Pathology of type 2 diabetes

In type 2 diabetes, the body either produces inadequate amounts of insulin to meet the demands of the body or insulin resistance has developed. Insulin resistance refers to when cells of the body such as the muscle, liver and fat cells fail to respond to insulin, even when levels are high. In fat cells, triglycerides are instead broken down to produce free fatty acids for energy; muscle cells are deprived of an energy source and liver cells fail to build up glycogen stores. This also leads to an overall rise in the level of glucose in the blood. Glycogen stores become markedly reduced and there is less glucose available for release when it may be needed. Obesity and lack of physical activity are thought to be major causes of insulin resistance.

Signs and symptoms

Many patients with type 2 diabetes are asymptomatic. Clinical manifestations include the following: Classic symptoms: Polyuria, polydipsia, polyphagia, and weight loss Blurred vision Lower-extremity paresthesias Yeast infections (eg, balanitis in men)

Prediabetes Prediabetes often precedes overt type 2 diabetes. Prediabetes is defined by a fasting blood glucose level of 100-125 mg/dL or a 2-hour post-oral glucose tolerance test (post-OGTT) glucose level of 140-200 mg/dL. Persons with prediabetes are at increased risk for macrovascular disease, as well as diabetes. [3] Often confused with prediabetes is the metabolic syndrome (also called syndrome X or the insulinresistance syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtly normal glucose tolerance, prediabetes, or diabetes. It is diagnosed when a patient has at least 3 of the following 5 conditions: Abdominal obesity Elevated triglyceride level Low level of high-density lipoprotein (HDL) cholesterol Elevated blood pressure Fasting glucose value of 100 mg/dL or higher Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin resistance is not possible to measure clinically, except in research settings. An elevated fasting blood glucose or triglyceride level may be the first indication of insulin resistance. Fasting insulin levels are generally increased at an earlier stage, but they are more directly related to insulin clearance than to insulin resistance. An effort to standardize insulin assays is under way and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future.

The goals in caring for patients with diabetes mellitus are to eliminate symptoms and to prevent, or at least slow, the development of complications. Microvascular (ie, eye and kidney disease) risk reduction is accomplished through control of glycemia and blood pressure; macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk reduction, through control of lipids and hypertension, smoking cessation, and aspirin therapy; and metabolic and neurologic risk reduction, through control of glycemia. Diabetes care is best provided by a multidisciplinary team of health professionals with expertise in diabetes, working in collaboration with the patient and family.[4]Management includes the following: Appropriate goal setting Dietary and exercise modifications Medications Appropriate self-monitoring of blood glucose (SMBG) Regular monitoring for complications Laboratory assessment

Prevention of Type 2 Diabetes Mellitus

Guidelines from the American College of Clinical Endocrinologists for the prevention of type 2 diabetes mellitus in patients at risk recommend the following measures: Weight reduction Proper nutrition Regular physical activity Cardiovascular risk factor reduction Aggressive treatment of hypertension and dyslipidemia

Lifestyle improvement
The Diabetes Prevention Program (DPP) trial has shown that modest lifestyle changes (eg, 4-5% sustained weight reduction for approximately 3 y) reduce the risk for diabetes in patients at high risk by 58%.[242] Eight health-care facilities participated in an instructive study of group-based lifestyle intervention that should help other agencies/states emulate strategies used to affect positive lifestyle changes for the prevention of diabetes.[243] In an 11-year, population-based cohort study of over 200,000 men and women without evidence of diabetes, heart disease, or cancer at baseline, good lifestyle decisions in combination significantly reduced the risk of developing diabetes. For each additional positive lifestyle factor (eg, with regard to diet, physical activity, or smoking) in the low-risk group, the odds for diabetes were 31% lower[244] Yeh et al found that although cigarette smokers are at increased risk for type 2 diabetes, smoking cessation leads to higher short-term risk.[245] In this prospective cohort study in 10,892 middle-aged, nondiabetic adults, 1254 persons developed type 2 diabetes during 9 years of follow up. The adjusted hazard ratio of incident diabetes among persons in the highest tertile of pack-years was 1.42, compared with persons who had never smoked. However, in the first 3 years after quitting smoking, the hazard ratio was 1.73; the risk then gradually decreased, disappearing completely at 12 years. Yeh et al recommended that smoking cessation in smokers at risk for diabetes be coupled with strategies for prevention and early detection of diabetes. A significant inverse correlation has been found between the risk of diabetes and the intake of magnesium, which plays an important role in insulin action and glucose homeostasis. In a meta-analysis, the summary relative risk of type 2 diabetes for every 100 mg/day increment in magnesium intake was 0.86.[246] Interest in the impact of phylloquinone intake on glucose tolerance and insulin sensitivity has a long history. A 2012 report suggests a beneficial role for phylloquinone in diabetes prevention in elderly

subjects with high cardiovascular risk. However, caution is advised in patients who are concurrently being treated with anticoagulant drugs such as warfarin.[247]

Pharmacologic prevention
Drugs from several classes have been studied in the prevention of diabetes. However, the FDA has not approved any drug for the treatment of prediabetes or the prevention of type 2 diabetes. [248] Metformin The ADA recommends that, in addition to lifestyle counseling, metformin be considered in selected patients with prediabetes.[4] ADA criteria for preventive metformin therapy are as follows: Obesity Age younger than 60 years Both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) Other risk factors (eg, HbA1C >6%, hypertension, low HDL cholesterol, elevated triglycerides, or a family history of diabetes in a first-degree relative) In the DPP, metformin 1700 mg daily was about half as effective as lifestyle intervention in reducing risk among subjects with elevated fasting and postload plasma glucose concentrations.[242] Over an average follow-up period of 2.8 years, the incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 personyears in the placebo, metformin, and lifestyle groups, respectively. Thiazolidinediones Analysis of available data from the DPP suggests that troglitazone was effective in preventing diabetes. This effect was also seen in the Troglitazone in Prevention of Diabetes (TRIPOD) study of Hispanic women with a history of gestational diabetes. After troglitazone was withdrawn from the market because of hepatotoxicity, the continuation of TRIPOD in the Pioglitazone in the Prevention of Diabetes Study demonstrated slowed progression of subclinical atherosclerosis with glitazone treatment.[249] In the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial, investigators concluded that rosiglitazone at 8 mg daily reduces the incidence of type 2 diabetes mellitus in patients with IFG and/or IGT. At the end of this prospective, multicenter study, composite outcome of diabetes or death from any cause was 11.6% in the rosiglitazone group versus 26% in the placebo group.[127] Ramipril did not produce significant reduction in the same composite outcome. [250]

Monitoring for Diabetic Complications

The ADA recommends initiation of complications monitoring at the time of diagnosis of diabetes mellitus.[4] This regimen should include yearly dilated eye examinations, annual microalbumin checks, and foot examinations at each visit. A study by Cigolle et al found that middle-aged and older adults with diabetes have an increased risk for the development of geriatric conditions (eg, cognitive, vision, and hearing impairments; falls). [205] These conditions substantially contribute to morbidity and functional impairment. The authors concluded that adults with diabetes should be monitored for the development of geriatric conditions at a younger age than was previously considered. The risk for early development of Parkinson disease is 36% higher in patients with diabetes mellitus.[206] However, a systematic review from Cereda et al found no conclusive evidence of this association.[207] A high overall risk for pancreatic neoplasm is noted in individuals with diabetes mellitus, particularly in those aged 45-65 years.[208] The incidence of complications widely vary among the Asian subgroups, suggesting the need for an ethnic stratified nuanced approach in evaluation and surveillance.[209] One size does not fit all.