T2D is driven by several pathophysiological defects, many of which can now be addressed with available therapies that enable individualizing treatment1,2
Multisystem contributors are associated with hyperglycemia and the progression of T2D1,2
The infographic titled "Multisystem Contributors Are Associated With Hyperglycemia and the Progression of T2D" illustrates how various physiological systems contribute to hyperglycemia. These include the colon/biome system which can result in abnormal microbiota and possible decreased GLP-1 secretion; neurotransmitter dysfunction which may result in increased appetite and food intake; the stomach and small intestine which may result in an increased rate of glucose absorption; the immune system which may result in dysregulation and inflammation; adipose tissue which can result in increased lipolysis; muscles which may result in decreased peripheral uptake of glucose due to insulin resistance; the liver which can result in increased glucose production and hepatic insulin resistance; the kidneys which may result in increased glucose reabsorption; pancreatic β-cells which may result in decreased insulin secretion, diminished incretin effect, and decreased β-cell mass; and pancreatic α-cells which may result in increased glucagon secretion. Each system is paired with an icon and a brief descriptor.
Many different systems contribute to hyperglycemia directly and indirectly. Excess adipose, including ectopic fat accumulation, contributes to insulin resistance and inflammation and is an important contributor. It is important to consider that many of these changes may begin years before a person is diagnosed and may continue to worsen in the absence of specific medical interventions.3-9
Treatment options to address hyperglycemia2,10,11
Medications treat core defects of T2D differently across classes1,2,10,11
| Class | Direct Primary Physiological Action(s) | Organ(s) Affected |
|---|---|---|
| Biguanide (metformin) |  |  |
| Sulfonylurea (SU) |  |  |
| Thiazolidinedione (TZD) | |  |
| Dipeptidyl peptidase-4 (DPP-4) inhibitor | |  |
| Sodium-glucose cotransporter-2 (SGLT2) inhibitor |  |  |
| Incretin receptor agonists* | |  |
Class Biguanide (metformin) Direct Primary Physiological Action(s): Organ(s) Affected: |
Class Sulfonylurea (SU) Direct Primary Physiological Action(s): Organ(s) Affected: |
Class Thiazolidinedione (TZD) Direct Primary Physiological Action(s): Organ(s) Affected: |
Class Dipeptidyl peptidase-4 (DPP-4) inhibitor Direct Primary Physiological Action(s): Organ(s) Affected: |
Class Sodium-glucose cotransporter-2 (SGLT2) inhibitor Direct Primary Physiological Action(s): Organ(s) Affected: |
Class Incretin receptor agonists* Direct Primary Physiological Action(s): Insulin secretion (glucose‑dependent) Glucagon secretion (glucose‑dependent) Delays gastric emptying Excess Weight Organ(s) Affected: |
The schematic is intended to provide an overview of T2D drugs and is not specific to only 1 product within each class listed. It is not limited to making any expressed or implied comparison among products. The classes shown are from the ADA Standards of Care and do not represent all T2D classes available to treat hyperglycemia.
*Only actions consistent in both classes of incretin receptor agonists shown
Which treatment class would you choose for a patient like Ted?
Ted is showing signs of multiple core defects of T2D, including insulin resistance and excess adiposity, based on his elevated HbA1c and waist-to-hip ratio. Most urgently, these defects tend to be progressive and indicate that Ted is likely experiencing an ongoing decline in his β-cell function.1,2
Medications with the ability to address multiple defects, including excess adiposity, enable more comprehensive and effective T2D management.1
References
- Schwartz SS, Epstein S, Corkey BE, et al. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema. Diabetes Care. 2016;39(2):179-186. doi:10.2337/dc15-1585
- DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. doi:10.2337/db09-9028
- Chait A, den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front Cardiovasc Med. 2020;7:22. doi:10.3389/fcvm.2020.00022
- de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105. doi:10.1016/j.febslet.2007.11.057
- Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. doi:10.1172/JCI19451
- Trouwborst I, Bowser SM, Goossens GH, Blaak EE. Ectopic fat accumulation in distinct insulin resistant phenotypes; targets for personalized nutritional interventions. Front Nutr. 2018;5:77. doi:10.3389/fnut.2018.00077
- Raji A, Seely EW, Arky RA, Simonson DC. Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. J Clin Endocrinol Metab. 2001;86(11):5366-5371. doi:10.1210/jcem.86.11.7992
- Kozawa J, Shimomura I. Ectopic fat accumulation in pancreas and heart. J Clin Med. 2021;10(6):1326. doi:10.3390/jcm10061326
- Ye R, Onodera T, Scherer PE. Lipotoxicity and β cell maintenance in obesity and type 2 diabetes. J Endocr Soc. 2019;3(3):617-631. doi:10.1210/js.2018-00372
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi:10.2337/dc14-2441
- Mounjaro (tirzepatide once weekly) [Summary of Product Characteristics]. Houten, The Netherlands: Eli Lilly and Company.