Glucose Metabolism. Glucose uptake and metabolism are essential for the proliferation and survival of cells, and may be enhanced in actively proliferating cell systems such as embryonic tissue.
One of the anabolic effects of insulin is to promote the uptake of fatty acids into adipose tissue. The amount of weight gain in the DCCT (type 1 patients) and UKPDS (type 2 patients) associated with insulin therapy was 4.6 kg and 4.0 kg respectively (69,70).
Insulin Signaling. Glucose metabolism is regulated at multiple sites, with transmembrane glucose transport being the rate-limiting step in healthy and diabetic subjects [15]. The primary insulin responsive glucose transporter (GLUT) in skeletal muscle and adipose tissue is GLUT-4.
PHARMACODYNAMICS The onset, peak, and duration of effect vary among insulin preparations. Insulin pharmacodynamics refers to the metabolic effect of insulin. Commercially available insulins are categorized as rapid-acting, short-acting, intermediate-acting, and long- acting. Insulins currently available in the United States are listed in Table 2.
The main actions that insulin has are to allow glucose to enter cells to be used as energy and to maintain the amount of glucose found in the bloodstream within normal levels. The release of insulin is tightly regulated in healthy people in order to balance food intake and the metabolic needs of the body.
Insulin promotes the absorption of blood glucose by liver, muscle and fat cells. Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high levels of glucose; and inhibit secretion of insulin when glucose levels are low.
Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain.
Glycogenesis is stimulated by the hormone insulin. Insulin facilitates the uptake of glucose into muscle cells, though it is not required for the transport of glucose into liver cells.
Insulin is an anabolic hormone that promotes glucose uptake, glycogenesis, lipogenesis, and protein synthesis of skeletal muscle and fat tissue through the tyrosine kinase receptor pathway.
Insulin and glucagon are vital for maintaining normal ranges of blood sugar. Insulin allows the cells to absorb glucose from the blood, while glucagon triggers a release of stored glucose from the liver.
Both hormones come from your pancreas — alpha cells in your pancreas make and release glucagon, and beta cells in your pancreas make and release insulin. The difference is in how these hormones contribute to blood sugar regulation. Glucagon increases blood sugar levels, whereas insulin decreases blood sugar levels.
Thus, the function of insulin is to promote the uptake of glucose by muscle cells that use it for energy and by fat cells that store it as triglycerides, or fats, and by liver cells.
Insulin helps blood sugar enter the body's cells so it can be used for energy. Insulin also signals the liver to store blood sugar for later use. Blood sugar enters cells, and levels in the bloodstream decrease, signaling insulin to decrease too.
The Kidney and Glucose Metabolism. Glucose metabolism can be impaired by defects in insulin secretion or from defects in cellular sensitivity to insulin. The kidney plays an important role in glucose metabolism.
The primary insulin responsive glucose transporter (GLUT) in skeletal muscle and adipose tissue is GLUT-4. Glucose transport in the skeletal muscle accounts for approximately 70% of whole-body insulin-mediated glucose uptake [100]. Insulin binds its plasma membrane receptor, leading to phosphorylation of the receptor and insulin receptor substrates (IRS-1), stimulation of phosphatidylinositol-3-kinase (PI-3 kinase), and, subsequently, translocation of GLUT-4 to the cell surface from intracellular vesicles [101]. Diminished translocation of GLUT-4 to the plasma membrane due to defective intracellular signaling may account for insulin resistance mainly in the skeletal muscle [101].
Vitamin D may improve glucose metabolism by stimulating insulin secretion from pancreatic beta cells and by improving peripheral insulin sensitivity. In seminal work by Norman and colleagues, administration of cholecalciferol to vitamin D-deficient rats more than doubled insulin secretion from isolated perfused pancreas. 91 Subsequent studies have suggested that the mechanism for this effect is increased insulin release through stimulation of intracellular free calcium. 92 Modulation of the immune system has been proposed as an additional mechanism through which vitamin D may preserve long-term beta cell function (and prevent type I diabetes), and vitamin D could potentially protect beta cells through effects on cell proliferation, differentiation, and apoptosis. 11,73 Vitamin D may also affect insulin sensitivity through actions on the insulin receptor. A vitamin D response element has been described in the promoter region of the human insulin receptor gene, and calcitriol stimulated insulin receptor expression and insulin responsiveness for glucose transplant in cultured human promonocytic cells. 93–95
Glucose metabolism modifications in the elderly are caused by a combination of genetic and environmental factors acting together with age-related changes in carbohydrate handling. At the pancreatic level, there are functional rather than anatomical changes regarding beta cell’s ability to produce and secrete insulin that characterize the aging process. On the other side, insulin action is impaired at muscular level while its hepatic action is not diminished. The increase in peripheral insulin resistance can be attributable to environmental-driven processes, such as those leading to modification in body mass composition. The increase in intraabdominal fat and in intramuscular fat and the contemporary reduction in muscle mass decrease both insulin and noninsulin-mediated glucose disposal. The accumulation of fat accounts for the development of a low-grade chronic inflammation in aging people and subsequent insulin resistance; different pathways link inflammation and glucose metabolism impairment. Among them, those leading to an increase of oxidative stress can affect energy handling and cause mitochondrial damage. Change in lifestyle via combined treatment programs addressing both dietary habits and physical activity levels can contrast and slow the development of visceral obesity and sarcopenia thus ameliorating carbohydrate metabolism. Altered glucose metabolism and impaired insulin action are linked to brain aging. There is evidence that in the brain insulin is a key hormone for both cell survival and normal function which opens the door to new scenarios for the prevention of cognitive decline and dementia in aging. Finally, dietary components can influence aging processes acting on glucose-related pathways so that a healthy diet can favor a healthy aging.
Metabolic acidosis also affects glucose metabolism in AKI by further deteriorating glucose tolerance [41]. Alterations in glucose and protein metabolism in AKI are interrelated, and several factors activating protein catabolism contribute to impaired glucose metabolism.
Lactate is taken up by the monocarboxylate transporter and is converted to pyruvate by the enzyme, lactate dehydrogenase, which is located in the cytosol ( Lesnefsky et al., 2001c; Dym et al., 2000 ). Mitochondrial substrate selection is tightly controlled and is affected not only by exogenous substrate availability but also by metabolic regulation in response to differing physiologic conditions ( Lesnefsky et al., 2001c ). Pyruvate dehydrogenase complex and CPT-I coregulate carbohydrate and fatty acid oxidation in a reciprocal manner via crosstalk mediated by metabolic intermediates and via regulation by intracellular signaling systems ( Lesnefsky et al., 2001c, 2016 ).
Glucose metabolism is the most efficient form of energy transfer, and all normal tissues have characteristic glucose metabolic rates.
Components of insulin preparations (e.g., zinc, protamine) and subcutaneous insulin aggregates are also thought to contribute to antibody formation (17). Commercially available human insulins are now virtually free of contaminants and contain <1 ppm of proinsulin (1).
The kidneys and liver account for the majority of insulin degradation. Normally, the liver degrades 50-60% of insulin released by the pancreas into the portal vein, and the kidneys ~35-45% (21,24). When insulin is injected exogenously, the degradation profile is altered since insulin is no longer delivered directly to the portal vein. The kidney has a greater role in insulin degradation with SQ insulin (~60%), with the liver degrading ~30-40% (25).
Because of the availability of human insulin and the increased potential for animal source insulin to be immunogenic, animal source insulins are no longer available in the United States. Rare hypersensitivity responses to insulin can be immediate-type, local or systemic IgE-mediated reactions (17).
Regular insulin is injected pre-meal to blunt the postprandial rise in glucose levels. It forms hexamers after injection into the SQ space slowing its absorption. Hexameric insulin progressively dissociates into absorbable insulin dimers and monomers. For this reason, regular insulin has a delayed onset of action of 30-60 minutes, and should be injected approximately 30 minutes before the meal to blunt the postprandial rise in blood glucose. Adherence to a 30-minute pre-meal schedule is inconvenient and difficult for many patients.
Insulin administered via SQ injection is absorbed directly into the bloodstream, with the lymphatic system playing a minor role in transport (1). The absorption of human insulin into the bloodstream after SQ absorption is the rate limiting step of insulin activity. This absorption is inconsistent with the coefficients of variation of T50% (time for 50% of the insulin dose to be absorbed) varying ~ 25% within an individual and up to 50% between patients (1,20). Most of this variability of insulin absorption is correlated to blood flow differences at the various sites of injection (abdomen, deltoid, gluteus, and thigh) (1). For regular insulin, the impact of this is a ~ 2 times faster rate of absorption from the abdomen than other subcutaneous sites (1). The clinical significance of this is that patients should avoid random use of different body regions for their injections. For example, if a patient prefers to use their thigh for a noontime injection, this site should be used consistently for this injection. The abdomen is the preferred site of injection because it is the least susceptible to factors affecting insulin absorption (see Table 1). Insulin aspart, glulisine and lispro appear to have less day-to-day variation in absorption rates and also less absorption variation from the different body regions (3,5,8,21). Insulin glargine’s pharmacokinetic profile is similar after abdominal, deltoid or thigh SQ administration (7). Similarly, the glucose-lowering effect of insulin degludec has not been found to vary between abdominal, upper arm, or thigh SQ sites (22).
In 1922, Canadian researchers were the first to demonstrate a physiologic response to injected animal insulin in a patient with type 1 diabetes. In 1955, insulin was the first protein to be fully sequenced. The insulin molecule consists of 51 amino acids arranged in two chains, an A chain (21 amino acids) and B chain (30 amino acids) that are linked by two disulfide bonds (1) (Figure 1). Proinsulin is the insulin precursor that is transported to the Golgi apparatus of the beta cell where it is processed and packaged into granules. Proinsulin, a single-chain 86 amino acid peptide, is cleaved into insulin and C-peptide (a connecting peptide); both are secreted in equimolar portions from the beta cell upon stimulation from glucose and other insulin secretagogues. While C-peptide has no known physiologic function, it can be measured to provide an estimate of endogenous insulin secretion.
The insulin molecule consists of 51 amino acids arranged in two chains, an A chain (21 amino acids) and B chain (30 amino acids) that are linked by two disulfide bonds (1) (Figure 1).