What does a risk factor do?
Insulin tells muscle, liver and fat tissue to take up glucose, and it holds back the release of fat. In some people the tissues respond less to insulin. Tissues that answer less well need more insulin to do the same job. The beta cells of the pancreas can make more insulin for a long time, so blood glucose stays normal while they keep pace.
That is the balance behind this topic. A risk factor is anything that pushes the tissues toward answering less well, or that leaves the beta cells less room to compensate. Type 2 diabetes does not develop at random, and several recognised risk factors make it more likely. They differ between adults and children and adolescents. The same factors decide when testing for the disease should begin, and they mark the people in whom screening is worthwhile.
Which of these factors matter most, and how do they reach the tissues?
How do inactivity and stored fat raise the risk?
Obesity and physical inactivity are the modifiable factors that matter most. They raise risk mainly by increasing insulin resistance, and each acts on a different tissue.
Muscle is one of the main tissues that insulin acts on. Physical activity improves the insulin sensitivity of skeletal muscle, so a person who is inactive loses some of that help.
The second route is fat. When intake consistently exceeds expenditure, the surplus is stored as fat. Expanding adipose tissue promotes insulin resistance.
So the balance between physical activity and calorie intake is one environmental influence. Does the environment change how much energy the body spends in other ways too?
Does the temperature around us matter?
Ambient temperature is the second environmental influence in the pathogenesis of type 2 diabetes. It sets how much energy the body spends producing heat. The body makes heat by spending energy, and cold exposure raises that spending. Energy expenditure is therefore higher in a cool environment and lower in a warm one, because in a warm setting less energy goes to making heat.
From this, rising indoor temperatures have been proposed as one contributor to weight gain. The size of that contribution is uncertain, and ambient temperature is only one influence among many.
These environmental influences apply beyond individual characteristics, and they act together with genes: the disease results from genetic and environmental factors together. So some of the risk is inherited. What runs in families?
Who is at risk through family and ethnic group?
A first-degree relative with diabetes is a risk factor in adults. Relatives share part of their genes, and the genes help set how easily the balance tips, while the environment supplies the load.
High-risk race or ethnicity is also a risk factor in adults. The groups are African American, Latino, Native American, Asian American and Pacific Islander.
Other conditions are associated with insulin resistance. Which ones travel with it?
Which conditions go with insulin resistance?
Its features often appear together in the same person: obesity, hypertension, dyslipidemia and cardiovascular disease. That is why these conditions sit side by side in the list of adult risk factors, and why “other conditions associated with insulin resistance” is itself a risk factor.
The adult list reads as follows.
- Hypertension, meaning ≥130/80 mm Hg or treatment for hypertension.
- HDL cholesterol below 35 mg/dL (0.90 mmol/L) and/or triglyceride above 250 mg/dL (2.8 mmol/L). Insulin resistance has an important role in this pattern of raised triglycerides and lowered HDL. A proposed route is that more fatty acids reach the liver.
- A history of cardiovascular disease.
- Polycystic ovary syndrome.
- Prediabetes, meaning HbA1c ≥5.7%, impaired glucose tolerance, or impaired fasting glucose.
- Other conditions associated with insulin resistance. Examples are severe obesity, acanthosis nigricans and metabolic dysfunction-associated steatotic liver disease. Acanthosis nigricans shows as dark, velvety thickening of the skin in body folds.
Risk is also carried in pregnancy and by some other high-risk groups.
What about pregnancy and other high-risk groups?
Pregnancy itself raises insulin resistance. Gestational diabetes is an inadequate beta-cell response to that rise. A woman diagnosed with gestational diabetes therefore carries a higher risk, and so does a woman who delivered a baby weighing more than 9 lb. A large baby is linked with glucose exposure in pregnancy. It is a link, not a cause.
Other high-risk groups are also listed as a risk factor in adults, with no single mechanism given. They include people with:
- HIV infection
- exposure to high-risk medicines
- periodontal disease
- a history of pancreatitis
Do the same factors work in children and adolescents, and how do they show there?
What changes in children and adolescents?
Children and adolescents have fewer risk factors than adults, and the factors are grouped by their source.
- Family history: type 2 diabetes in a first- or second-degree relative.
- Race and ethnicity: Native American, African American, Latino, Asian American or Pacific Islander.
- Signs of insulin resistance: acanthosis nigricans, hypertension, dyslipidemia, small-for-gestational-age birth weight and polycystic ovary syndrome. Hypertension and dyslipidemia are the same features that travel with insulin resistance in adults.
- Maternal history: diabetes or gestational diabetes during the child’s gestation. Maternal diabetes is linked with a higher risk of the child developing impaired glucose tolerance and obesity in adulthood.
All these factors act on one balance between insulin and the tissues. How does the body normally keep blood glucose steady between meals and dispose of a glucose load after eating, and what does insulin do to glucose?