Biochemistry, Insulin Metabolic Effects

Fundamentals

Key Metabolic Process Definitions

• Gluconeogenesis: Synthesis of glucose using non-carbohydrate precursors
• Glycolysis: Degradation of glucose into pyruvic acid and energy for cell metabolism
• Glycogenesis: Synthesis of glycogen from glucose
• Glycogenolysis: Degradation of glycogen into glucose
• Lipogenesis: Conversion of acetyl-CoA into fatty acids and subsequent triglyceride synthesis
• Lipolysis: Degradation of lipids and triglycerides into free fatty acids

Cellular Level

Cells of the muscle tissue, vascular endothelium, heart, and liver carry out the insulin-dependent cascade. The response generated by insulin’s effects in these cells is tissue-specific. In adipose tissue, skeletal muscle, and the heart, the result is glucose metabolism via glucose uptake into cells. Nitric oxide (NO) vasodilation is seen in the vascular endothelium and heart. The liver exhibits a decrease in gluconeogenesis and increases in glycogenesis in response to insulin. Insulin’s effect stretches to lipid and protein metabolism as well. It stimulates lipogenesis and protein synthesis and, conversely, inhibits lipolysis and protein degradation.

Molecular Level

Insulin is a peptide hormone comprised of 51 amino acids distributed among 2 peptide chains, the A and B chains, of 21 and 30 amino acid residues, respectively. Disulfide bonds of cysteine residues connect the 2 chains. Preproinsulin is the original precursor protein of insulin. It is a single-chain polypeptide consisting of proinsulin and signal peptide sequences. After translating into the endoplasmic reticulum, preproinsulin cleaves at its signal peptide, releasing proinsulin. Proinsulin is a single chain containing insulin’s A and B chains continuously, joined through a segment known as the C domain. Dibasic residues flank the C domain at each end. At the site of each dibasic residue, a trypsin-like enzyme cleaves proinsulin. This cleavage finally releases insulin along with a C-peptide. Until metabolically needed, insulin is stored within glucose-regulated secretory vesicles as zinc insulin hexamers.[4]

Function

Role in Glucose Metabolism

The homeostasis of glucose metabolism is carried out by 2 signaling cascades: insulin-mediated glucose uptake (IMGU) and glucose-stimulated insulin secretion (GSIS). The IMGU cascade allows insulin to increase glucose uptake from skeletal muscle and adipose tissue and suppresses glucose generation by hepatic cells. Activation of the insulin cascade’s downstream signaling begins when insulin extracellularly interacts with the insulin receptor’s alpha subunit. This interaction leads to conformational changes in the insulin-receptor complex, eventually leading to tyrosine kinase phosphorylation of insulin receptor substrates and subsequent activation of phosphatidylinositol-3-kinase. These downstream events cause the desired translocation of the GLUT-4 transporter from intracellular to extracellular onto the skeletal muscle cell’s plasma membrane. Intracellularly, GLUT4 is present within vesicles. The rate at which these GLUT4-vesicles are exocytosed increases due to insulin’s actions or exercise. Thus, by increasing GLUT-4’s presence on the plasma membrane, insulin allows glucose to enter skeletal muscle cells for metabolism into glycogen.

Role in Glycogen Metabolism

In the liver, insulin affects glycogen metabolism by stimulating glycogen synthesis. Protein phosphatase I (PPI) is the key molecule in regulating glycogen metabolism. Via dephosphorylation, PPI slows the rate of glycogenolysis by inactivating phosphorylase kinase and phosphorylase A. In contrast, PPI accelerates glycogenesis by activating glycogen synthase B. Insulin increases PPI substrate-specific activity on glycogen particles, stimulating glycogen synthesis from glucose in the liver.

A variety of hepatic metabolic enzymes are under the direct control of insulin through gene transcription, which affects gene expression in metabolic pathways. In gluconeogenesis, insulin inhibits gene expression of the rate-limiting step, phosphoenolpyruvate carboxylase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase. In glycolysis, gene expression of glucokinase and pyruvate kinase increases. Lipogenesis increases the expression of fatty acid synthase, pyruvate dehydrogenase, and acetyl-CoA carboxylase.

Role in Lipid Metabolism

As previously mentioned, insulin increases the expression of some lipogenic enzymes. This is due to glucose stored as a lipid within adipocytes. Thus, an increase in fatty acid generation increases glucose uptake by the cells. Insulin further regulates this process by dephosphorylating and subsequently inhibiting hormone-sensitive lipase, leading to inhibition of lipolysis. Ultimately, insulin decreases serum-free fatty acid levels.

Role in Protein Metabolism

The protein turnover rate is regulated in part by insulin. Protein synthesis is stimulated by insulin’s increase in intracellular uptake of alanine, arginine, and glutamine (short-chain amino acids) and gene expression of albumin and muscle myosin heavy chain alpha. The regulation of protein breakdown is affected by insulin’s downregulation of hepatic and muscle cell enzymes, which are responsible for protein degradation. The impacted enzymes include ATP-ubiquitin-dependent proteases, ATP-independent lysosomal proteases, and hydrolases.

Role in Inflammation and Vasodilation

Insulin’s actions within endothelial cells and macrophages have an anti-inflammatory effect on the body. Within endothelial cells, insulin stimulates the expression of endothelial nitric oxide synthase (eNOS). eNOS functions to release nitric oxide (NO), which leads to vasodilation. Insulin suppresses nuclear factor-kappa-B (NF-kB) found intracellularly in endothelial cells. Endothelial NF-KB activates the expression of adhesion molecules, E-selectin, and ICAM-1, which release soluble cell adhesion molecules into the circulation. Studies have linked the presence of cell adhesion molecules on vascular endothelium to the development of atherosclerotic arterial plaques.

Insulin suppresses the generation of O2 radicals and reactive oxygen species (ROS). Within the macrophage, insulin inhibits NADPH oxidase expression by suppressing 1 of its key components, p47phox. NADPH oxidase aids in generating oxygen radicals, activating the NF-kB kinase beta inhibitor (IKKB). IKKB phosphorylates IkB, leading to its degradation. This degradation releases NF-kB, allowing for its translocation in the macrophage’s nucleus. Once in the nucleus, NF-kB stimulates gene transcription of pro-inflammatory proteins that are released into the circulation, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein (MCP-1), and matrix metalloproteinase (MMP).

Clinical Significance

There is a group of metabolic diseases in which the body experiences chronic hyperglycemia. Type 1, insulin-dependent diabetes mellitus is when the pancreas has low or absent insulin production. Type 2, insulin-independent diabetes mellitus (DM) is a condition in which the body produces insulin but cannot keep up with its glucose metabolic demands effectively. This supply and demand mismatch leads to insulin resistance and abnormal glucose metabolism. In both type 1 and type 2 DM, glucose remains elevated in the bloodstream because its proper transport into cells and metabolism is not occurring normally. Type 2 DM has reached epidemic standards within the United States. This is of significant concern due to the vast complications caused by DM. These include neuropathy, renal failure, retinopathy, cardiovascular disease, and peripheral vascular disease.[5][6][7][8][9]

During the early stage of type 2 DM development, although the body experiences high blood glucose levels, the pancreatic beta cells produce enough insulin to maintain euglycemia. Insulin production becomes ineffective for adequate glucose metabolism when part of the insulin-mediated glucose uptake cascade is dysfunctional. Specifically, glucose transport across the plasma membrane via GLUT-4 transporters becomes impaired, causing insulin resistance to glycogenesis in muscle cells. GLUT-4 transporter impairment may occur due to persistent hyperglycemia or may have been inherently present.[10][11]