Insulin Abnormalities in Metabolic Syndrome and T2D

Insulin resistance presents a biomarker for poor metabolic health. 

Based on the pathophysiology of type 2 diabetes, it is understood that it develops because of failure of the beta cells in the pancreas to sustain over secretion of insulin, causing excess insulin in the body to play a significant role, which is termed insulin resistance and is harmful to the body, root cause for type 2 diabetes, and all problems related to metabolic syndrome. On the other hand, insulin resistance has a positive view where it protects tissues of the body from metabolic injuries in situations of chronic nutrient excess. 

Insulin sensitivity is an essential mechanism by which the body controls nutrient division between tissues, necessitated by variations in dietary intake and exercise, lifestyle, pregnancy, illnesses, and age. For instance, a pregnant woman will divert nutrients to a growing fetus, and insulin resistance in the mother is the mechanism by which it is achieved. The take home is an adaptation to insulin sensitivity, because excess nutrients vary based on many factors, and this is when insulin resistance helps by protecting tissues. 

A failure to limit excess glucose at times of concomitant high fat-free fatty acid (FFA) availability will cause cell injury by the method of glucolipotoxicity. As a result, severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin resistance (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD) were five subgroups in a study reported from Scandinavia. The SIRD subgroup was predominantly people with obesity and severe hyperinsulinemia and insulin resistance. The individuals in the group were also likely to develop diabetic neuropathy and coronary events. The age at which the people in Scandinavia had the onset of diabetes was high, related to their ethnicity. The RISE study also reported that insulin resistance tends to be expected in young people presenting with obesity-related type 2 diabetes. In the SIDD, MOD, and MARD subgroups, insulin resistance is lesser, but islet beta cells must still be part of the mechanism. A precise medical approach must be used in the treatment of diabetes in these subgroups, and their phenotype and genotypes should also be taken into account whether the cause for insulin resistance is due to failure of islet beta cells or is unknown. 

While insulin resistance is a prominent biomarker for poor metabolic health, it is also a defensive mechanism against hyperinsulinemia and nutrient overload. In so doing, it becomes the primary driver, with insulin hypersecretion and the resulting hyperinsulinemia taking up a position as the unifying mechanism instead of being compensated for insulin resistance. There comes the new framework and paradigm shift. Therefore, it is vital to manage metabolic homeostasis in people with type 2 diabetes, and it could cause obesity. The use of pharmacological therapies like sodium-glucose transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonist (GLP1), or bariatric surgery should be beneficial in most patients who have type 2 diabetes. In the RISE study, neither three months of insulin glargine followed by nine months of metformin nor 12 months of metformin alone slowed the progressive deterioration of β-cell function in young people with early T2D, suggesting different approaches are required. An alternate scenario of intracellular nutrient depletion in patients with hyperinsulinemia diabetes is also important to consider; SGLT2 inhibitors should be avoided. 

It was necessary to point out the relationship between the Mets and ASCVD, NAFLD, PCOS, and type 2 diabetes; after explaining and going over the pathophysiology of T2M, the researchers put insulin hypersecretion into the role while taking insulin resistance into account as a protective downstream response.  

Practice Pearls:  

• Patients with insulin resistance present a biomarker for poor metabolic health and should be screened for other MetS like T2D, PCOS, NAFLD, and ASCVD.  
• Therapies for the treatment of diabetes should be treated considering their age; In patients greater than or equal to 75 years old, these therapies have been associated with increased risk for all-cause of mortality. 
• Nutrient status should be considered when treating diabetes. 

Nolan, Christopher J, and Marc Prentki. “Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift.” Diabetes & vascular disease research vol. 16,2 (2019): 118-127. doi:10.1177/1479164119827611 

Milane Kenguim, PharmD Candidate, South College School of Pharmacy