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The Journal of Clinical Endocrinology... Sep 2023The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood.
CONTEXT
The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood.
OBJECTIVE
This study investigates potential crosstalk between FGF23 and glucose homeostasis.
METHODS
First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI.
RESULTS
After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P < .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI.
CONCLUSION
Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.
Topics: Female; Humans; Male; Middle Aged; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucose; Homeostasis; Obesity; Phosphates; Proinsulin
PubMed: 37139691
DOI: 10.1210/clinem/dgad246 -
Diabetes Care Dec 2023This study aimed to evaluate the efficacy of closed-loop insulin delivery postpartum. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aimed to evaluate the efficacy of closed-loop insulin delivery postpartum.
RESEARCH DESIGN AND METHODS
In this open-label, randomized controlled trial, postpartum individuals with type 1 diabetes were randomized to hybrid closed-loop insulin delivery with the MiniMed 670G/770G system in automode or sensor-augmented pump therapy in the first 12-weeks postpartum followed by a continuation phase with closed-loop insulin delivery for all until 24 weeks postpartum.
RESULTS
Eighteen participants (mean ± SD age 32 ± 3.5 years, diabetes duration 22 ± 7.3 years, and early pregnancy HbA1c 52 ± 6.8 mmol/mol [6.9 ± 0.9%]) completed 24 weeks of postpartum follow-up. In the randomized phase, percent time in range 70-180 mg/dL (3.9-10 mmol/L) did not differ between groups (79.2 ± 8.7% vs. 78.2 ± 6.0%; P = 0.41). Participants randomized to closed-loop insulin delivery spent less time <70 mg/dL (3.9 mmol/L) and <54 mg/dL (3.0 mmol/L) (1.7 ± 0.8% vs. 5.5 ± 3.3% [P < 0.001] and 0.3 ± 0.2% vs. 1.1 ± 0.9% [P = 0.008]). Time >180 mg/dL (10 mmol/L) was not different between groups (18.7 ± 8.8% vs. 15.9 ± 7.7%; P = 0.21). In the continuation phase, those initially randomized to sensor-augmented pump therapy had less time <70 mg/dL after initiation of closed-loop insulin delivery (5.5 ± 3.3% vs. 3.3 ± 2.2%; P = 0.039). The closed-loop group maintained similar glycemic metrics in both study phases. There were no episodes of diabetic ketoacidosis or severe hypoglycemia in the randomized or continuation phase in either group.
CONCLUSIONS
Women randomized to closed-loop insulin delivery postpartum had less hypoglycemia than those randomized to sensor-augmented pump therapy. There were no safety concerns. These findings are reassuring for use of closed-loop insulin delivery postpartum because of its potential to reduce hypoglycemia.
Topics: Pregnancy; Humans; Female; Adult; Insulin; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Blood Glucose; Treatment Outcome; Insulin Infusion Systems; Cross-Over Studies; Hypoglycemia; Insulin, Regular, Human; Postpartum Period
PubMed: 37824779
DOI: 10.2337/dc23-0882 -
The Lancet. Diabetes & Endocrinology Dec 2023Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes.
METHODS
21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test.
FINDINGS
6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA. For HbA, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods.
INTERPRETATION
Interventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials.
FUNDING
JDRF and Diabetes UK.
Topics: Adult; Child; Humans; Diabetes Mellitus, Type 1; C-Peptide; Cross-Sectional Studies; Glycated Hemoglobin; Hypoglycemic Agents; Insulin
PubMed: 37931637
DOI: 10.1016/S2213-8587(23)00267-X -
Clinical Chemistry Aug 2023Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these...
BACKGROUND
Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for laboratory analysis in patients with diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments in the full version of the guideline). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association.
CONTENT
Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the patients measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring; genetic testing; and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed.
SUMMARY
The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.
Topics: Humans; United States; Glycated Hemoglobin; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus; Insulin
PubMed: 37562009
DOI: 10.1093/clinchem/hvad079 -
Journal of Materials Chemistry. B Sep 2023Glucose oxidase (GOx) has attracted a lot of attention in the field of diabetes diagnosis and treatment in recent years owing to its inherent biocompatibility and... (Review)
Review
Glucose oxidase (GOx) has attracted a lot of attention in the field of diabetes diagnosis and treatment in recent years owing to its inherent biocompatibility and glucose-specific catalysis. GOx can effectively catalyze the oxidation of glucose in the blood to hydrogen peroxide (HO) and glucuronic acid and can be used as a sensitive element in biosensors to detect blood glucose concentrations. Nanomaterials based on the immobilization of GOx can significantly improve the performance of glucose sensors through, for example, reduced electron tunneling distance. Moreover, various insulin-loaded nanomaterials (, metal-organic backbones, and mesoporous silica nanoparticles) have been developed for the control of blood glucose concentrations based on GOx catalytic chemistry. These nano-delivery carriers are capable of releasing insulin in response to GOx-mediated changes in the microenvironment, allowing for a rapid return of the blood microenvironment to a normal state. Therefore, glucose biosensors and insulin delivery vehicles immobilized with GOx are important tools for the diagnosis and treatment of diabetes. This paper reviews the characteristics of various GOx-based nanomaterials developed for glucose biosensing and insulin-responsive release as well as research progress, and also highlights the current challenges and opportunities facing this field.
Topics: Humans; Blood Glucose; Glucose Oxidase; Hydrogen Peroxide; Glucose; Diabetes Mellitus; Nanocomposites; Insulin; Insulin, Regular, Human
PubMed: 37522237
DOI: 10.1039/d3tb01097j -
Nature Structural & Molecular Biology Sep 2023
Topics: Insulin; RNA, Messenger; Protein Biosynthesis; Ribosomes
PubMed: 37537335
DOI: 10.1038/s41594-023-01049-w -
The Cochrane Database of Systematic... Nov 2023Health authorities stress the temperature sensitivity of human insulin, advising protection from heat and freezing, with manufacturers suggesting low-temperature storage... (Review)
Review
BACKGROUND
Health authorities stress the temperature sensitivity of human insulin, advising protection from heat and freezing, with manufacturers suggesting low-temperature storage for intact vials, and once opened, storage at room temperature for four to six weeks, though usage time and maximum temperature recommendations vary. For human insulin, the recommendations of current shelf life in use may range from 10 to 45 days, and the maximum temperature in use varies between 25 °C and 37 °C. Optimal cold-chain management of human insulin from manufacturing until the point of delivery to people with diabetes should always be maintained, and people with diabetes and access to reliable refrigeration should follow manufacturers' recommendations. However, a growing segment of the diabetes-affected global population resides in challenging environments, confronting prolonged exposure to extreme heat due to the climate crisis, all while grappling with limited access to refrigeration.
OBJECTIVES
To analyse the effects of storing human insulin above or below the manufacturers' recommended insulin temperature storage range or advised usage time, or both, after dispensing human insulin to people with diabetes.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 12 July 2023.
SELECTION CRITERIA
We included clinical and laboratory studies investigating the storage of human insulin above or below manufacturers' recommended temperature storage range, advised usage time, or both.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for the clinical study. Most information emerged from in vitro studies, mainly from pharmaceutical companies. There is no validated risk of bias and certainty of evidence rating for in vitro studies. We thus presented a narrative summary of the results.
MAIN RESULTS
We included 17 eligible studies (22 articles) and additional information from pharmaceutical companies. Pilot clinical study One pilot clinical study investigated temperature conditions for insulin stored for six weeks in an unglazed clay pot with temperatures ranging between 25 °C and 27 °C. The mean fall in plasma glucose in eight healthy volunteers after clay pot-stored insulin injection was comparable to refrigerator-stored insulin injection (very low-certainty evidence). In-vitro studies Nine, three and four laboratory studies investigated storage conditions for insulin vials, insulin cartridges/pens and prefilled plastic syringes, respectively. The included studies reported numerous methods, laboratory measurements and storage conditions. Three studies on prefilled syringes investigating insulin potency at 4 °C up to 23 °C for up to 28 days showed no clinically relevant loss of insulin activity. Nine studies examined unopened vials and cartridges. In studies with no clinically relevant loss of insulin activity for human short-acting insulin (SAI), intermediate-acting insulin (IAI) and mixed insulin (MI) temperatures ranged between 28.9 °C and 37 °C for up to four months. Two studies reported up to 18% loss of insulin activity after one week to 28 days at 37 °C. Four studies examined opened vials and cartridges at up to 37 °C for up to 12 weeks, indicating no clinically relevant reduction in insulin activity. Two studies analysed storage conditions for oscillating temperatures ranging between 25 °C and 37 °C for up to 12 weeks and observed no loss of insulin activity for SAI, IAI and MI. Four studies, two on vials (including one on opened vials), and two on prefilled syringes, investigated sterility and reported no microbial contamination. Data from pharmaceutical companies Four manufacturers (BIOTON, Eli Lilly and Company, Novo Nordisk and Sanofi) provided previously unreleased human insulin thermostability data mostly referring to unopened containers (vials, cartridges). We could not include the data from Sanofi because the company announced the permanent discontinuation of the production of human insulins Insuman Rapid, Basal and Comb 25. BIOTON provided data on SAI after one, three and six months at 25 °C: all investigated parameters were within reference values, and, compared to baseline, loss of insulin activity was 1.1%, 1.0% and 1.7%, respectively. Eli Lilly and Company provided summary data: at below 25 °C or 30 °C SAI/IAI/MI could be stored for up to 25 days or 12 days, respectively. Thereafter, patient in-use was possible for up to 28 days. Novo Nordisk provided extensive data: compared to baseline, after three and six months at 25 °C, loss of SAI activity was 1.8% and 3.2% to 3.5%, respectively. Loss of IAI activity was 1.2% to 1.9% after three months and 2.0% to 2.3% after six months. Compared to baseline, after one, two and three months at 37 °C, loss of SAI activity was 2.2% to 2.8%, 5.7% and 8.3% to 8.6%, respectively. Loss IAI activity was 1.4% to 1.8%, 3.0% to 3.8% and 4.7% to 5.3%, respectively. There was no relevant increase in insulin degradation products observed. Up to six months at 25 °C and up to two months at 37 °C high molecular weight proteins were within specifications. Appearance, visible particles or macroscopy, particulate matter, zinc, pH, metacresol and phenol complied with specifications. There were no data for cold environmental conditions and insulin pumps.
AUTHORS' CONCLUSIONS
Under difficult living conditions, pharmaceutical companies' data indicate that it is possible to store unopened SAI and IAI vials and cartridges at up to 25 °C for a maximum of six months and at up to 37 °C for a maximum of two months without a clinically relevant loss of insulin potency. Also, oscillating temperatures between 25 °C and 37 °C for up to three months result in no loss of insulin activity for SAI, IAI and MI. In addition, ambient temperature can be lowered by use of simple cooling devices such as clay pots for insulin storage. Clinical studies on opened and unopened insulin containers should be performed to measure insulin potency and stability after varying storage conditions. Furthermore, more data are needed on MI, insulin pumps, sterility and cold climate conditions.
Topics: Insulin; Temperature; Drug Stability; Drug Storage
PubMed: 37930742
DOI: 10.1002/14651858.CD015385.pub2 -
Communications Biology Aug 2023Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose...
Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.
Topics: Humans; Mice; Animals; Glucose; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Hyperglycemia; Insulin, Regular, Human; Muscle, Skeletal; Insulin
PubMed: 37626210
DOI: 10.1038/s42003-023-05255-6 -
Nutrients Sep 2023Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose,... (Review)
Review
Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose, amino acids (AAs), and lipid metabolism. Notably, the interplay of glucagon with nutrient intake, particularly of AAs, and non-nutrient components is central to its secretion. Fasting and postprandial hyperglucagonemia have long been linked to the development and progression of type 2 diabetes (T2DM). However, recent studies have brought to light the positive impact of glucagon agonists on lipid metabolism and energy homeostasis. This review explores the multifaceted actions of glucagon, focusing on its regulation, signaling pathways, and effects on glucose, AAs, and lipid metabolism. The interplay between glucagon and other hormones, including insulin and incretins, is examined to provide a mechanistic understanding of its functions. Notably, the liver-α-cell axis, which involves glucagon and amino acids, emerges as a critical aspect of metabolic regulation. The dysregulation of glucagon secretion and its impact on conditions such as T2DM are discussed. The review highlights the potential therapeutic applications of targeting the glucagon pathway in the treatment of metabolic disorders.
Topics: Humans; Glucagon; Diabetes Mellitus, Type 2; Insulin; Amino Acids; Glucose
PubMed: 37764697
DOI: 10.3390/nu15183913 -
Frontiers in Immunology 2023Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report...
Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8, whilst proinsulin-specific clones were both CD8 and CD4. Proinsulin-specific CD8 clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.
Topics: Humans; Autoantigens; Proinsulin; Gold; Injections, Intradermal; Single-Cell Gene Expression Analysis; Metal Nanoparticles; Diabetes Mellitus, Type 1; Peptides; Receptors, Antigen, T-Cell
PubMed: 37908349
DOI: 10.3389/fimmu.2023.1276255