Diabetes and genetics

• ALSO KNOWN AS: Diabetes mellitus; juvenile, insulin-dependent diabetes, type 1 diabetes; adult-onset, non-insulin-dependent diabetes, type 2 diabetes; gestational diabetes; diabetes insipidus; unspecified diabetes mellitus; prediabetes; “sugar.”

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; according to the US Centers for Disease Control and Prevention (CDC), an estimated 40 million persons in the United States were affected in the mid-2020s, up from 26 million in 2010. Of those with diabetes, one in four people are not aware that they have the disease. An additional 115 million adults have prediabetes. Increasing activity levels and losing weight can prevent prediabetes from developing into type 2 diabetes. Diabetes is a disease related to both genetics and environmental or lifestyle factors.

Risk Factors

The Centers for Disease Control and Prevention (CDC) reported in the mid-2020s that type 1 diabetes accounted for about 5 to 10 percent of diagnosed cases of diabetes in the United States, while type 2 accounted for about 90 to 95 percent of cases. The primary risk factor for type 1 diabetes is having a parent or sibling with the disease. The most common type of diabetes, type 2, has multiple risk factors, both genetic and environmental. These include excessive food intake or unhealthy eating habits that result in obesity especially around the waist area, an inactive or sedentary lifestyle, increased age (over forty-five years old), high blood pressure (140/90 mmHg or greater), family history, gestational (during pregnancy) diabetes, and high cholesterol (HDL under thirty-five and 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 a number of different diseases, primarily type 1 and type 2 diabetes. Genetics plays a role in both types of diabetes, although both are thought to result from the interaction between genetics and the environment. In both, the body’s ability to process sugars is impaired, 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. Normally, blood glucose rises when carbohydrates are ingested. At a certain level, the 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. In type 1 diabetes, also called juvenile-onset or insulin-dependent diabetes, this is caused by destruction of the insulin-secreting cells in the pancreas. In type 2 (adult-onset, maturity-onset, or non-insulin-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 a bad 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 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 HLA 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 assist the body in differentiating its own immune cells from external substances. These immune cells continually watch for small chained amino acids such as those found in tumor cells or infectious bacteria. Under normal circumstances, the immune cells will attack these chained amino acids to protect the body. The CTLA4 gene that hinders this action has been associated with a number of diseases including type 1 diabetes.

In addition, a rare type of autoimmune diabetes, resembling type 1, occurs as part of a syndrome called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by mutation in AIRE, an autoimmune regulator gene. Although the function of AIRE is not known, expression of the gene has been detected in the thymus, pancreas, and adrenal cortex, and developmental studies suggest that mutations in AIRE might cause the thymus (which is integral to proper immune system function) to develop incorrectly.

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 disease, 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 a genetic susceptibility, but the development of actual disease may be dependent upon an environmental trigger. Some possible triggers include aging, a sedentary lifestyle, and abdominal obesity. 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. Between 80 to 90 percent of people with type 2 diabetes 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, the likelihood is about 70 percent that the second twin will develop type 2 diabetes once the first twin has developed the disease.

Mutant alleles for a number of genes have been implicated in susceptibility and development of type 2 diabetes. The first genes to be implicated were the insulin gene, genes encoding important 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. By 2016, 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. By the 2020s, hundreds more variants had been identified. One study published in 2024 found 650 genetic variants. As more genes and their mutant alleles are discovered, better treatment options should become available, possibly even some tailored to specific types of mutations.

One way to discover susceptibility for type 2 is through whole-genome linkage studies of families. Researchers have found the genes calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A) are suspect for type 2 diabetes. The CAPN10 gene has been linked to high rates of type 2 diabetes in Mexican Americans. A mutated CAPN10 may in some way alter insulin secretion as well as affect liver glucose production. Likewise, the HNF4A gene transcription factor found around chromosome 20 is linked to type 2 diabetes. HNF4A located in the liver is related to embryo development, and HNF4A found in the beta cells of the pancreas is related to insulin secretion. Many other genes are under study for their impact on type 2 diabetes.

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 is diminished. 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 adequate 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, a 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 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 screening is not cost-effective, while others state that this method of prevention can save the healthcare 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, either the fasting plasma glucose test (FPG) or the fasting two-hour oral glucose tolerance test (GTT) is used. 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 the possibility of 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 necessary. Even with medication, successful therapy must include weight control through regular physical activity and diet modification. In the twenty-first century, a new class of injectable medications called GLP-1 agonists and similar medications became increasingly popular in the management of type 2 diabetes. These medications mimic the GLP-1 hormone, a naturally occurring hormone made by the small intestine and have been effective in managing blood sugar by triggering the pancreas to release more insulin and slowing digestion.

Once the genetic factors related to diabetes have been completely 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 the development of diabetes, personal choice can also impact the prevention of this disease. The primary prevention approaches for diabetes include choosing a healthy lifestyle and maintaining normal weight. Regular physical activity, a balanced diet with adequate fiber and whole grains, weight loss to the optimal level for the person’s height and build, not smoking, and early screening for those at high risk are important. The CDC recommends that people eat a balanced diet and be active.

Both types of diabetes lead to increased risk of heart and vascular disease, kidney problems, blindness, 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.

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