Glucose Intolerance

Etiology

The precise etiology of glucose intolerance remains unclear. There appears to be an interaction between genetic and epigenetic factors with a sedentary lifestyle and poor dietary habits. Defects in both insulin resistance and insulin secretion are important in declaring the clinical syndrome.

Epidemiology

From 2009 through 2012, the prevalence of pre-diabetes in the United States was 37% in adults older than 20 years and 51% in those older than 65 years. According to ADA, in 2015, 84.1 million Americans age 18 and older had prediabetes. People with IGT are generally asymptomatic and have only increased glucose level; therefore, a large proportion of these patients remains undiagnosed.

In 2010, the worldwide prevalence of glucose intolerance was about 8% [2]. In the United States, about 57 million people had IFG while 30 million had IGT. In a study of progression from normal glucose tolerance (NGT) to IGT, 14% of participants with NGT had progressed to IFG and 48% to IGT by 10 years. The progress from NGT to IGT is about 4-times greater than the progression from NGT to IFG. Persons older than 65 years have higher rates of progression to abnormal 2-hour value during a GTT than younger persons.

Zhang et al. did a systematic review on the A1C level and future risk of diabetes and found that as A1C increased from 6.0% to 6.5%, 5-year incidence of diabetes showed an increase of 25% to 50%. Conversion from GI to diabetes varies with population characteristics and criteria used for diagnosis.

Pathophysiology

In healthy individuals, levels of glucose in the circulation are strictly regulated. The exit and entry of glucose are predominantly regulated by insulin and glucagon respectively. During an overnight fast of 10 to 14 hours, glucose is produced primarily in the liver by glycogenolysis and gluconeogenesis. This is known as endogenous glucose production (EGP) and is directly related to both fat-free mass and fasting plasma glucose (FPG) concentration[3]. In the postprandial state, EGP is suppressed by an increase in insulin concentration and a decrease in glucagon levels.

IFG and IGT are insulin resistance conditions with associated beta cell dysfunction. Initially, there is a compensatory increase in insulin secretion which maintains glucose levels in normal range. As the condition progresses, beta cells change, and the insulin secretion is unable to maintain glucose homeostasis, producing glucose intolerance. Under normal physiological conditions, postprandial insulin release is not in steady state but pulsatile. This pattern of pulsatile secretion  is blunted in individuals with glucose intolerance, reflecting the lost ability of beta cells to sense and respond to changes in plasma glucose levels.

Due to insulin resistance, the FPG concentrations are higher in GI than in those with NGT. In overweight or obese individuals, increased liver fat oxidation is also seen.

The two subsets of glucose intolerance, IFG and IGT differ in the site of insulin resistance as well as the pattern of insulin secretion. IFG is characterized predominantly by hepatic insulin resistance and normal muscle insulin sensitivity. People with IFG show a defect in early phase insulin secretory response to glucose. IGT is mainly associated with muscle insulin resistance. In addition to the defective early-phase insulin-secretory response, IGT also shows a severe deficit in late-phase insulin secretion. Evolving data suggest a role for impaired lipolysis, abnormal incretin biology, glucagon dysregulation and inflammation in both IGT and IFG Nathan DM 2007[4].

History and Physical

These patients are usually asymptomatic since they have prediabetes. The family history of diabetes and any previous history of gestational diabetes mellitus should be obtained. If they are diabetic, they will present with polyuria, polydipsia, infections and neuropathy.

Height, weight, and body mass index (BMI) should be recorded. There is a high prevalence of metabolic syndrome; therefore, patients with IFG are at risk for ASCVD and might present with hypertension. Retinopathy needs to be excluded in Diabetic  patients. All pulses should be palpated to examine for the peripheral arterial disease.

Evaluation

Screening

It is estimated that the onset of DM occurs 4 to 7 years before its clinical diagnosis. Screening for hyperglycemia can identify individuals who are at risk for preventable diabetes complications. Persons more than 40 years of age should be screened annually. More frequent screening is recommended in individuals with additional risk factors for diabetes. These include:

• Certain races/ethnicities (Native American, African American, Hispanics or Asian American, Pacific Islander)
• Overweight or obese persons: BMI greater than or equal to 25 kg/m2 or 23 kg/m2 in Asian Americans
• First-degree relative with diabetes
• History of CVD, hypertension, low HDL-cholesterol or hypertriglyceridemia
• Women with polycystic ovarian syndrome
• Physical inactivity
• Conditions associated with insulin resistance such as acanthosis nigricans

Women who are diagnosed with gestational diabetes mellitus (GDM) should have life-long testing at least every 3 years. For all other patients, testing should begin at age 45 years, and if results are normal, testing should be repeated at a minimum of 3-year intervals.

FPG and A1C are recommended screening tests. The 75-gm GTT can be used and needed for the diagnosis of IGT but has poor reproducibility and needs adequate preparation.

Diagnosis

Three 3 types of blood tests can diagnose GI.

Fasting plasma glucose (FPG)

The blood sample is taken after an 8 hour overnight fast. As per ADA, FPG levels between 100 and 125 mg/dL (5.6 to 6.9 mmol/L) are diagnostic of IFG. Several organizations, including World Health Organization (WHO), diagnose IFG at FPG between 110 and 125 mg/dl (6.1 and 6.9 mmol/L).The diagnosis of diabetes requires FPG greater than or equal to 126 mg/dl. FPG is fast and easy to perform and an established standard but has a high day to day variability.

Two-Hour Oral Glucose Tolerance Test (GTT)

In this test, plasma glucose level is measured before and 2 hours after ingestion of 75 gm of glucose. IGT is diagnosed if plasma glucose (PG) level in the 2-hour sample is between 140 to 199 mg/dL (7.8 to 11.0 mmol/L). DM is diagnosed if the PG is greater than or equal to 200 mg/dl. It is also a standard test but is inconvenient and more costly than FPG and has major variability issues. Patients need to consume a diet with at least 150 g per day of carbohydrates for 3 to 5 days and not take any medications that can impact glucose tolerance such as steroids and thiazide diuretics.

Glycated Hemoglobin (A1C)

This test gives an average of blood glucose over last two to three months. Patients with A1C between 5.7% to 6.4% (39 to 47 mmol/mol) are diagnosed as having increased risk of diabetes or prediabetes, the latter has stigmatization and should be avoided where possible. For a diagnosis of diabetes, the A1C levels should be greater than or equal to 6.5% (48 mmol/mol). A1C is a convenient, standardized test but is costly and has many issues as discussed below including lower sensitivity.

For all of the above tests, if the person is asymptomatic testing should be repeated on another occasion to make a diagnosis of diabetes.

The disadvantage with GTT is that it requires patient preparation and is poorly reproducible. Measuring A1C is convenient as fasting is not required. Also, it shows less variation due to pre-analytical variables and is not much affected by acute illness or stress. However, A1C should be measured using National Glycohemoglobin Standardization Program (NGSP) certified method which has been standardized for Diabetes Control and Complications Trial (DCCT) assay. In cases where there is a significant difference in plasma glucose values and A1C levels, interference due to hemoglobin variants is possible, and other glucose assays should be considered. In conditions such as sickle cell disease, pregnancy, hemodialysis, blood loss or transfusion, or erythropoietin therapy, which are known to be associated with increased red cell turnover, only plasma glucose should be used. Also, A1C is costly and may not be available everywhere. It has not been well validated in non-Caucasian populations.

Anemia due to deficiency of iron or vitamin B12 leads to spurious elevation of A1C, limiting its use in countries with high prevalence of anemia. Also, in children and elderly, the relation between A1C and FPG is suboptimal [5].

FPG, 2-hour PG during 75-g GTT, and A1C are equally appropriate for diagnosis of glucose intolerance. There is no concordance between the results of these tests. An individual with increased FPG may have normal postprandial glucose or A1C measurements. While all 3 tests can be used, given how cumbersome the GTT is, it appears that FPG and A1C will be most practical globally bearing in mind the caveats of the tests [6][7].

Treatment / Management

As glucose intolerance is a state with increased risk for diabetes and its complications, intervention can reduce the progression to diabetes. Interventions are more beneficial in IGT with or without IFG in comparison to isolated IFG.

Diet and Exercise

Lifestyle modifications which improve insulin sensitivity and beta cell function are very important in the management of glucose intolerance. Several studies have shown that lifestyle intervention can reduce conversion to type 2 diabetes. The aim is to achieve and maintain 7% loss of initial body weight. It should include moderate-intensity physical activity (such as brisk walking) for at least 150 minutes per week, with a minimum frequency of 3 times a week.

Reducing caloric intake is of paramount importance for those at high risk for developing type 2 DM. The quality of fats consumed in the diet is more important than the total quantity. Diets relatively high in monounsaturated fats can help prevent T2DM. Higher intakes of nuts, berries, yogurt and high fiber food, and tea are associated with reduced diabetes risk. Conversely, red meats and sugar-sweetened beverages are associated with an increased risk of type 2 diabetes. Both the Mediterranean diet and the dietary approaches to stop hypertension (DASH) diet are reasonable strategies.

Metformin

Metformin is a biguanide which inhibits hepatic glucose production and improves insulin sensitivity. It has been shown to prevent progression to diabetes. Patients with combined IFG and IGT show benefit on treatment with metformin.  It might have greater benefit in patients under 60 years with significant obesity with a BMI greater than 35, and in women with a history of gestational DM. The role of other pharmacotherapies is not well endorsed by all organizations [8][9] [10][11].

Differential Diagnosis

• Alpha interferon

• Antiretroviral drugs

• Atypical antipsychotics

• Beta-adrenergic agonists

• Calcineurin inhibitors

• Diazoxide

• Glucocorticoids

• Insulin resistance

• Nicotinic acid

• Oral contraceptives

• Pentamidine

• Thyroid hormone

• Type 1 diabetes mellitus

• Type 2 diabetes mellitus

• Vacor