Type 2 Diabetes

A blood testing pen

In people with type 2 diabetes (T2D), cells in muscle, fat, and liver tissue do not properly respond to insulin, a condition referred to as insulin resistance. As a result, the pancreas must compensate by producing more insulin. Gradually, however, the pancreatic β (beta) cells lose their ability to secrete enough insulin to compensate for the increased demand, resulting in blood glucose rising to levels that meet criteria for the diagnosis of diabetes. Diabetes increases risk for premature death, increases risk of cardiovascular disease, kidney disease, blindness, and numerous other serious complications. NIDDK research seeks to reduce the burden of this serious and all too common disease. Gestational diabetes (GDM) is a form of diabetes that appears in pregnancy. Untreated, any form of diabetes during pregnancy increases the risk of serious complications for the mother and baby before, during, and after delivery; and GDM increases the risk of T2D in the mother later in life.

Yesterday

  • With the rising prevalence of obesity among other reasons, T2D became increasingly common in the late 20th century, with the largest increases occurring among minority groups and the poor. The causes of T2D were unknown and there was no way to prevent it.
  • The discovery of insulin in 1921, which was initially used as a life-saving therapy for type 1 diabetes, also provided the first effective means to treat T2D. Sulfonylureas—oral medications developed in the 1950s—stimulate the pancreas to release more insulin. Metformin was first marketed in the United States to help lower glucose levels in people with T2D in 1995, although it was widely prescribed in Europe before that.
  • The 10-year, 3,867-participant UK Prospective Diabetes Study (UKPDS), partly supported by NIDDK, showed that in newly diagnosed adults with T2D, use of these medications at doses adjusted to maintain A1c (a measure of blood glucose control) at 7 percent or less lowered incidence of disease complications as well as all-cause mortality. Metformin was shown to have a very good risk-benefit profile, particularly in people with T2D and overweight/obesity, among whom it often leads to modest but sustained weight loss. These findings shaped long-standing treatment goals for T2D and helped establish metformin as a drug to be considered as a first-line therapy for people with the disease.
  • Both insulin and sulfonylurea drugs carry the risk of causing hypoglycemia (blood glucose levels that are too low). While metformin does not have this serious side effect, it also does not work well in everyone and is usually insufficient for long-term blood glucose control. Insulin-sensitizing drugs called thiazolidinediones, (e.g., rosiglitazone, pioglitazone) were approved for T2D in the late 1990s and soon became extremely popular. However, reported side effects such as a possible risk of worsening heart disease eventually led to a decline in their use. Thus, new and better medications for treating T2D were urgently needed.

Today and Tomorrow

Today

  • The landmark NIDDK-led Diabetes Prevention Program (DPP) clinical trial demonstrated that an intensive lifestyle intervention designed to yield 7 percent weight loss could prevent or delay T2D in people at high-risk for the disease. Metformin was also effective, although to a lower degree. Lifestyle was particularly effective among the oldest DPP participants—those at least 60 years old when the study began. Metformin was most effective among the youngest participants—those between 25 and 44 years old—as well as among women with a history of gestational diabetes. The ongoing DPP Outcomes Study has shown the interventions to be highly cost-effective, and durable to a significant degree.
  • NIDDK-supported translational research has made it possible to deliver adaptations of the DPP lifestyle intervention at scale to millions of people at risk for diabetes in the United States.

Tomorrow

  • While DPP-adapted lifestyle interventions are gradually being offered to more people, it is hoped that one day all those at high risk for T2D will have the opportunity to receive them.
  • Biomarkers of T2D risk may one day help target prevention efforts to those most likely to benefit, and improved prevention methods may dramatically reduce the number of people who develop T2D.

Today

  • Several new classes of drugs are available for treating adults with T2D. These include: GLP-1 receptor agonists, whose beneficial effects include boosting the pancreatic response to elevated glucose levels; and SGLT2 inhibitors, which reduce glucose re-uptake in the kidney. Importantly, medications in both classes have been shown to reduce cardiovascular and/or kidney complications of T2D, and to promote weight loss, while being less likely than some other T2D medications to cause blood glucose levels to become too low.
  • Bariatric surgery often leads to long-term remission of T2D in people with obesity, and it appears that maintenance of weight loss and duration of diabetes are key factors in determining who is most likely to remain in remission. Recent evidence suggests that substantial weight loss from an intensive dietary intervention, if maintained over time, may also result in T2D remission.
  • Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study seeks to determine which of four commonly used glucose-lowering drugs, when added to metformin, is best for achieving good glycemic control, has the fewest side effects, and is the most beneficial for overall health in long-term treatment for people with T2D.

Tomorrow

  • Study of rare gene variants that protect against T2D may lead to new and better treatment or prevention methods.
  • Study of T2D subtypes may lead to new disease classification and help optimize care for those with the disease, while biomarkers and genetic risk factors may one day indicate who is most at risk for disease progression and/or development of complications, as well as who will be most likely to benefit from specific therapeutic approaches.

Today

  • Once referred to as “adult-onset” diabetes, T2D is most commonly found in older individuals, but diagnosis in children and adolescents is on the rise. Among the young, T2D disproportionately affects youth from racial and ethnic minority populations in the United States. Although metformin is an excellent medication for adults, it appears to be less effective and have a higher failure rate in people younger than 20 compared with middle-aged and older adults. Indeed, no medication has proved effective for treating T2D in the young over the long term. Compared to adults with T2D, disease progression and development of complications occur faster in young people with the disease. Youth-onset T2D is marked by greater pancreatic dysfunction and insulin resistance than when the disease develops later in life.
  • The Action to Control Cardiovascular Risk in Diabetes clinical Trial showed that in 10,000 middle-aged and older participants with T2D and cardiovascular disease (CVD) or risk factors for CVD, intensive effort to reduce A1c below 8 percent actually increased mortality and did not significantly reduce major cardiovascular events during the 3 ½ years of the study.

Tomorrow

  • Research will lead to improved methods for treating T2D in the young, and better methods for managing care while limiting potential risks in older patients with more advanced disease.

Today

  • In 2008, the landmark NIH-funded Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study reported findings of health problems associated with untreated glucose levels during pregnancy that were above normal, but not high enough to be considered diabetes by traditional criteria in 23,000 racially and ethnically diverse pregnant women and their babies. These health problems included increased risk of multiple adverse delivery and neonatal outcomes for the mother and child.
  • Primarily as a result of HAPO, alternative criteria for diagnosing GDM at lower blood glucose levels were proposed and adopted by some international organizations. However, these criteria are not widely used in the United States, largely due to findings from an expert panel NIH convened in 2013 that noted: gaps in knowledge about how best to treat women diagnosed with the alternative criteria; the absence of evidence about long-term outcomes and benefits for these women with or without treatment; and the potential for short-term harms, such as the additional stress a woman can experience when diagnosed with GDM.
  • Results from the NIDDK-led HAPO Follow Up Study have demonstrated long-term metabolic impacts of hyperglycemia during pregnancy at levels lower than overt diabetes on both mothers and offspring, including greatly increased risk of later T2D diagnosis in mothers, increased risk of obesity in children, and higher blood glucose levels in children when evaluated 10 to 14 years later.

Tomorrow

  • NIDDK-supported studies will determine how maternal blood glucose levels change across the entire course of pregnancy; whether screening for GDM and/or treating it earlier in pregnancy would improve outcomes; and whether providing treatment for intermediate maternal blood glucose levels (higher than normal, but less than GDM) would result in health benefits for mothers and children.