Prediabetes

Prediabetes is the state in which some but not all of the diagnostic criteria for diabetes are met. It is often described as the “gray area” between normal blood sugar and diabetic levels.

Impaired fasting glycaemia
Impaired fasting glycaemia or impaired fasting glucose (IFG) refers to a condition in which the fasting blood glucose 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. IFG is also a risk factor for mortality.

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 can also 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. 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).


 * 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.

Signs and symptoms
Prediabetes typically has no distinct signs or symptoms. Patients should monitor for signs and symptoms of type 2 diabetes mellitus. These include the following:


 * 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

Cause

 * Sleep disorders
 * Family history of diabetes
 * Impaired glucose levels and/or metabolic syndrome
 * Cardiovascular disease
 * Hypertension (high blood pressure)
 * Increased triglycerides levels
 * Low levels of good cholesterol (HDL)
 * Overweight or obesity
 * Women who have had gestational diabetes, had high birth weight babies (greater than 9 lbs.), and/or has Polycystic Ovarian Syndrome (PCOS)

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.

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

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

Pathophysiology
Diabetes mellitus (DM) is a group of metabolic diseases that are characterized by hyperglycemia 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 can be insidious, the diagnosis is often delayed. Effects of the disease can be macrovascular, as seen in the cardiovascular system/arthrosclerosis, or microvascular, as seen with retinopathy, nephropathy, and neuropathy.

Normal glucose homeostasis is controlled by three interrelated processes. There is 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 islet cells. What triggers the production and release of insulin from the pancreas is the presence of glucose in the body. The main function of insulin is to increase the rate of transport of glucose into certain cells of the body, such as striated muscles, fibroblasts, and fat cells. It is also 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 by first 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 from a lack of pancreatic hormone release or failure of target tissues to respond to the insulin present or both.

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 can have a significant impact on overall health.

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
 * 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)

Diagnosis
Prediabetes is usually diagnosed with a blood test:
 * Fasting blood sugar (glucose) level of:
 * 110 to 125 mg/dL (6.1 mM to 6.9 mM) - WHO criteria
 * 100 to 125 mg/dL (5.6 mM to 6.9 mM) - 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).
 * Glycated hemoglobin between 5.7 and 6.4 percent

Levels above these limits would be a diagnosis for diabetes.

Management
Intensive weight loss and lifestyle intervention, if sustained, can substantially improve glucose tolerance and prevent progression from IGT to type 2 diabetes. The Diabetes Prevention Program (DPP) 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. The ADA guidelines 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 can 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. Metformin 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.

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.

Epidemiology
Studies conducted from 1988-1994 indicated that at that time, of the US population 40–74 years of age, 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.