Exploring Glycemic Challenges With Experts in T2DM
Explore the physiology of glucose homeostasis and how its dysregulation in type 2 diabetes may lead to challenges in controlling hemoglobin A1c levels, with Dr. Steven Edelman.
One of the important themes of this video series is the need to consider the different physiologic abnormalities that disrupt glucose homeostasis when managing type 2 diabetes.
Therefore, the natural balancing act that manages blood glucose levels, while familiar, deserves attention.
In essence, glucose levels are regulated by the release of the pancreatic hormones insulin and glucagon. Insulin lowers blood glucose while glucagon increases it, the balance dictated by how much glucose is in the blood.
Looking just a little deeper, we know that other organs play a role in glucose homeostasis. For example, low blood glucose levels stimulate glucagon secretion, which prompts the liver to release glucose into the circulation. When blood glucose levels rise, insulin secreted by the pancreas suppresses hepatic glucose production and leads to increased glucose uptake by skeletal muscle, the liver, and fat cells.
Glucose homeostasis is also influenced by hormones secreted from the small intestine called incretins. One such incretin is glucagon-like peptide-1 or GLP-1. In response to food consumption, GLP-1 is released from intestinal L- cells. GLP-1 signals the pancreas to increase insulin secretion and decrease glucagon secretion in a glucose-dependent manner. This helps manage glycemic spikes after meals. GLP-1 also delays gastric emptying, which also contributes to reducing blood glucose spikes after a meal. This hormone is rapidly degraded by the enzyme dipeptidyl peptidase-4, or DPP-4.
What disturbs this glucose homeostasis balancing act?
An early change that occurs is the onset of insulin resistance in muscle tissue and the liver. The liver begins to overproduce glucose, while muscle removes less glucose from the blood.
Insulin secretion rises to compensate for the defects in early stages of the disease, but postprandial hyperglycemia is already apparent. Eventually, the β-cells can no longer counteract the increasing insulin resistance, and the production of insulin decreases.
Roughly 50% of β-cell function is lost before the typical person with type 2 diabetes is even diagnosed. Along with these physiologic defects is another—reduced secretion of, and lower β-cells sensitivity to incretins. With the onset of diabetes, hyperglycemia also becomes apparent in the basal, fasting state.
Since type 2 diabetes is not defined by insulin deficit alone, no single approach can address its complexity. Combinations of therapies that target different physiologic abnormalities may be considered to address such complexity. The ADA and AACE guidelines agree; both recommend combinations of oral therapies and combinations of injectable therapies for patients who are not at their A1c target levels. Combining therapies with different mechanisms of action may allow a tailored approach to better serve individual patient’s needs.
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