author

Samuel T Olatunbosun, MD, FACP, Chief, Internal Medicine, 56th Medical Group, Luke Air Force Base
Samuel T Olatunbosun, MD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, and American Diabetes Association
Disclosure: Nothing to disclose.

Coauthor(s)

Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP, Professor of Medicine, Program Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center
Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Royal College of Physicians
Disclosure: Eli Lilly None Speaking and teaching; GlaxoSmithKline None Speaking and teaching; Merck None Speaking and teaching

Medical Editor

David S Schade, MD, Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center
David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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