Definition

Diabetes mellitus is a syndrome in which the body cannot metabolize glucose (sugar) appropriately. The subsequent sustained elevated levels cause significant damage to the eyes, heart, kidneys, and other organs. Diabetes is a significant and growing public health problem; in 2014, the US Centers for Disease Control and Prevention (CDC) reported that an estimated 29.1 million persons in the United States were affected in 2012, up from 26 million in 2010. Of those with diabetes, about 25 percent are not aware that they have the disease. An additional 86 million adults age twenty or older have prediabetes. Of these, the CDC reports that 15 to 30 percent will go on to have in type 2 diabetes within five years if they do not reduce their weight and are not moderately physically active. Diabetes is a disease related to both genetics and environmental or lifestyle factors.

Risk Factors

The National Diabetes Information Clearing House (NDIC) reported in 2014 that type 1 diabetes accounted for about 5 to 10 percent of diagnosed diabetes cases in the United States, while type 2 accounted for about 90 to 95 percent of cases. Having a parent or sibling with type 1 diabetes mellitus is the primary risk factor for this disease. The most common type of diabetes, type 2, has multiple risk factors, both genetic and environmental. These include a family history of type 2 diabetes or gestational (during pregnancy) diabetes. Behavioral fac-tors include excessive food intake or unhealthy eating habits that result in obesity (especially around the waist area), and an inactive or sedentary lifestyle. Additional risk factors include increased age (over forty-five years old), high blood pressure (140/90 mmHg or greater), and high blood levels of cholesterol (high-density lipoprotein [HDL] under thirty-five) and fats (triglycerides over 250 mg/dL). African Americans, Hispanic Americans, Pacific Islanders, and Native Americans have a higher incidence of diabetes.

Etiology and Genetics

Diabetes mellitus comprises several different diseases, primarily type 1 and type 2 diabetes. Although genetics contributes to both types of diabetes, they result from the interaction between genetics and the environment. In both types of diabetes mellitus, patients present an impaired capacity to metabolically process sugars, with consequences that can lead to death if untreated.

Glucose is a simple sugar required by all cells for normal functioning. Most of the body’s glucose initially comes from carbohydrates broken down during digestion. Typically, carbohydrate ingestion raises blood glucose levels. This rise in blood glucose triggers the pancreas to release insulin, causing the blood glucose level to drop by increasing the uptake in muscle, fat, the liver, and the gut.

Patients with either type of diabetes have difficulty metabolizing glucose, with a subsequent rise in fasting and postprandial (after meals) blood sugar levels. Type 1 diabetes (also called juvenile-onset or less often, insulin-dependent diabetes), results from the destruction of the insulin-secreting beta cells in the pancreatic islets. In type 2 (adult-onset, maturity-onset, or noninsulin-dependent diabetes), cells become resistant to the effects of insulin even though the pancreas is still producing some insulin.

Genetics plays a significant role in the development of diabetes. Type 1 diabetes mellitus is a chronic autoimmune disease that results from a combination of genetic and environmental factors. Certain persons are born with a genetic susceptibility to the disease. The genetic basis for developing type 1 diabetes appears to involve not so much mutant genes, but rather an unfortunate combination of particular alleles. Some seventeen regions, labeled INS, IDDM3, IDDM4, SUMO4, IDDM6 to IDDM9, IL2RA, IDDM11, CTLA4, and IDDM13 to IDDM18, of the genome (the complete set of deoxyribonucleic acid [DNA] with genes in the nucleus of each cell) are suspect for linking to type I diabetes. Under primary investigation is IDDM1, containing human leukocyte antigen (HLA), complex genes related to immune response proteins. These genes may increase susceptibility to type 1 diabetes, but not always. IDMM2 is the non-HLA insulin gene. (According to the HUGO Gene Nomenclature Committee both IDDM1 and IDDM2 are now known by the approved name INS.) Research on the remaining regions continues for links to type 1 diabetes.

The HLA genes on chromosome 6 help the immune system distinguish between its cells from invading substances. These immune cells continually watch for protein segments, such as those found in tumor cells or infectious bacteria. Under normal circumstances, the immune cells will attack these polypeptides to protect the body. The CTLA4 gene product downregulates this activity, and alleles of this gene have a strong association with many diseases, including type 1 diabetes.

Also, a rare type of autoimmune diabetes, resem-bling type 1 diabetes mellitus, occurs as part of a syndrome called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by mutations in the AIRE gene. The clinical manifestations of APECED include relent-less attacks by the immune system upon several endocrine glands (polyendocrine autoimmunity). Immune system-mediated destruction of the adrenal cortex causes Addison’s disease, damage of the parathyroid gland results in hypoparathy-roidism, and disabling the pancreatic beta cells causes type 1 diabetes mellitus. The AIRE gene encodes the autoimmune regulator protein, a tran-scription factor expressed in the thymus, pancreas, and adrenal cortex. In the thymus, AIRE directs the expression of organ-specific proteins. Developing T-cells that react with these organ-specific proteins undergo programmed cell death. When developing T-cells fail to experience this rigorous screening process, they mature, exit the thymus, and attack the tissues and organs of the body.

Diabetes mellitus type 2 is the more common type of diabetes. Type 2 diabetes appears to be a group of diseases, rather than a single condition, in which there are two defects: beta-cell dysfunction, leading to somewhat decreased production of insulin (although elevated levels of insulin also occur), and tissue resistance to insulin. As with type 1, people who develop type 2 are born with genetic susceptibility, but the development of the actual dis-ease may be dependent upon an environmental trigger. Some possible triggers include a sedentary lifestyle, abdominal obesity, and advanced age.

Obesity plays a significant role in the development of type 2 diabetes. Among North Americans, Europeans, and Africans with type 2 diabetes, between 60 and 70 percent are obese. In 2014 the NDIC reported that 80 percent of type 2 diabetics are overweight or obese.

As with type 1, epidemiologic evidence suggests a strong genetic component to type 2 diabetes. In identical twins over forty years of age, about 70 per-cent of the time, the second twin will develop type 2 diabetes once the first twin has developed it.

Mutant alleles for several genes are associated with susceptibility to and development of type 2 diabetes. The first genes to be implicated were the insulin gene, genes encoding essential components of the insulin secretion pathways, and other genes involved in glucose homeostasis. Mutations are diverse and can include not only the genes themselves but also the transcription factors and control sequences. In March 2008, the National Institutes of Health (NIH) announced that international scientists had confirmed six additional genetic variants connected to type 2 diabetes, bringing the total genetic risk factors to sixteen. As of 2013, genome-wide association studies had identified more than sixty-five genetic variants that increase the risk of type 2 diabetes by 10 to 30 percent. The discovery of more genes and their mutant alleles could expand treatment options and even tailor therapeutic strategies to specific types of mutations.

One way to discover susceptibility for type 2 is through whole-genome linkage studies of families. Researchers have found that mutations in the genes that encode calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A) increase the risk for type 2 diabetes mellitus. The CAPN10 gene is associated with high rates of type 2 diabetes in Mexican American, Finnish, and Spanish populations. Mutations in CAPN10 seem to alter insulin secretion and affect liver glucose production. Likewise, the HNF4A gene, located on chromosome 20, regulates the amount of insulin produced by the pancreas. Mutations in the HNF4A gene reduce the amount of insulin produced as you get older. Many other genes are under study for their impact on type 2 diabetes.

Other genome-wide association studies con-ducted in different countries and ethnic groups have identified approximately 75 genes that contribute to the risk for T2DM. Examples of such genes include KCNJ11, TCF7L2, IRS1, MTNR1B, PPARG2, IGF2BP2, HHEX, and FTO. KCNJ11 encodes the Kir6.2 protein, an ATP-sensitive potas-sium channel found on the surfaces of pancreatic islet cells. This protein is the target of sulfonylureas, one of the groups of drugs used to treat type 2 diabetes mellitus. The TCF7L2 gene encodes a tran-scription factor that controls the expression of the proglucagon and glucagon-like peptide-1 genes. The IRS1 gene encodes the insulin receptor sub-strate, which relays the signal that insulin generates with it binds its receptor to the inside of the cell. MTNR1B encodes one of the melatonin receptors, which, when bound by melatonin, mediates circa-dian rhythm and affects metabolic regulation. PPARG2 encodes a transcription factor called the peroxisome proliferator-activated receptor-, modu-lating the differentiation of adipocytes (fat cells). PPAR-is a target for thiazolidinediones, another class of drugs used to treat type 2 diabetes mellitus. IGF2BP2 encodes the insulin-like growth factor-2 binding protein-2, a protein that is intimately involved in pancreas development, growth, and stimulation of insulin action. HHEX affects cell development, and FTO, or the fat mass and obesity-associated gene, encodes an ribonucleic acid (RNA) demethylase that increases the expression of genes in the brain that intensify hunger and feeding. Mutations in the FTO gene predisposes people to diabetes by acting on BMI (body mass index). There are still many unsorted loci for the T2DM pathogenesis.

Symptoms

In type 1, the first recognizable symptom is a condition called prediabetes in which the usual insulin release in response to elevated blood sugar levels in the blood diminishes. At a certain point, commonly between the ages of ten and fourteen, the person develops full-blown diabetes, with excessive thirst and urination, as well as weight loss despite ade-quate or increased caloric intake. In type 2 diabetes, symptoms may develop slowly over time and include excessive thirst and hunger, frequent urination, unexplained fatigue or weight loss, impaired healing of sores, higher incidence of infections, and blurred vision.

Screening and Diagnosis

Screening people at high risk but without symptoms can lead to early diagnosis and avert long-term chronic disease resulting from a lack of therapeutic intervention. The American Diabetes Association recommends screening based on risks such as advanced age, family history, personal gestational history, and central obesity (apple-shaped body type with fat around the waist and upper body). The practice of screening is controversial, but diabetes often goes undetected in the early stages and, therefore, untreated. Some research shows that testing is not cost-effective, while others show that this prevention method can save the health-care system the high cost of treatment for complications from untreated diabetes.

The methods of screening for diabetes generally begin with a random plasma glucose test. If this yields abnormal values, the patient either takes the fasting plasma glucose test (FPG) or the fasting two-hour oral glucose tolerance test (GTT). Values greater than 140 mg/dL for the FPG or greater than 200 mg/dL on the GTT require further assessment and intervention.

Treatment and Therapy

Treatment for type 1 diabetes includes regular blood glucose monitoring and management with insulin. The person with type 1 may need lifestyle changes to optimize self-care and minimize other complications from the disease, such as ketoacidosis. Choosing a healthy diet with regular meals, balanced with adequate activity and insulin, is essential for disease management. Consultation with a registered dietitian may be useful to choose meals and snacks with the proper amounts of carbohydrates and fats.

Type 2 diabetes treatment requires similar approaches, but the patient may try initial control with diet and exercise. If that approach is ineffective, therapy can progress to oral medications that increase tissue sensitivity to circulating insulin, stimulate increased insulin secretion, or alter insulin action. Later, insulin therapy may be neces-sary. Even with medication, successful treatment must include weight control through regular physical activity and diet modification.

Once the genetic factors related to diabetes have been wholly elucidated for all types of diabetes, treatments to modify the genes may become a reality. Genome technology could remove the risks of side effects currently caused by treatment with medications.

Prevention and Outcomes

Although genetics has a definite role in diabetes development, personal choices can also help prevent this disease. The primary prevention approaches for diabetes include choosing a healthy lifestyle and maintaining a normal weight. Regular physical activity, balanced diet with adequate fiber and whole grains, weight loss to an optimal level for the person’s height and build, not smoking, and early screening for those at high risk are essential. The CDC recommends that people eat right and be active.

Both types of diabetes lead to increased risk of heart and vascular disease, kidney problems, blind-ness, neurological problems, and other serious medical consequences. Related health concerns include increased infections, delayed healing, foot and skin problems, depression, neuropathy (nerve damage), impaired vision, gingivitis, and dental disease.

Further Reading