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Abstract
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

CONCLUSIONS
Hyperinsulinemia is a condition associated with obesity and
early stage T2DM. Recent studies have implicated hyperinsulinemia in multiple pathological conditions including insulin
resistance, inflammation, obesity, and cancer. Modest inhibition of insulin production or insulin signaling is sufficient to increase of lifespans in a variety of animal models, from invertebrates to mice. Additional studies are required to elucidate the
relationship between insulin and IGF during aging, as well as
the shared and distinct molecular mechanisms. Conventionally,
hyperinsulinemia was considered to be an adaptation to obesity-induced insulin resistance. However, evidence continues to
mount that hyperinsulinemia can precede and cause obesity
and insulin resistance. Animal models with reduced endogenous insulin secretions were protected from diet-, age-, and
leptin-induced obesity, which clearly demonstrates the causal
role of hyperinsulinemia in obesity. It is also clear that insulin
resistance can lead to hyperinsulinemia, including at the level of
the pancreatic β-cells, suggesting at least a bi- or tri-directional
relationship. Future studies will be required to determine the
nature of the complex vicious cycles that lead to T2DM. The
metabolic importance of insulin has been long recognized but
now the field is beginning to appreciate its importance in cancers. Both clinical and epidemiological studies demonstrated
hyperinsulinemia is associated with increased cancer morbidity
and mortality. Furthermore, direct animal studies have shown
hyperinsulinemia could promote tumorigenesis, especially for
pancreatic. Invertebrate models of hyperinsulinemia-induced
cancer provide opportunities for powerful screens [369] that
may uncover the specific molecular mechanisms involved and
lead to targeted therapeutics. In summary, while insulin is essential for maintain normal life, the negative consequences of
hyperinsulinemia shed light on the importance of maintaining
insulin levels within a healthy range. Lifestyle interventions or
therapeutics with mild insulin suppressing actions provide new
opportunities to prevent and treat certain disorders like obesity,
chronic inflammation and cancers.