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Optical and Structural Properties of Biological Tissues under Simulated Diabetes Mellitus Conditions
Published in Andrey V. Dunaev, Valery V. Tuchin, Biomedical Photonics for Diabetes Research, 2023
Daria K. Tuchina, Alla B. Bucharskaya, Polina A. Dyachenko (Timoshina), Nataliya I. Dikht, Georgy S. Terentyuk, Valery V. Tuchin
Biochemical mechanisms of hyperglycemia in T2DM are discussed in Ref. [8]. These include insulin resistance in the muscle tissue and liver and impaired insulin secretion by pancreatic β-cells, whose resistance to glucagon-like peptide 1 (GLP1) contributes to progressive β-cell dysfunction. However, an increased level of glucagon and hypersensitivity of the liver to it contribute to excess production of glucose in the liver. Insulin resistance in adipocytes leads to accelerated lipolysis and an increase in plasma free fatty acids (FFAs), which exacerbates insulin resistance in the muscle tissue and liver and contributes to further β-cell dysfunction. Increased renal glucose reabsorption by sodium/glucose co-transporter 2 (SGLT2) and increased urinary glucose excretion threshold also contribute to hyperglycemia. Resistance to appetite-suppressing effects of insulin, leptin, GLP1, amylin, and YY peptide, as well as low dopamine and high brain serotonin levels, contribute to weight gain, which exacerbates the resistance. In addition, vascular insulin resistance and concomitant inflammation are associated with the expression of adenosine monophosphate (AMP)-activated protein kinase, dipeptidyl peptidase 4, inhibitors of NF-κB, mitogen-activated protein kinase, nuclear transcription factor-κB (NF-κB), receptor agonists, reactive oxygen species (ROS), Toll-like receptor 4, tumor necrosis factor (TNF), and thiazolidinediones.
Diabetes mellitus and cardiovascular disease in the elderly
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of glucose-lowering drugs. They lower glucose by inhibiting the reabsorption of glucose at the proximal renal tubule. Normally, virtually all filtered glucose is reabsorbed, leaving none excreted into the urine. Inhibition of renal glucose reabsorption by blocking the glucose transport protein SGLT2 results in urinary glucose excretion and reduction in hyperglycemia. These drugs work independently of insulin and can therefore be used with other classes of glucose-lowering medication. Randomized, controlled studies demonstrate that SGLT2 inhibitors result in mean reductions of hemoglobin A1C levels of –0.69% (95% CI, −0.75 to −0.62). In addition body weight is reduced by a mean of −2.1 kg (95% CI, −2.3 to −2.0) and systolic blood pressure by a mean of −3.9 mmHg (95% CI, −4.6 to −3.3) (145).
Organ Cross-Talk Regulates (Brain) Insulin Action
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
FGF21 is a 19 kDa protein and belongs to the endocrine subfamily of 22 mammalian FGFs, which are considered intracrine, autocrine, or paracrine. Unlike the majority of FGFs which bind heparan sulfate glycosaminoglycans (HSGAGs) and become predominantly captured within the extracellular matrix, preventing their distribution from their cell of origin (74), FGF21 enters the circulation upon secretion due to its reduced HSGAGs binding. Circulating FGF21 is primarily derived from the liver, but is also expressed in the thymus, gut, brain, white adipose tissue (WAT), brown adipose tissue (BAT), muscle, heart, and pancreas (75–77). FGF21 signals through a cell-surface receptor complex comprised of both the ubiquitously expressed fibroblast growth factor receptor (FGFR), FGFR1c, and the FGF co-receptor β-klotho (78). The extracellular signal-regulated kinases 1/2 (ERK1/2) and other downstream kinases are activated afterward. In dependency on the β-klotho expression, FGF21 targets a variety of different organs, such as the liver, pancreas, WAT, BAT, hypothalamus, and brainstem (75, 79–81). Exogenously administered FGF21 acts directly on adipose tissue to decrease blood glucose levels and improve hepatic and possibly peripheral insulin sensitivity, reduce body weight and serum lipids (82, 83). In adipocytes, FGF21 induces glucose transporter-1 (GLUT1) expression and glucose uptake (84). FGF21 treatment causes browning of WAT, increases thermogenesis in BAT and WAT (83), and reduces hepatic lipogenesis (66). The direct administration of FGF21 into the brain has been shown to induce activation of BAT and to increase energy expenditure and insulin sensitivity in the liver (85, 86). Furthermore, FGF21 increases insulin sensitivity through specific expansion of subcutaneous fat (87). Because circulating FGF21 levels positively correlate with the subcutaneous adipose tissue in insulin-sensitive obese individuals, it might be concluded that elevated endogenous FGF21 in obesity serves as a defense mechanism against systemic insulin resistance (87). FGF21’s antidiabetic properties can be attributed to renal glucose reabsorption as well, given that FGF21 enhances hyperglycemia in part via reducing renal glucose reabsorption through the PPARδ-mediated SGLT2 pathway (88). Studies investigating whether FGF21 modulates insulin sensitivity in the brain are still missing. So far, FGF21-stimulated adiponectin secretion might partly explain the effects on insulin sensitivity (59). The improvements in hepatic and muscle insulin resistance - via chronic FGF21 infusion - were abolished in adiponectin knockout mice (59). However, the possible role of FGF21 and its insulin actions in the brain in regulating glucose metabolism remains unknown.
Sodium-glucose transporter (SGLT2) inhibition: A potential target for treatment of type-2 Diabetes Mellitus with Natural and Synthetic compounds
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Shubham Batra, Prabhjeet Kaur Bamrah, Manjusha Choudhary
A relative or complete shortage of insulin characterizes diabetes mellitus, a metabolic condition that is dangerous to human health. It also causes several difficulties in various organs. An attractive treatment method for hyperglycemia is to stop renal glucose reabsorption by blocking SGLT2. The new SGLT-2 selective inhibitor medication family promises an innovative therapeutic strategy for blood glucose management in type II diabetes mellitus. Additionally, this new class demonstrates other benefits like a decrease in blood pressure and body weight, reduce hospitalizations for heart failure, and delay in the course of renal disease which is particularly desirable in several linked conditions. SGLT2 inhibitors are considered most appropriate in overweight or obese T2DM patients but they may increase your risk of developing vaginal infections and diabetic ketoacidosis.
Effects of sodium-glucose co-transporter-2 inhibitors on anthropometric indices and metabolic markers in overweight/obese individuals without diabetes: a systematic review and meta-analysis
Published in Current Medical Research and Opinion, 2022
Behnaz Abiri, Amirhossein Ramezani Ahmadi, Amir Ebadinejad, Farhad Hosseinpanah, Majid Valizadeh
Studies have explored the use of glucose-lowering therapies in obese individuals due to their effect on weight loss8. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are particularly interesting. The SGLT2 inhibitors (including empagliflozin, dapagliflozin, and canagliflozin) are used to treat diabetes but are also effective in reducing body weight, primarily through the reduction of body fat levels9–12. By inducing glycosuria through SGLT2 inhibitors, one can also reduce insulin resistance and preserve the function of pancreatic β-cells with several beneficial impacts in different insulin target tissues, such as ameliorating fatty liver, reducing visceral fat mass, or enhancing glucose uptake in the skeletal muscles13. It is thought that SGLT2 inhibitors cause glucosuria by lowering renal glucose reabsorption. Thus, weight loss and a reduction in systolic blood pressure (SBP) are related to mild diuresis and calorie excretion14.
Anti-diabetic drugs and NASH: from current options to promising perspectives
Published in Expert Opinion on Investigational Drugs, 2021
Sarra Smati, Clémence M Canivet, Jérôme Boursier, Bertrand Cariou
SGLT1 accounts for ~10% of renal glucose reabsorption and is the primary transporter for intestinal absorption of glucose and galactose [81]. In contrast to SGLT2 inhibitors, studies assessing SGLT1 inhibition on liver function are scarce. In a NASH mouse model, luseogliflozin (a selective SGLT2 inhibitor with little affinity for SGLT1) reduced lipid accumulation and ALT concentrations [88]. Ipragliflozin, a selective SGLT2 inhibitor with modest affinity for SGLT1, also reduced steatosis in high-fat-fed and leptin-deficient obese (ob/ob) mice [89]. Ipragliflozin also improved liver function tests in individuals with T2D [89]. SGLT1, but not SGLT2, is expressed in liver bile ducts and cholangiocytes, where it might affect bile flow and the biliohepatic circulation of glucose [81].