A Systematic Review of Type 2 Diabetes: Chronic Metabolic Disorder

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia. It may be due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Chronic hyperglycemia in synergy with the other metabolic aberrations in patients with diabetes mellitus can cause damage to various organ systems, leading to the development of disabling and life-threatening health complications, most prominent of which are microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications leading to a 2-fold to 4-fold increased risk of cardiovascular diseases.

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world. As a result of this trend, it is fast becoming an epidemic in some countries of the world with the number of people affected expected to double in the next decade due to increase in ageing population, thereby adding to the already existing burden for healthcare providers, especially in poorly developed countries. This review is based on a search of Medline, the Cochrane Database of Systemic Reviews, and citation lists of relevant publications. Subject heading and key words used include type 2 diabetes mellitus, prevalence, current diagnosis, and current treatment. Only articles in English were included. Screening and diagnosis is still based on World Health Organization (WHO) and American Diabetes Association (ADA) criteria which include both clinical and laboratory parameters. No cure has yet been found for the disease; however, treatment modalities include lifestyle modifications, treatment of obesity, oral hypoglycemic agents, and insulin sensitizers like metformin, a biguanide that reduces insulin resistance, is still the recommended first line medication especially for obese patients. Other effective medications include non-sulfonylurea secretagogues, thiazolidinediones, alpha glucosidase inhibitors, and insulin.

Diabetes mellitus (DM) is probably one of the oldest diseases known to man. It was first reported in Egyptian manuscript about 3000 years ago. In 1936, the distinction between type 1 and type 2 DM was clearly made. Type 2 DM was first described as a component of metabolic syndrome in 1988. Type 2 DM (formerly known as non-insulin dependent DM) is the most common form of DM characterized by hyperglycemia, insulin resistance, and relative insulin deficiency. Type 2 DM results from interaction between genetic, environmental and behavioral risk factors.

It is estimated that 366 million people had DM in 2011; by 2030 this would have risen to 552 million. The number of people with type 2 DM is increasing in every country with 80% of people with DM living in low- and middle-income countries. DM caused 4.6 million deaths in 2011. It is estimated that 439 million people would have type 2 DM by the year 2030. The incidence of type 2 DM varies substantially from one geographical region to the other as a result of environmental and lifestyle risk factors. 

Lifestyle, Genetics, and Medical Conditions

Type 2 DM is due primarily to lifestyle factors and genetics. A number of lifestyle factors are known to be important to the development of type 2 DM. These are physical inactivity, sedentary lifestyle, cigarette smoking and generous consumption of alcohol. Obesity has been found to contribute to approximately 55% of cases of type 2 DM. The increased rate of childhood obesity between the 1960s and 2000s is believed to have led to the increase in type 2 DM in children and adolescents.

Pathophysiology

Type 2 DM is characterized by insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual pancreatic beta-cell failure. This leads to a decrease in glucose transport into the liver, muscle cells, and fat cells. There is an increase in the breakdown of fat with hyperglycemia. The involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 DM. 

As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. The incretins are important gut mediators of insulin release, and in the case of GLP-1, of glucagon suppression. 

Screening and Diagnosis

Tests for screening and diagnosis of DM are readily available. The test recommended for screening is the same as that for making diagnosis, with the result that a positive screen is equivalent to a diagnosis of pre-diabetes or DM. Although about 25% of patients with type 2 DM already have microvascular complications at the time of diagnosis suggesting that they have had the disease for more than 5 years at the time of diagnosis.

Management

Through lifestyle and diet modification. Studies have shown that there was significant reduction in the incidence of type 2 DM with a combination of maintenance of body mass index of 25 kg/m2, eating high fibre and unsaturated fat and diet low in saturated and trans-fats and glycemic index, regular exercise, abstinence from smoking and moderate consumption of alcohol.

Pharmacological Agents

Biguanides 

Biguanides, of which metformin is the most commonly used in overweight and obese patients, suppresses hepatic glucose production, increases insulin sensitivity, enhances glucose uptake by phosphorylating GLUT-enhancer factor, increases fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract.

Sulfonylureas

These generally well tolerated but because they stimulate endogenous insulin secretion, they carry a risk of hypoglycemia. Elderly patients, with DM who are treated with sulfonylureas have a 36% increased risk of hypoglycemia compared to younger patients.

Meglitinides

Repaglinide and nateglinide are non-sulfonylurea secretagogues which act on the ATP-dependent K-channel in the pancreatic beta cells thereby stimulating the release of insulin from the beta cells, similar to sulfonylurea, though the binding site is different. Meglitinides have a rapid onset and a short duration of action (4-6 hrs) and thus lower risk of hypoglycemia. 

 Thiazolidinediones 

Thiazolidinedione is an insulin sensitizer, selective ligands transcription factor peroxisomes proliferator-activated gamma. They are the first drugs to address the basic problem of insulin resistance in type 2 DM patients, whose class now includes mainly pioglitazone after the restricted use of rosiglitazone recommended by Food and Drug Administration (FDA) recently due to increased cardiovascular events reported with rosiglitazone.

Alpha-Glucosidase Inhibitors 

Acarbose, Voglibose and Miglitol have not widely been used to treat type 2 DM individuals but are likely to be safe and effective. These agents are most effective for postprandial hyperglycemia and should be avoided in patients with significant renal impairment. Their use is usually limited due to high rates of side-effects such as diarrhoea and flatulence.

Insulin 

Insulin is used alone or in combination with oral hypoglycemic agents. Augmentation therapy with basal insulin is useful if some beta cell function remains. Replacement of basal-bolus insulin is necessary if beta cell exhaustion occurs. Rescue therapy using replacement is necessary in cases of glucose toxicity which should mimic the normal release of insulin by the beta cells of the pancreas.

Type 2 DM is a metabolic disease that can be prevented through lifestyle modification, diet control, and control of overweight and obesity. Education of the populace is still key to the control of this emerging epidemic. Novel drugs are being developed, yet no cure is available in sight for the disease, despite new insight into the pathophysiology of the disease.