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Physiological Reports Jan 2023Glucose homeostasis is the maintenance and regulation of blood glucose concentration within a tight physiological range, essential for the functioning of most tissues... (Review)
Review
Glucose homeostasis is the maintenance and regulation of blood glucose concentration within a tight physiological range, essential for the functioning of most tissues and organs. This is primarily achieved by pancreatic secretion of insulin and glucagon. Deficient pancreatic endocrine function, coupled with or without peripheral insulin resistance leads to prolonged hyperglycemia with chronic impairment of glucose homeostasis, most commonly seen in diabetes mellitus. High protein diets (HPDs) are thought to modulate glucose homeostasis through various metabolic pathways. Insulin secretion can be directly modulated by the amino acid products of protein digestion, which activate nutrient receptors and nutrient transporters expressed by the endocrine pancreas. Insulin secretion can also be modulated indirectly, through incretin release from enteroendocrine cells, and via vagal neuronal pathways. Additionally, glucose homeostasis can be promoted by the satiating effects of anorectic hormones released following HPD consumption. This review summarizes the insulinotropic mechanisms by which amino acids and HPDs may influence glucose homeostasis, with a particular focus on their applicability in the management of Type 2 diabetes mellitus.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Secretion; Glucagon-Like Peptide 1; Insulin; Amino Acids; Glucose; Diet, High-Protein
PubMed: 36695783
DOI: 10.14814/phy2.15577 -
Oxidative Medicine and Cellular... 2020Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in... (Review)
Review
Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in response to declining blood glucose. However, glucagon hypersecretion contributes to the pathogenesis of type 2 diabetes. Moreover, diabetes is associated with relative glucagon undersecretion at low blood glucose and oversecretion at normal and high blood glucose. The mechanisms of such alpha cell dysfunctions are not well understood. This article reviews the genesis of alpha cell dysfunctions during the pathogenesis of type 2 diabetes and after the onset of type 1 and type 2 diabetes. It unravels a signaling pathway that contributes to glucose- or hydrogen peroxide-induced glucagon secretion, whose overstimulation contributes to glucagon dysregulation, partly through oxidative stress and reduced ATP synthesis. The signaling pathway involves phosphatidylinositol-3-kinase, protein kinase B, protein kinase C delta, non-receptor tyrosine kinase Src, and phospholipase C gamma-1. This knowledge will be useful in the design of new antidiabetic agents or regimens.
Topics: Blood Glucose; Glucagon; Humans
PubMed: 32774668
DOI: 10.1155/2020/3089139 -
Journal of Diabetes Science and... Mar 2023On March 23, 2020, all insulin products were reclassified as biologics instead of drugs under the Biological Price Competition and Innovation (BPCI) Act of 2009. This... (Review)
Review
On March 23, 2020, all insulin products were reclassified as biologics instead of drugs under the Biological Price Competition and Innovation (BPCI) Act of 2009. This allows biosimilar insulin products to be manufactured when the patent expires for the reference biologic, sometimes called the originator or brand name product. A biosimilar product may not be substituted for the reference biologic at the pharmacy counter unless the biosimilar undergoes further switch trials to earn the designation as an interchangeable biosimilar. Insulin glargine-yfgn 100 units/mL is the first biosimilar insulin to attain interchangeable status with the reference insulin glargine. In the INSTRIDE 1 and INSTRIDE 2 trials, insulin glargine-yfgn has proven noninferiority regarding blood glucose reduction and adverse effect profile versus reference insulin glargine; even in the INSTRIDE 3 trial in which treatment of diabetes was switched between insulin glargine-yfgn and reference insulin glargine throughout the trial without statistically significant changes to glucose levels or adverse effects. Insulin glargine-yfgn may be substituted at the pharmacy counter without consultation with the prescriber, in accordance with state laws. In suit with other biosimilars, insulin glargine-yfgn's list price is significantly lower than other insulin glargine products. This increases market competition leading to decreases in costs of other insulin glargine products. Many patients who could not previously afford insulin therapy may now have significantly improved access to treatment. Providers will need education to increase awareness of these new biosimilars and interchangeable biosimilar insulin products, cost benefits, and substitution allowances.
Topics: Humans; Biosimilar Pharmaceuticals; Insulin Glargine; Insulin; Insulin, Regular, Human; Pharmaceutical Services
PubMed: 34971335
DOI: 10.1177/19322968211067511 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Dec 2022Acute pancreatitis (AP) is inflammation of pancreas in which pancreas enzymatic activity is increased. Parasym-pathetic innervation of pancreas plays an important role...
BACKGROUND
Acute pancreatitis (AP) is inflammation of pancreas in which pancreas enzymatic activity is increased. Parasym-pathetic innervation of pancreas plays an important role in several functions of pancreas. Botulinum toxin (BTx) might be a tool to suppress the pancreas activity in AP.
METHODS
In the preliminary experimental study, BTx (15U/kg) was administered directly and intraductal ways. After 10 days, blood amylase, lipase, trypsinogen, insulin, and glucagon levels were compared and no significant difference was seen between groups. Intraductal BTx administration is preferred for experimental AP model in rats; control, AP, intraductal BTx, and AP with Intraductal BTx (AP+BTx). AP was created by intraperitoneal injection of cerulean 20 µg/kg/injection (5 times). After 24 h, serum amylase, lipase, IL-6, IL-1β, TNF-α, and IL-10 were measured and pancreas tissue was evaluated for inflammation and necrosis.
RESULTS
Mean serum amylase, lipase IL-6, IL-1β, and TNF-α levels of the AP group were significantly higher compared to the other groups (p<0.05). However, there was no significant difference between the amylase and lipase levels of control, BTx, and AP+BTx groups. Serum insulin and glucagon levels in AP group were significantly higher than control and BTx groups (p<0.05). However, there is no significant difference between the insulin and glucagon levels of AP and AP+BTx groups. in pathological evaluation. In AP+ BTx group, there is less amount of centrilobular necrosis and there is mild inflammation and hyperplasia of pancreatic duct epithelium.
CONCLUSION
Administration of intraductal BTx suppressed the AP without making significant suppression in endogenous activity of pancreas.
Topics: Animals; Rats; Pancreatitis; Tumor Necrosis Factor-alpha; Acute Disease; Glucagon; Interleukin-6; Inflammation; Amylases; Necrosis; Lipase; Botulinum Toxins; Insulins
PubMed: 36453789
DOI: 10.14744/tjtes.2021.90140 -
Pancreatic β-cell glutaminase 2 maintains glucose homeostasis under the condition of hyperglycaemia.Scientific Reports May 2023Glutaminase 2 (GLS2), a master regulator of glutaminolysis that is induced by p53 and converts glutamine to glutamate, is abundant in the liver but also exists in...
Glutaminase 2 (GLS2), a master regulator of glutaminolysis that is induced by p53 and converts glutamine to glutamate, is abundant in the liver but also exists in pancreatic β-cells. However, the roles of GLS2 in islets associated with glucose metabolism are unknown, presenting a critical issue. To investigate the roles of GLS2 in pancreatic β-cells in vivo, we generated β-cell-specific Gls2 conditional knockout mice (Gls2 CKO), examined their glucose homeostasis, and validated the findings using a human islet single-cell analysis database. GLS2 expression markedly increased along with p53 in β-cells from control (RIP-Cre) mice fed a high-fat diet. Furthermore, Gls2 CKO exhibited significant diabetes mellitus with gluconeogenesis and insulin resistance when fed a high-fat diet. Despite marked hyperglycaemia, impaired insulin secretion and paradoxical glucagon elevation were observed in high-fat diet-fed Gls2 CKO mice. GLS2 silencing in the pancreatic β-cell line MIN6 revealed downregulation of insulin secretion and intracellular ATP levels, which were closely related to glucose-stimulated insulin secretion. Additionally, analysis of single-cell RNA-sequencing data from human pancreatic islet cells also revealed that GLS2 expression was elevated in β-cells from diabetic donors compared to nondiabetic donors. Consistent with the results of Gls2 CKO, downregulated GLS2 expression in human pancreatic β-cells from diabetic donors was associated with significantly lower insulin gene expression as well as lower expression of members of the insulin secretion pathway, including ATPase and several molecules that signal to insulin secretory granules, in β-cells but higher glucagon gene expression in α-cells. Although the exact mechanism by which β-cell-specific GLS2 regulates insulin and glucagon requires further study, our data indicate that GLS2 in pancreatic β-cells maintains glucose homeostasis under the condition of hyperglycaemia.
Topics: Mice; Humans; Animals; Hyperglycemia; Glucagon; Glutaminase; Tumor Suppressor Protein p53; Insulin-Secreting Cells; Islets of Langerhans; Insulin; Glucose; Mice, Knockout; Homeostasis
PubMed: 37147373
DOI: 10.1038/s41598-023-34336-z -
The Journal of Endocrinology Nov 2023The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in...
The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received five daily doses of STZ (50 mg/kg, i.p.) or 10 daily doses of HC (70 mg/kg, i.p.), with parameters assessed on day 11. STZ-induced hyperglycaemia was evident in both sexes, alongside impaired glucose tolerance and reduced insulin concentrations. HC also had similar metabolic effects in male and female mice resulting in classical increases of circulating insulin indicative of insulin resistance. Control male mice had larger pancreatic islets than females and displayed a greater reduction of islet and beta-cell area in response to STZ insult. In addition, female STZ mice had lower levels of beta-cell apoptosis than male counterparts. Following HC administration, female mouse islets contained a greater proportion of alpha cells when compared to males. All HC mice presented with relatively comparable increases in beta- and alpha-cell turnover rates, with female mice being slightly more susceptible to HC-induced beta-cell apoptosis. Interestingly, healthy control female mice had inherently increased alpha-to-beta-cell transdifferentiation rates, which was decreased by HC treatment. The number of glucagon-positive alpha cells altering their lineage to insulin-positive beta cells was increased in male, but not female, STZ mice. Taken together, although there was no obvious sex-specific alteration of metabolic profile in STZ or HC mice, subtle differences in pancreatic islet morphology emphasises the impact of sex hormones on islets and importance of taking care when interpreting observations between males and females.
Topics: Female; Male; Mice; Animals; Islets of Langerhans; Insulin; Glucagon-Secreting Cells; Glucagon; Mice, Transgenic; Hydrocortisone
PubMed: 37650517
DOI: 10.1530/JOE-23-0174 -
Frontiers in Endocrinology 2022The beta-cell identity gene, pancreatic duodenal homeobox 1 (), plays critical roles in many aspects of the life of beta-cells including differentiation, maturation,... (Review)
Review
The beta-cell identity gene, pancreatic duodenal homeobox 1 (), plays critical roles in many aspects of the life of beta-cells including differentiation, maturation, function, survival and proliferation. High levels of reactive oxygen species (ROS) are extremely toxic to cells and especially to beta-cells due to their relatively low expression of antioxidant enzymes. One of the major mechanisms for beta-cell dysfunction in type-2 diabetes results from oxidative stress-dependent inhibition of PDX1 levels and function. ROS inhibits Pdx1 by reducing mRNA and protein levels, inhibiting PDX1 nuclear localization, and suppressing PDX1 coactivator complexes. The nuclear factor erythroid 2-related factor () antioxidant pathway controls the redox balance and allows the maintenance of high Pdx1 levels. Therefore, pharmacological activation of the pathway may alleviate diabetes by preserving Pdx1 levels.
Topics: Antioxidants; NF-E2-Related Factor 2; Oxidative Stress; Pancreatic Hormones; Reactive Oxygen Species
PubMed: 36187092
DOI: 10.3389/fendo.2022.1011187 -
Physiological Reviews Jan 2022Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but... (Review)
Review
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors, of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues defines prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, pro-islet amyloid polypeptide (proIAPP), and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin-to-C-peptide ratio for progression to type 2 diabetes, and elevated proinsulin or proinsulin-to-C-peptide ratio is predictive for development of type 1 diabetes in at-risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP, and proinsulin may be an autoantigen in type 1 diabetes. Furthermore, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes, leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
Topics: Animals; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Proglucagon; Proinsulin; Protein Precursors
PubMed: 34280055
DOI: 10.1152/physrev.00008.2021 -
International Journal of Molecular... Apr 2024Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse... (Review)
Review
Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse family of ionic channels that includes ATP-dependent potassium (KATP) channels in the potassium rectifier channel subfamily. These channels were initially described in heart muscle and then in other tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle tissues. In pancreatic beta cells, KATP channels are primarily responsible for maintaining the membrane potential and for depolarization-mediated insulin release, and their decreased density and activity may be related to insulin resistance. KATP channels' relationship with insulin resistance is beginning to be explored in extra-pancreatic beta tissues like the skeletal muscle, where KATP channels are involved in insulin-dependent glucose recapture and their activation may lead to insulin resistance. In adipose tissues, KATP channels containing Kir6.2 protein subunits could be related to the increase in free fatty acids and insulin resistance; therefore, pathological processes that promote prolonged adipocyte KATP channel inhibition might lead to obesity due to insulin resistance. In the central nervous system, KATP channel activation can regulate peripheric glycemia and lead to brain insulin resistance, an early peripheral alteration that can lead to the development of pathologies such as obesity and Type 2 Diabetes Mellitus (T2DM). In this review, we aim to discuss the characteristics of KATP channels, their relationship with clinical disorders, and their mechanisms and potential associations with peripheral and central insulin resistance.
Topics: Humans; Potassium Channels; Insulin Resistance; Diabetes Mellitus, Type 2; Insulin; Insulin, Regular, Human; Pancreatic Hormones; KATP Channels; Obesity; Potassium; Adenosine Triphosphate
PubMed: 38612888
DOI: 10.3390/ijms25074079 -
Journal of Diabetes Science and... Jul 2023Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in...
Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in the delivered amount of insulin during basal rate and consecutive bolus delivery in some PP, calling for a more systematic characterization of these periodic delivery patterns. Here, it was found that during basal rate delivery of 1 U/h, some devices of OP, OP-D, and A6 showed deviations of up to ±30% from target delivery that consistently repeated every 5 hours, whereas ACS showed no clear periodicity with considerably lower deviations. Similar results were found during consecutive bolus delivery of 1 U, where deviations repeated consistently every five boluses in some devices of OP, OP-D, and A6. However, there was a large variability in the periodic delivery patterns between individual devices of the same PP model. Examining their pumping techniques indicated a connection between the insulin delivery mechanism and observed delivery patterns of the PP. However, the clinical impact of such patterns is unclear.
Topics: Humans; Insulin; Hypoglycemic Agents; Insulin Infusion Systems; Insulin, Regular, Human; Transdermal Patch
PubMed: 35466704
DOI: 10.1177/19322968221091843