Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

Abstract

Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.

Figure 1

Feedback loop between the islet β-cell and the insulin-sensitive tissues. (A) Insulin acts in the liver to suppress glucose production, and in the muscle and adipose tissue to stimulate the uptake of glucose, amino acids and fatty acids. The amount of insulin released to maintain normal glucose homeostasis is determined by the prevailing insulin sensitivity. This feedback is likely mediated through neuronal and humoral mechanisms, but the exact mediators are still not known. (B) When insulin resistance develops in the insulin-sensitive tissues, feedback to the β-cell ensures that it increases insulin output to maintain normal glucose tolerance. (C) When the β-cell is incapable of increasing insulin output in the presence of insulin resistance, the result is the development of elevated glucose levels, initially manifest as impaired glucose tolerance. As β-cell dysfunction progresses, further elevations in glycaemia occur and diabetes is the eventual result.

Figure 2

Role of genes and the environment in the development of obesity and type 2 diabetes. The interaction of genes that influence body adiposity with environmental factors results in the development of obesity and its associated insulin resistance. However, only when genes for abnormal β-cell function are present along with those for body adiposity does the interaction with the environment result in the development of type 2 diabetes.

Figure 3

(A) Timeline of the introduction of medications for treating type 2 diabetes. The rate of introduction of new classes of medications has accelerated over the last 20 years. The two classes indicated in red, animal insulin and inhaled insulin, are essentially no longer available as therapeutics. (B) Organ systems on which the different classes of medications have their primary mode of action. In the case of insulin, this is as replacement for this natural product of the islet β-cell. The classical organ systems are targets for which available and new interventions have been targeted for decades and comprise the pancreatic islet, liver, muscle and adipose tissue. The non-classical targets have been a focus more recently and include the intestine, kidney and brain.

Figure 3

(A) Timeline of the introduction of medications for treating type 2 diabetes. The rate of introduction of new classes of medications has accelerated over the last 20 years. The two classes indicated in red, animal insulin and inhaled insulin, are essentially no longer available as therapeutics. (B) Organ systems on which the different classes of medications have their primary mode of action. In the case of insulin, this is as replacement for this natural product of the islet β-cell. The classical organ systems are targets for which available and new interventions have been targeted for decades and comprise the pancreatic islet, liver, muscle and adipose tissue. The non-classical targets have been a focus more recently and include the intestine, kidney and brain.