Key Points
Disease summary:
Diabetes is a chronic metabolic disorder characterized by high levels of blood glucose that may lead to micro- and macrovascular complications if not controlled effectively. Type 2 diabetes mellitus (T2DM), which is characterized by defects in insulin secretion and insulin action, is the most common form of diabetes.
Differential diagnosis:
Secondary causes of hyperglycemia should be considered. The classic differential diagnosis includes type 1 diabetes, maturity-onset diabetes of the young (MODY), pancreatic dysfunction, gestational diabetes, and other causes of obesity and insulin resistance, such as Cushing syndrome, acromegaly, polycystic ovarian disease, and drug-induced hyperglycemia (glucocorticoids).
Screening:
Routine screening for T2DM should be performed in overweight patients, including children, possessing additional risk factors at least in every 3 years. In the absence of risk factors, testing for diabetes should begin at age 45.
Hereditary basis:
T2DM is a polygenic disorder with 40% to 60% heritability. About 2% to 3% of diabetes is inherited as monogenic forms of diabetes; the most common monogenic forms are referred as MODY to distinguish them from type 1 and type 2 diabetes.
Family history and twin studies:
The risk of developing T2DM in siblings of patients with T2DM is up to three times higher than that of the general population. Monozygotic twins have a 60% or higher long-term concordance rate for diabetes, much higher than the 25% concordance rate observed for T1DM in monozygotic twins.
Environmental factors:
Obesity, sedentary lifestyle
Genome-wide associations:
At least 37 variants have been associated with T2DM. All have small effect sizes and the known risk alleles, even collectively, do a poor job at predicting the future development of diabetes.
Pharmacogenetics:
Identifying genetic variants that predict response to the blood glucose-lowering effects of antidiabetic medications is of great interest because of the high prevalence of diabetes and the large number of patients prescribed such medications. At present, there is insufficient basis for prescribing medication based on genotype.
Diagnostic Criteria and Clinical Characteristics
One of the following
Fasting plasma glucose (FPG) greater than or equal to 126 mg/dL
Two-hour plasma glucose greater than or equal to 200 mg/dL during an oral glucose tolerance test (OGTT).
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose greater than or equal to 200 mg/dL
Hemoglobin A1c greater than or equal to 6.5%
One of the following
FPG between 100 to 125 mg/dL
Two-hour plasma glucose of 140 to 199 mg/dL during a 75-g OGTT
Hemoglobin A1c of 5.7% to 6.4%
Diabetes is characterized by high levels of plasma glucose. T2DM, which is due to defects in insulin sensitivity and/or insulin secretion, is the most common form of diabetes, affecting 8.3% of the US population with 18.8 million people diagnosed and about 7 million undiagnosed. The clinical symptoms include weight loss, increased urination, increased thirst, hunger, blurred vision, asthenia, tiredness, irritability, and a characteristic darkening of skin in body folds and creases (acanthosis nigricans). Patients with T2DM can present with frequent and recurrent infections of the bladder, gums, skin, and vagina, ulcers that are difficult to heal, and numbness and tingling sensation of the hands and feet with or without other classic symptoms of diabetes. The discovery of abnormal blood glucose readings is frequently made during routine screening, emphasizing the importance of screening and counseling of these patients.
The major T2DM-associated complications arise from micro- and macrovascular complications, and may include retinopathy, nephropathy, neuropathy, cardiovascular disease, cerebrovascular disease, and autonomic dysfunction in the form of erectile dysfunction, postural hypotension, and urinary incontinence.
Screening and Counseling
Screening for type 2 diabetes is noteworthy because the same test that is used for screening is also used for the diagnosis of the disease. Routine screening for diabetes should follow these guidelines:
Testing should be considered in all adults who are overweight (body mass index [BMI] ≥25 kg/m2) and have additional risk factors:
Physical inactivity; first-degree relative with diabetes; high-risk race or ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander); women who delivered a baby weighing 9 lb or greater or previously diagnosed with gestational diabetes (GDM); hypertension (140/90 mm Hg or on therapy for hypertension); high-density lipoprotein (HDL) cholesterol level less than 35 mg/dL and/or a triglyceride level greater than 250 mg/dL; women with polycystic ovarian syndrome (PCOS); hemoglobin A1c greater than 5.7%, impaired glucose tolerance, or impaired fasting glucose on previous testing; other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans); or history of cardiovascular disease
In the absence of the above criteria, testing for diabetes should begin at age 45.
If screening results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results and risk.
FPG, hemoglobin A1c, or OGTT is appropriate to screen for diabetes and to assess the risk for future diabetes.
Obesity and T2DM are appearing at alarming rates in children. The recommended screening in children and youth according to American Diabetes Association (ADA) guidelines includes the following:
Overweight (BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height)
Plus any of the two of the following four risk factors
Family history of T2DM in a first- or second-degree relative
Race or ethnicity (Native American, African American, Latino, Asian American, Pacific Islander)
Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS, or small-for-gestational-age birth weight)
Maternal history of diabetes or GDM during the child’s gestation
In these high-risk children, it is recommended that testing be initiated at age 10 years or at the time of puberty (whichever is earlier), and that testing be repeated in every 3 years.
While the heritability of T2DM is 40% to 60%, consistent with a moderate tendency of the disease to cluster in families, there is not a strong genotype-phenotype correlation; that is, the known risk alleles for T2DM have a relatively low penetrance. If a patient has T2DM, the lifetime risk of his or her sibling becoming affected is up to three times higher than that of the general population. Monozygotic twins have a 60% or higher long-term concordance rate for diabetes, much higher than the 25% concordance rate observed for T1DM in monozygotic twins. Much of the familial clustering of T2DM is thought to be due to shared lifestyle risk factors among family members against the backdrop of an increased genetic susceptibility. Counseling to prevent T2DM thus chiefly involves promoting diabetes protective behaviors, such as physical activity and weight control.
Management and Treatment
A primary goal of blood glucose screening is to detect prediabetes and prevent or delay the onset of diabetes through effective lifestyle intervention and counseling. The beneficial effects of lifestyle changes and weight management on reducing diabetes risk have been well established. In the Diabetes Prevention Program nondiabetic individuals with elevated fasting and postprandial glucose concentrations were randomized into placebo, metformin, and intensive lifestyle intervention arms. The goals of the intensive lifestyle intervention arm were a 7% decrease (or greater) in body weight and at least 150 min/wk of physical activity. After 3 years of follow-up, diabetes incidence was 58% lower in the lifestyle group (and 31% lower in the metformin group) compared to the placebo group. Based on these and other data, the American Diabetes Association (ADA) recommends lifestyle change as a cornerstone in the treatment of diabetes.
Management of established T2DM is typically based on intensive lifestyle changes coupled with pharmacotherapy with the goal of reducing the micro- and macrovascular complications that accompany the disease. A hemoglobin A1C goal of less than 7% has been recommended by ADA and less than 6.5% by the American Association of Clinical Endocrinologists. The Veterans Administration guidelines recommend individualizing glycemic targets for individuals based on the presence or absence of comorbidities.
This includes medical nutrition therapy, diabetes self-management, and counseling that stress the importance of physical activity to effectively manage blood glucose control and improve insulin sensitivity.
