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International Journal of Molecular... Aug 2020Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic... (Review)
Review
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Homeostasis; Humans; Insulin Secretion
PubMed: 32872570
DOI: 10.3390/ijms21176275 -
Diabetes & Metabolism Journal Sep 2021The impaired insulin secretion and increased insulin resistance (or decreased insulin sensitivity) play a major role in the pathogenesis of all types of diabetes... (Review)
Review
The impaired insulin secretion and increased insulin resistance (or decreased insulin sensitivity) play a major role in the pathogenesis of all types of diabetes mellitus (DM). It is very important to assess the pancreatic β-cell function and insulin resistance/ sensitivity to determine the type of DM and to plan an optimal management and prevention strategy for DM. So far, various methods and indices have been developed to assess the β-cell function and insulin resistance/sensitivity based on static, dynamic test and calculation of their results. In fact, since the metabolism of glucose and insulin is made through a complex process related with various stimuli in several tissues, it is difficult to fully reflect the real physiology. In order to solve the theoretical and practical difficulties, research on new index is still in progress. Also, it is important to select the appropriate method and index for the purpose of use and clinical situation. This review summarized a variety of traditional methods and indices to evaluate pancreatic β-cell function and insulin resistance/sensitivity and introduced novel indices.
Topics: Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion
PubMed: 34610719
DOI: 10.4093/dmj.2021.0220 -
International Journal of Molecular... Jun 2021Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate... (Review)
Review
Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.
Topics: Animals; Disease; Health; Humans; Insulin; Insulin Secretion; Liver; Signal Transduction
PubMed: 34203830
DOI: 10.3390/ijms22126403 -
Frontiers in Endocrinology 2020Sarcopenic obesity and diabetes are two increasing health problems worldwide, which both share many common risk factors, such as aging, and general obesity. The... (Review)
Review
Sarcopenic obesity and diabetes are two increasing health problems worldwide, which both share many common risk factors, such as aging, and general obesity. The pathogenesis of sarcopenic obesity includes aging, physical inactivity, malnutrition, low-grade inflammation, insulin resistance, and hormonal changes. Nevertheless, there are two major reasons to cause diabetes: impaired insulin secretion and impaired insulin action. Furthermore, the individual diagnosis of obesity and sarcopenia should be combined to adequately define sarcopenic obesity. Also, the diagnosis of diabetes includes fasting plasma glucose test (FPG), 2-h oral glucose tolerance test (OGTT), glycated hemoglobin (A1C), and random plasma glucose coupled with symptoms. Healthy diet and physical activity are beneficial to both sarcopenic obesity and diabetes, but there are only recommended drugs for diabetes. This review consolidates and discusses the latest research in pathogenesis, diagnosis, and treatments of diabetes and sarcopenic obesity.
Topics: Aging; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin Secretion; Obesity; Sarcopenia
PubMed: 32982969
DOI: 10.3389/fendo.2020.00568 -
Cell Metabolism Jul 2022In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the "canonical" model, in which... (Review)
Review
In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the "canonical" model, in which an oxidative phosphorylation-driven rise in ATP production closes K channels. We discuss the importance of intrinsic β cell metabolic oscillations; the phasic alignment of relevant metabolic cycles, shuttles, and shunts; and how their temporal and compartmental relationships align with the triggering phase or the secretory phase of pulsatile insulin secretion. Metabolic signaling components are assigned regulatory, effectory, and/or homeostatic roles vis-à-vis their contribution to glucose sensing, signal transmission, and resetting the system. Taken together, these functions provide a framework for understanding how allostery, anaplerosis, and oxidative metabolism are integrated into the oscillatory behavior of the secretory pathway. By incorporating these temporal as well as newly discovered spatial aspects of β cell metabolism, we propose a much-refined Mito-Mito model of the signaling process for the field to evaluate.
Topics: Adenosine Triphosphate; Glucose; Insulin; Insulin Secretion; Islets of Langerhans
PubMed: 35728586
DOI: 10.1016/j.cmet.2022.06.003 -
Biomedicine & Pharmacotherapy =... Nov 2020Diabetes mellitus (DM) is a metabolic disorder that occurs in the body because of decreased insulin activity and/or insulin secretion. Pathological changes such as... (Review)
Review
Diabetes mellitus (DM) is a metabolic disorder that occurs in the body because of decreased insulin activity and/or insulin secretion. Pathological changes such as nephropathy, retinopathy, and cardiovascular complications inevitably occur in the body with the progression of the disease. DM is mainly categorized into 2 sub-types, type I DM and type II DM. While type I DM is generally treated through insulin replacement therapy, type II DM is treated with oral hypoglycaemics. The major drug therapy for type II DM comprises of insulin secretagogues, biguanides, insulin sensitizers, alpha glucosidase inhibitors, incretin mimetics, amylin antagonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Dual drug therapies are often recommended in patients who are unable to achieve therapeutic goals with first line oral hypoglycaemic agents as monotherapy. Inspite of the appreciable therapeutic benefits, the conventional dosage forms depicts differential bioavailability and short half-life, mandating frequent dosage and causing greater side effects leading to therapy ineffectiveness and patient non-compliance. Given the pathological complexity of the said disease, nanotechnology-based approaches are more enticing as it comes with added advantage of site-specific drug delivery with higher bioavailability and reduced dosage regimen. In the present review article, we have made an attempt to explore the pathophysiology of type II DM, the conventional treatment approaches (mono and combination therapy) as well as the nano based drug delivery approaches for the treatment of type II DM.
Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin Secretion
PubMed: 32927252
DOI: 10.1016/j.biopha.2020.110708 -
International Journal of Molecular... Jan 2021Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the... (Review)
Review
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as 'flight and fight' hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing's syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs' side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
Topics: Adipose Tissue; Animals; Glucocorticoids; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver; Muscle, Skeletal; Pancreas; Signal Transduction
PubMed: 33435513
DOI: 10.3390/ijms22020623 -
Biomedical Papers of the Medical... Sep 2019There is a steady increase in the number of overweight and obese people worldwide and increasingly, younger people. Excess adipose tissue impairs the action of insulin,... (Review)
Review
There is a steady increase in the number of overweight and obese people worldwide and increasingly, younger people. Excess adipose tissue impairs the action of insulin, leading to insulin resistance (IR). Tissue IR is a major factor in relation to cardiovascular disease, metabolic syndrome and diabetes. Thus, it is important to recognize at the pre-disease stage with the possibility of therapeutic intervention. IR is assessed using indicators of epidemiological significance, most often calculated from fasting and postprandial glucose and insulin values, so-called indirect indicators of insulin resistance. The most commonly used parameter is the Homeostatic Model Assessment (HOMA). Although the Quantitative Insulin Sensitivity Check Index (QUICKI), Matsuda Index and the Insulin Secretion-Sensitivity Index-2 (ISSI-2) are also used, the values of these indices established for IR vary for different age, sex, populations and ethnic groups. Thus, appropriate reference values of indirect indices should be determined for such groups, and when this is precluded, data from published studies carried out on the most ethnically, socio-economically and age-matched populations should be applied.
Topics: Blood Glucose; Female; Glucose Tolerance Test; Glycemic Index; Homeostasis; Humans; Insulin Resistance; Insulin Secretion; Male; Reference Values
PubMed: 31165793
DOI: 10.5507/bp.2019.021 -
Endocrinology Jul 2021The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even... (Review)
Review
The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin; Insulin Secretion; Postprandial Period; Receptors, Gastrointestinal Hormone
PubMed: 33782700
DOI: 10.1210/endocr/bqab065 -
Nature Reviews. Endocrinology Aug 2021Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or... (Review)
Review
Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca storage organelle, generating Ca signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.
Topics: Animals; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Hypoglycemic Agents; Insulin Secretion; Insulin-Secreting Cells; Molecular Targeted Therapy; Proinsulin
PubMed: 34163039
DOI: 10.1038/s41574-021-00510-4