Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

Abstract

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

Effects of family history of diabetes on pancreatic β-cell function and diabetic ketoacidosis in newly diagnosed patients with type 2 diabetes: a cross-sectional study in China

“…Furthermore, insulin resistance also leads to poor β-cell function. 34 However, there was no statistically significant association between a sibling history of diabetes and insulin resistance in our study.…”

“…Furthermore, insulin resistance also leads to poor β-cell function. 34 However, there was no statistically significant association between a sibling history of diabetes and insulin resistance in our study. An FHD, an easily obtainable and relatively useful screening tool, has been proven to be a potential risk factor for T2DM.…”

Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

“…Such a pathological condition in the human body indicates resistance to the effects of insulin, with a requirement of beyond-normal insulin concentrations to maintain euglycemic status and ineffective strength of insulin signaling from the receptor, downstream to the final substrates of its action. The transmembrane insulin receptor consists of two extracellular a and two intracellular b subunits linked by disulphide bonds[ 3 ]. Binding of insulin to the α subunits can activate the tyrosine kinase in the β subunits.…”

“…PIP3 is a potent inducer for activating various kinases, PKB in particular, to facilitate the entry of glucose into cells by translocating glucose transporter 4 (GLUT4) to the cell surface and to promote the synthesis of glycogen by suppressing the inhibitory glycogen synthase kinase-3β[ 9 - 12 ]. Most of the physiological effects of insulin are mediated by the signaling pathway involving the activated IRS and SH2 domain proteins[ 1 - 3 ], leading to activation of multiple downstream effectors to regulate cell differentiation, growth, survival, and metabolism via a variety of intracellular pathways.…”

Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes

“…These rhythmic processes are compromised in the course of obesity and type 2 diabetes (T2D) development, indicating impairment of the functions (deregulation of signaling and metabolic pathways) of interstitial cells of Cajal, vascular, and pancreatic α, β, and δ cells, which is manifested as diabetic gastropathy, hypertension and atherosclerosis, and insulin and glucagon resistance, respectively [ 21 , 25 , 26 , 27 , 28 ]. Additionally, hypertension is characterized by acetylcholine resistance and accompanied by the loss of fast and slow rhythmic contractions in aortas of obese and diabetic animals [ 29 ].…”