Prediabetes

Prediabetes is the precursor stage before diabetes mellitus in which not all of the symptoms required to diagnose diabetes are present, but blood sugar is abnormally high. This stage is often referred to as the "grey area."^[1] It is not a disease; the American Diabetes Association says,^[2] "Prediabetes should not be viewed as a clinical entity in its own right but rather as an increased risk for diabetes and cardiovascular disease (CVD). Prediabetes is associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension."^[2] It is thus a metabolic diathesis or syndrome, and it usually involves no symptoms and only high blood sugar as the sole sign.

Impaired fasting blood sugar and impaired glucose tolerance are two forms of prediabetes that are similar in clinical definition (glucose levels too high for their context) but are physiologically distinct.^[3] Insulin resistance, the insulin resistance syndrome (metabolic syndrome or syndrome X), and prediabetes are closely related to one another and have overlapping aspects.

Classification

Impaired fasting glycaemia

Impaired fasting glycaemia or impaired fasting glucose (IFG) refers to a condition in which the fasting blood glucose or the 3-month average blood glucose (A1C) is elevated above what is considered normal levels but is not high enough to be classified as diabetes mellitus. It is considered a pre-diabetic state, associated with insulin resistance and increased risk of cardiovascular pathology, although of lesser risk than impaired glucose tolerance (IGT). IFG sometimes progresses to type 2 diabetes mellitus. There is a 50% risk over 10 years of progressing to overt diabetes. Many newly identified IFG patients progress to diabetes in less than three years.^[4] IFG is also a risk factor for mortality.^[5]

Fasting blood glucose levels are in a continuum within a given population, with higher fasting glucose levels corresponding to a higher risk for complications caused by the high glucose levels. Impaired fasting glucose is defined as a fasting glucose that is higher than the upper limit of normal, but not high enough to be classified as diabetes mellitus. Some patients with impaired fasting glucose also may be diagnosed with impaired glucose tolerance, but many have normal responses to a glucose tolerance test.

World Health Organization (WHO) criteria for impaired fasting glucose differs from the American Diabetes Association (ADA) criteria, because the normal range of glucose is defined differently by each. Fasting plasma glucose levels 100 mg/dL (5.5 mmol/L) and higher have been shown to increase complication rates significantly, however, WHO opted to keep its upper limit of normal at under 110 mg/dL for fear of causing too many people to be diagnosed as having impaired fasting glucose, whereas the ADA lowered the upper limit of normal to a fasting plasma glucose under 100 mg/dL.

• WHO criteria: fasting plasma glucose level from 6.1 mmol/l (110 mg/dL) to 6.9 mmol/L (125 mg/dL) ^[6][7]
• ADA criteria: fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL)

Impaired glucose tolerance

Impaired glucose tolerance (IGT) is a pre-diabetic state of dysglycemia, that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years. IGT is also a risk factor for mortality.^[5]

Signs and symptoms

Prediabetes typically has no distinct signs or symptoms except the sole sign of high blood sugar. Patients should monitor for signs and symptoms of type 2 diabetes mellitus. These include the following:^[8]

• Constant hunger
• Unexplained weight loss
• Weight gain
• Flu-like symptoms, including weakness and fatigue
• Blurred vision
• Slow healing of cuts or bruises
• Tingling or loss of feeling in hands or feet
• Recurring gum or skin infections
• Recurring vaginal or bladder infections
• A high BMI (Body Mass Index) result^[9]

Causes

• Sleep disorders
• Family history of diabetes
• Cardiovascular disease
• Increased triglycerides levels
• Low levels of good cholesterol (HDL)
• Overweight or obesity
• Elevated blood pressure^[10]
• Elevated fasting plasma glucose^[10][11]
• Women who have had gestational diabetes, had high birth weight babies (greater than 9 lbs.), and/or have polycystic ovarian syndrome (PCOS)^[12]

These are associated with insulin resistance and are risk factors for the development of type 2 diabetes mellitus. Those in this stratum (IGT or IFG) are at increased risk of cardiovascular disease. Of the two, impaired glucose tolerance better predicts cardiovascular disease and mortality.^[13][14][15]

In a way, prediabetes is a misnomer since it is an early stage of diabetes. It now is known that the health complications associated with type 2 diabetes often occur before the medical diagnosis of diabetes is made.^[16]

Genetics

Type 2 DM, which is the condition for which prediabetes is a precursor, has 90–100% concordance in twins; there is no HLA association.^[17] Genetics play a relatively small role, however, in the widespread occurrence of type 2 diabetes. This may be deduced logically from the huge increase in the occurrence of type 2 diabetes that has correlated with the significant change in western lifestyle and diet.^[17] As the human genome is further explored, it is possible that multiple genetic anomalies at different loci will be found that confer varying degrees of predisposition to type 2 diabetes.^[18]

Pathophysiology

Diabetes mellitus (DM) is a group of metabolic diseases that are characterised by hyperglycaemia and defects in insulin production in the pancreas and/or impaired tolerance to insulin effects. DM is a leading cause of morbidity and mortality. Because the disease may be insidious, the diagnosis often is delayed. Effects of the disease may affect larger blood vessels (e.g., atherosclerosis within the larger arteries of the cardiovascular system) or smaller blood vessels, as seen with damage to the retina of the eye, damage to the kidney, and damage to the nerves.^[17]

Normal glucose homeostasis is controlled by three interrelated processes. These processes include gluconeogenesis (glucose production that occurs in the liver), uptake and utilization of glucose by the peripheral tissues of the body, and insulin secretion by the pancreatic beta islet cells. The presence of glucose in the bloodstream triggers the production and release of insulin from the pancreas' beta islet cells. The main function of insulin is to increase the rate of transport of glucose from the bloodstream into certain cells of the body, such as striated muscles, fibroblasts, and fat cells. It also is necessary for transport of amino acids, glycogen formation in the liver and skeletal muscles, triglyceride formation from glucose, nucleic acid synthesis, and protein synthesis.

Insulin enters cells first by binding to target insulin receptors. DM and some of those with prediabetes have impaired glucose tolerance—in these individuals, blood glucose rises to abnormally high levels. This may be due to a lack of pancreatic hormone release or failure of targeted tissues to respond to the insulin present or both.^[17]

Diagnosis

Usually, prediabetes is diagnosed with a blood test:^[19]

• Fasting blood sugar (glucose) level of:
  • 110 to 125 mg/dL (6.1 mM/L to 6.9 mM/L) - WHO criteria
  • 100 to 125 mg/dL (5.6 mM/L to 6.9 mM/L) - ADA criteria
• Two hour glucose tolerance test after ingesting the standardized 75 Gm glucose solution the blood sugar level of 140 to 199 mg/dL (7.8 to 11.0 mM) ^[20]
• Glycated haemoglobin between 5.7 and 6.4 percent ^[21]

Glycated hemoglobin is; however, of questionable accuracy and while fasting glucose can indicate the diagnosis when positive if it is negative it is not very accurate.^[22] A 2016 review found worse outcomes when blood sugar levels were over 100 mg/dL and glycated haemoglobin over 5.7%.^[23]

Levels above these limits would justify a diagnosis for diabetes.

Screening

Fasting plasma glucose screening should begin at age 30-45 and be repeated at least every three years. Earlier and more frequent screening should be conducted in at-risk individuals. The risk factors for which are listed below:

• Family history (parent or sibling)
• Dyslipidemia (triglycerides > 200 or HDL < 35)
• Overweight or obesity (body mass index > 25)
• History of gestational diabetes or infant born with birth weight greater than 9 lb (4 kg)
• High risk ethnic group
• Hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg)
• Prior fasting blood glucose > 99
• Known vascular disease
• Markers of insulin resistance (PCOS, acanthosis nigricans)^[24][25]

Prevention

The American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) have developed lifestyle intervention guidelines for preventing the onset of type 2 diabetes:

• Healthy meals (a diet low in saturated fat, sugars, and refined carbohydrates, as well as limited sodium and total calories)
• Physical exercise (45 minutes of exercise per day, five days a week)
• Reducing weight by as little as 5-10 percent may have a significant impact on overall health

Management

There is evidence that prediabetes is a curable disease state.^[26] Intensive weight loss and lifestyle intervention, if sustained, may improve glucose tolerance substantially and prevent progression from IGT to type 2 diabetes. The Diabetes Prevention Program (DPP)^[27] study found a 16% reduction in diabetes risk for every kilogram of weight loss. Reducing weight by 7% through a low-fat diet and performing 150 minutes of exercise a week is the goal. In observational studies, individuals following vegetarian diets are about half as likely to develop diabetes, compared with non-vegetarians.^[28] The ADA guidelines^[29] recommend modest weight loss (5-10% body weight), moderate-intensity exercise (30 minutes daily), and smoking cessation.

For patients with severe risk factors, prescription medication may be appropriate. This may be considered in patients for whom lifestyle therapy has failed, or is not sustainable, and who are at high-risk for developing type 2 diabetes.^[30] Metformin^[31] and acarbose help prevent the development of frank diabetes, and also have a good safety profile. Evidence also supports thiazolidinediones but there are safety concerns, and data on newer agents such as GLP-1 receptor agonists, DPP4 inhibitors or meglitinides are lacking.^[32]

Prognosis

The progression to type 2 diabetes mellitus is not inevitable for those with prediabetes. The progression into diabetes mellitus from prediabetes is approximately 25% over three to five years.^[33]

Epidemiology

Studies conducted from 1988-1994 indicated that of the total population of U.S in the age group 40–74 years, 33.8% had IFG, 15.4% had IGT, and 40.1% had prediabetes (IFG, IGT, or both). Eighteen million people (6.3% of the population) had type 2 diabetes in 2002.^[34]

The incidence of diabetes is growing. In 2014, 29.1 million people or 9.3% of the U.S. population had diabetes.^[35] In 2011-2012, the prevalence of diabetes in the U.S. using hemoglobin A1C, fasting plasma glucose or the two-hour plasma glucose definition was 14.3% for total diabetes, 9.1% for diagnosed diabetes, 5.2% for undiagnosed diabetes and 38.0% for prediabetes.^[36]

References