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Trends in Cell Biology Mar 2024β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice... (Review)
Review
β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity.
Topics: Humans; Mice; Animals; Insulin; Glucagon; Glucagon-Secreting Cells; Insulin-Secreting Cells
PubMed: 37626005
DOI: 10.1016/j.tcb.2023.07.004 -
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 -
Peptides Nov 2023The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally... (Review)
Review
The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally could affect brain functions. This led Kastin to propose that peptides could cross the blood-brain barrier (BBB). Although initially very controversial, Kastin, I, and others demonstrated not only that peptides can cross the BBB, but elucidated many fundamental characteristics of that passage. That work was in large part the basis of the 2022 Viktor Mutt Lectureship. Here, we review some of the early work with current updates on topics related to the penetration of peptides across the BBB. We briefly review mechanisms by which peripherally administered peptides can affect brain function without crossing the BBB, and then review the major mechanisms by which peptides and their analogs have been show to cross the BBB: transmembrane diffusion, saturable transport, and adsorptive transcytosis. Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, the transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB.
Topics: Blood-Brain Barrier; Biological Transport; Pituitary Adenylate Cyclase-Activating Polypeptide; Insulin
PubMed: 37598757
DOI: 10.1016/j.peptides.2023.171079 -
Proceedings of the National Academy of... Aug 2023Interneuron populations within the nucleus accumbens (NAc) orchestrate excitatory-inhibitory balance, undergo experience-dependent plasticity, and gate-motivated...
Interneuron populations within the nucleus accumbens (NAc) orchestrate excitatory-inhibitory balance, undergo experience-dependent plasticity, and gate-motivated behavior, all biobehavioral processes heavily modulated by endogenous cannabinoid (eCB) signaling. While eCBs are well known to regulate synaptic plasticity onto NAc medium spiny neurons and modulate NAc function at the behavioral level, how eCBs regulate NAc interneuron function is less well understood. Here, we show that eCB signaling differentially regulates glutamatergic and feedforward GABAergic transmission onto NAc somatostatin-expressing interneurons (NAc) in an input-specific manner, while simultaneously increasing postsynaptic excitability of NAc neurons, ultimately biasing toward vHPC (ventral hippocampal), and away from BLA (basolateral amygdalalar), activation of NAc neurons. We further demonstrate that NAc are activated by stress in vivo and undergo stress-dependent plasticity, evident as a global increase in intrinsic excitability and an increase in excitation-inhibition balance specifically at vHPC, but not BLA, inputs onto NAc neurons. Importantly, both forms of stress-induced plasticity are dependent on eCB signaling at cannabinoid type 1 receptors. These findings reveal eCB-dependent mechanisms that sculpt afferent input and excitability of NAc neurons and demonstrate a key role for eCB signaling in stress-induced plasticity of NAc-associated circuits.
Topics: Endocannabinoids; Nucleus Accumbens; Neurons; Somatostatin; Cannabinoids
PubMed: 37590414
DOI: 10.1073/pnas.2300585120 -
Biotechnic & Histochemistry : Official... Nov 2023The endocrine component of the pancreas is located primarily in the islets of Langerhans, but is also found as single cells among the acinar cells and duct epithelium....
The endocrine component of the pancreas is located primarily in the islets of Langerhans, but is also found as single cells among the acinar cells and duct epithelium. It currently is thought that endocrine tumors of the pancreas (PETs) arise from pluripotent stem cells located within the ductal epithelium rather than from existing endocrine cells. Islet cell components include alpha, beta, PP, delta and epsilon cells, which secrete glucagon, insulin, pancreatic polypeptide, somatostatin and ghrelin, respectively. We investigated immunohistochemical labeling of 24 formalin fixed paraffin embedded PETs to identify which hormones were produced most frequently. Glucagon was the most frequently secreted hormone (83%) in PETS followed by insulin, ghrelin, pancreatic polypeptide and somatostatin.
Topics: Humans; Pancreatic Polypeptide; Glucagon; Ghrelin; Pancreatic Neoplasms; Insulin; Somatostatin
PubMed: 37787578
DOI: 10.1080/10520295.2023.2260307 -
Physical Chemistry Chemical Physics :... Sep 2023Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling... (Review)
Review
Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling the aggregation kinetics has been observed. Quantitative analysis of aggregation includes data of gradual monomeric depletion followed by the formation of subvisible particles. Kinetic and thermodynamic studies are essential to gain key insights into the aggregation process. Despite being the medical marvel in the world of diabetes, insulin suffers from the challenge of aggregation. Physicochemical stresses are experienced by insulin during industrial formulation, storage, delivery, and transport, considerably impacting product quality, efficacy, and effectiveness. The present review briefly describes the pathways, mathematical kinetic models, and thermodynamics of protein misfolding and aggregation. With a specific focus on insulin, further discussions include the structural heterogeneity and modifications of the intermediates incurred during insulin fibrillation. Finally, different model equations to fit the kinetic data of insulin fibrillation are discussed. We believe that this review will shed light on the conditions that induce structural changes in insulin during the lag phase of fibrillation and will motivate scientists to devise strategies to block the initialization of the aggregation cascade. Subsequent abrogation of insulin fibrillation during bioprocessing will ensure stable and globally accessible insulin for efficient management of diabetes.
Topics: Humans; Insulin; Kinetics; Thermodynamics; Protein Aggregates; Proteostasis Deficiencies
PubMed: 37674360
DOI: 10.1039/d3cp03103a -
Diabetes Sep 2023The family of proglucagon peptides Includes glucagon and glucagon-like peptide 1 (GLP-1), two unique peptides derived from the same prohormone. Despite numerous...
The family of proglucagon peptides Includes glucagon and glucagon-like peptide 1 (GLP-1), two unique peptides derived from the same prohormone. Despite numerous similarities between the peptides, these have long been viewed as having opposing actions on metabolism. GLP-1 is described as a postprandial hormone that stimulates anabolic actions via insulin, while glucagon is viewed as a fasting hormone that drives catabolic actions to maintain euglycemia. Here, we revisit a classic article in Diabetes that first established that glucagon and GLP-1 have more in common than previously appreciated, including actions at the same receptor. Furthermore, we discuss how the impact of this observation has guided research decades later that has reshaped the view of how proglucagon hormones regulate metabolism.
Topics: Glucagon; Proglucagon; Insulin; Glucagon-Like Peptide 1; Fasting
PubMed: 37603722
DOI: 10.2337/dbi23-0014 -
American Journal of Physiology.... Aug 2023The acute effect of exercise on β-cell function during a high-fat meal (HFM) in young adults (YA) versus old adults (OA) is unclear. In this randomized crossover trial,... (Randomized Controlled Trial)
Randomized Controlled Trial
The acute effect of exercise on β-cell function during a high-fat meal (HFM) in young adults (YA) versus old adults (OA) is unclear. In this randomized crossover trial, YA ( = 5 M/7 F, 23.3 ± 3.9 yr) and OA ( = 8 M/4 F, 67.7 ± 6.0 yr) underwent a 180-min HFM (12 kcal/kg body wt; 57% fat, 37% CHO) after a rest or exercise [∼65% heart rate peak (HR)] condition ∼12 h earlier. After an overnight fast, plasma lipids, glucose, insulin, and free fatty acid (FFA) were determined to estimate peripheral, or skeletal muscle, insulin sensitivity (Matsuda index) as well as hepatic [homeostatic model assessment of insulin resistance (HOMA-IR)] and adipose insulin resistance (adipose-IR). β-Cell function was derived from C-peptide and defined as early-phase (0-30 min) and total-phase (0-180 min) disposition index [DI, glucose-stimulated insulin secretion (GSIS) adjusted for insulin sensitivity/resistance]. Hepatic insulin extraction (HIE), body composition [dual-energy X-ray absorptiometry (DXA)], and peak oxygen consumption (V̇o) were also assessed. OA had higher total cholesterol (TC), LDL, HIE, and DI across organs as well as lower adipose-IR (all, < 0.05) and V̇o ( = 0.056) despite similar body composition and glucose tolerance. Exercise lowered early-phase TC and LDL in OA versus YA ( < 0.05). However, C-peptide area under the curve (AUC), total phase GSIS, and adipose-IR were reduced postexercise in YA versus OA ( < 0.05). Skeletal muscle DI increased in YA and OA after exercise ( < 0.05), whereas adipose DI tended to decline in OA ( = 0.06 and = 0.08). Exercise-induced skeletal muscle insulin sensitivity ( = -0.44, = 0.02) and total-phase DI ( = -0.65, = 0.005) correlated with reduced glucose AUC. Together, exercise improved skeletal muscle insulin sensitivity/DI in relation to glucose tolerance in YA and OA, but only raised adipose-IR and reduced adipose-DI in OA. High-fat diets may induce β-cell dysfunction. This study compared how young and older adults responded to a high-fat meal with regard to β-cell function and whether exercise comparably impacted glucose regulation. Older adults secreted more insulin during the high-fat meal than younger adults. Although exercise increased β-cell function adjusted for skeletal muscle insulin sensitivity in relation to glucose tolerance, it raised adipose insulin resistance and reduced pancreatic β-cell function relative to adipose tissue in older adults. Additional work is needed to discern nutrient-exercise interactions across age to mitigate chronic disease risk.
Topics: Young Adult; Humans; Aged; Insulin Resistance; C-Peptide; Adipose Tissue; Glucose; Insulin; Obesity; Blood Glucose
PubMed: 37306399
DOI: 10.1152/ajpregu.00047.2023 -
Journal of Diabetes Science and... Nov 2023A wave of expiring patents for first-generation insulin analogues has created opportunities in the global insulin market for highly similar versions of these products,... (Review)
Review
BACKGROUND
A wave of expiring patents for first-generation insulin analogues has created opportunities in the global insulin market for highly similar versions of these products, biosimilar insulins. Biologics are generally large, complex molecules produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell. Since manufacturing processes of biologics vary, biosimilars cannot be exact copies of their reference product but must exhibit a high degree of functional and structural similarity. Biosimilarity is proven by analytical approaches in comparative assessments, preclinical cell-based and animal studies, as well as clinical studies in humans facilitating the accumulation of evidence across all assessments. The approval of biosimilars follows detailed regulatory pathways derived from those of their reference products and established by agencies such as the European Medicines Agency and the US Food and Drug Administration. Regulatory authorities impose requirements to ensure that biosimilars meet high standards of quality, safety, and efficacy and are highly similar to their reference product.
PURPOSE
This review aims to aid clinical understanding of the high standards of development, manufacturing, and regulation of biosimilar insulins.
METHODS
Recent relevant studies indexed by PubMed and regulatory documents were included.
CONCLUSIONS
Driven by price competition, the emergence of biosimilar insulins may help expand global access to current insulin analogues. To maximize the impact of the advantage for falling retail costs of biosimilar insulins compared with that of reference insulins, healthcare professionals and insulin users must gain further awareness and confidence.
Topics: Animals; United States; Humans; Biosimilar Pharmaceuticals; Insulin; Insulins; Insulin, Regular, Human; United States Food and Drug Administration; Drug Approval
PubMed: 35818669
DOI: 10.1177/19322968221105864 -
Journal of Diabetes and Its... Oct 2023One of the greatest barriers to the treatment of T2DM is nonadherence which particularly applies to insulin therapy. There is a need for a comprehensive overview of all... (Review)
Review
BACKGROUND AND AIM
One of the greatest barriers to the treatment of T2DM is nonadherence which particularly applies to insulin therapy. There is a need for a comprehensive overview of all factors associated with nonadherence to insulin therapy. The aim of this study was to identify factors associated with adherence or nonadherence to insulin therapy among adults with T2DM.
METHODS
A scoping review was conducted in accordance with the PRISMA 2020 statement. A systematic search was performed in PubMed, Cinahl, and Web of Science (January 2013 to March 2023).
RESULTS
A final sample of 48 studies was included in the scoping review. The synthesis revealed 30 factors associated with adherence or nonadherence. The factors were grouped into 6 themes: demographics, attitude and perceptions, management of diabetes, impact on daily living, disease and medication, and healthcare system.
CONCLUSION
The most prominent factors identified were age, cost of healthcare, personal beliefs towards insulin therapy, social stigma, patient education, complexity of diabetes treatment, impact of insulin therapy on daily life, and fear of side effects. The results indicate a need for further research to determine threshold values for the factors associated with adherence or nonadherence.
Topics: Humans; Adult; Diabetes Mellitus, Type 2; Insulin; Medication Adherence; Insulin, Regular, Human; Drug-Related Side Effects and Adverse Reactions
PubMed: 37651772
DOI: 10.1016/j.jdiacomp.2023.108596