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Frontiers in Endocrinology 2023The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to... (Review)
Review
The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to diagnosing and treating diseases related to insulin resistance. In this mini-review, the authors attempt to synthesize the updated discoveries to unravel the related mechanisms and inform the development of novel applications. Firstly, we depict the insulin signaling pathway to explain the physiology of insulin action starting at the receptor sites of insulin and downstream the signaling of the insulin signaling pathway. Based on this, the next part will analyze the mechanisms of insulin resistance with two major provenances: the defects caused by receptors and the defects due to extra-receptor causes, but in this study, we focus on post-receptor causes. Finally, we discuss the recent applications including the diseases related to insulin resistance (obesity, cardiovascular disease, Alzheimer's disease, and cancer) and the potential treatment of those based on insulin resistance mechanisms.
Topics: Humans; Insulin; Insulin Resistance; Signal Transduction; Alzheimer Disease; Binding Sites
PubMed: 37664840
DOI: 10.3389/fendo.2023.1226655 -
Diabetes Care Oct 2023Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies... (Review)
Review
BACKGROUND
Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially.
APPROACH
An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of 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). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for 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 (HbA1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of HbA1c. 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; Glycated Hemoglobin; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus; Insulin; Diabetes Mellitus, Type 1
PubMed: 37471273
DOI: 10.2337/dci23-0036 -
The New England Journal of Medicine Sep 2023Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency.
METHODS
We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome.
RESULTS
Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control.
CONCLUSIONS
In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).
Topics: Humans; Blood Glucose; Glucose; Hypoglycemia; Insulin; Intensive Care Units; Glycemic Control; Parenteral Nutrition; Algorithms; Critical Illness
PubMed: 37754283
DOI: 10.1056/NEJMoa2304855 -
Diabetes Care Oct 2023In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1...
OBJECTIVE
In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10.
RESEARCH DESIGN AND METHODS
To provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted.
RESULTS
The primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted.
CONCLUSIONS
These data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment.
Topics: Adult; Child; Humans; Diabetes Mellitus, Type 1; C-Peptide; Insulin, Regular, Human; Antibodies, Monoclonal, Humanized; Insulin
PubMed: 37607392
DOI: 10.2337/dc23-0675 -
Nature Reviews. Endocrinology Jul 2023A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and... (Review)
Review
A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and α-cells are dysfunctional. Dysfunction, however, progresses to death only for β-cells. Recent findings indicate important differences between these two cell types. First, expression of BCL2L1, a key antiapoptotic gene, is higher in α-cells than in β-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptotic CHOP in β-cells than in α-cells and higher expression levels of HSPA5 (which encodes the protective chaperone BiP) in α-cells than in β-cells. Third, expression of viral recognition and innate immune response genes is higher in α-cells than in β-cells, contributing to the enhanced resistance of α-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in α-cells than in β-cells. Of note, α-cells are less immunogenic than β-cells, and the CD8 T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the α-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.
Topics: Humans; Diabetes Mellitus, Type 1; Proinsulin; CD8-Positive T-Lymphocytes; Insulin-Secreting Cells; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Immune System
PubMed: 37072614
DOI: 10.1038/s41574-023-00826-3 -
Nutrients Sep 2023The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle... (Review)
Review
The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing. In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.
Topics: Humans; Aged; Sarcopenia; Muscle, Skeletal; Nutritional Status; Exercise; Insulin
PubMed: 37764858
DOI: 10.3390/nu15184073 -
The Lancet. Diabetes & Endocrinology Sep 2023
Topics: Humans; Insulin; Music; Diabetes Mellitus
PubMed: 37620062
DOI: 10.1016/S2213-8587(23)00153-5 -
Trends in Endocrinology and Metabolism:... Oct 2023Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients... (Review)
Review
Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients with concurrent IDDM and SPS often manifest insulin resistance, and SPS-associated IDDM probably has heterogeneous causes. Some patients manifest IDDM associated only with high titers of anti-GAD65 caused by SPS. By contrast, other patients develop IDDM only after being treated with high-dose corticosteroids or they progress to insulin dependency following their treatment with high-dose corticosteroids. The profile of autoantibodies differs markedly between type 1 diabetes mellitus (T1DM), late-onset diabetes mellitus, and SPS-associated IDDM. Therefore, as with new-onset diabetes after transplantation (NODAT), SPS-associated IDDM should be classified as a specific diabetes entity, the pathophysiology of which requires increased attention.
Topics: Humans; Diabetes Mellitus, Type 1; Stiff-Person Syndrome; Diabetes Mellitus, Type 2; Insulin; Autoantibodies
PubMed: 37586963
DOI: 10.1016/j.tem.2023.07.005 -
Diabetologia Nov 2023Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in type 1 and type 2 diabetes. Previous studies have suggested...
AIMS/HYPOTHESIS
Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in type 1 and type 2 diabetes. Previous studies have suggested that Ca signalling within beta cells regulates insulin processing and secretion; however, the mechanisms that link impaired Ca signalling with defective insulin maturation remain incompletely understood.
METHODS
We generated mice with beta cell-specific sarcoendoplasmic reticulum Ca ATPase-2 (SERCA2) deletion (βS2KO mice) and used an INS-1 cell line model of SERCA2 deficiency. Whole-body metabolic phenotyping, Ca imaging, RNA-seq and protein processing assays were used to determine how loss of SERCA2 impacts beta cell function. To test key findings in human model systems, cadaveric islets were treated with diabetogenic stressors and prohormone convertase expression patterns were characterised.
RESULTS
βS2KO mice exhibited age-dependent glucose intolerance and increased plasma and pancreatic levels of proinsulin, while endoplasmic reticulum (ER) Ca levels and glucose-stimulated Ca synchronicity were reduced in βS2KO islets. Islets isolated from βS2KO mice and SERCA2-deficient INS-1 cells showed decreased expression of the active forms of the proinsulin processing enzymes PC1/3 and PC2. Additionally, immunofluorescence staining revealed mis-location and abnormal accumulation of proinsulin and proPC2 in the intermediate region between the ER and the Golgi (i.e. the ERGIC) and in the cis-Golgi in beta cells of βS2KO mice. Treatment of islets from human donors without diabetes with high glucose and palmitate concentrations led to reduced expression of the active forms of the proinsulin processing enzymes, thus phenocopying the findings observed in βS2KO islets and SERCA2-deficient INS-1 cells. Similar findings were observed in wild-type mouse islets treated with brefeldin A, a compound that perturbs ER-to-Golgi trafficking.
CONCLUSIONS/INTERPRETATION
Taken together, these data highlight an important link between ER Ca homeostasis and proinsulin processing in beta cells. Our findings suggest a model whereby chronic ER Ca depletion due to SERCA2 deficiency impairs the spatial regulation of prohormone trafficking, processing and maturation within the secretory pathway.
DATA AVAILABILITY
RNA-seq data have been deposited in the Gene Expression Omnibus (GEO; accession no.: GSE207498).
Topics: Mice; Humans; Animals; Proinsulin; Insulin-Secreting Cells; Diabetes Mellitus, Type 2; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Insulin; Glucose; Islets of Langerhans
PubMed: 37537395
DOI: 10.1007/s00125-023-05979-4 -
Revue Medicale Suisse Sep 2023
Topics: Humans; Insulin
PubMed: 37753920
DOI: 10.53738/REVMED.2023.19.843.1767