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Turkish Journal of Medical Sciences 2023Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding...
BACKGROUND/AIM
Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding of the molecular mechanisms involved in the differentiation of embryonic stem cells (ESCs) into IPCs may help us improve the therapeutic strategies for treating T1DM. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (Pfkfb1-4) are key regulators of glucose metabolism. Although Pfkfb3 has been shown to be required for the growth of early differentiated mouse ESCs (mESCs), more studies are needed to further assess the roles of Pfkfb isoenzymes in embryonic development and differentiation, particularly into specific cell types. In this study, we aimed to elucidate the changes in the expression of Pfkfb isoenzymes on the differentiation of mESCs into IPCs.
MATERIALS AND METHODS
A 3-step protocol was used to differentiate R1 and J1 mESCs into IPCs. The changes in the gene expression of MafA, MafB, Ins2, and Nkx6.1 (IPC specific markers) and Pfkfb1-4 were analyzed using real-time quantitative polymerase chain reaction (qPCR). Insulin expression and secretion were determined by immunofluorescence (IF) staining and the enzyme linked immunosorbent assay (ELISA), respectively.
RESULTS
Upon differentiation, the IPC specific markers in differentiated cells were upregulated. Continued differentiation was confirmed by the development of insulin-positive islet-like clusters that secreted insulin in response to glucose uptake. Expressions of the Pfkfb2 and Pfkfb3 isoenzymes were markedly increased in various stages of differentiation.
CONCLUSION
These findings suggest that Pfkfb2 and Pfkfb3 may impact the differentiation of mESCs into IPCs and the regulation of the insulin response to glucose levels. This study also lays a foundation for researchers to further probe the roles of Pfkfb isoenzymes on the differentiation of mESCs into IPCs and may open new avenues for regenerative medicine.
Topics: Animals; Phosphofructokinase-2; Cell Differentiation; Mice; Mouse Embryonic Stem Cells; Isoenzymes; Insulin-Secreting Cells; Insulin
PubMed: 38813509
DOI: 10.55730/1300-0144.5725 -
Cardiovascular Diabetology May 2024Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation.
METHODS
We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis.
RESULTS
Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group.
CONCLUSIONS
Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy.
TRIAL REGISTRATION
clinicaltrials.gov (NCT02752113).
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Glomerular Filtration Rate; Male; Diabetes Mellitus, Type 2; Middle Aged; Female; Benzhydryl Compounds; Aged; Treatment Outcome; Kidney; Glucosides; Time Factors; Linagliptin; Pulse Wave Analysis; Metformin; Insulin; Diabetic Nephropathies; Vascular Stiffness; Drug Therapy, Combination; Hypoglycemic Agents; Biomarkers; Clinical Relevance; Sodium-Glucose Transporter 2
PubMed: 38811998
DOI: 10.1186/s12933-024-02223-0 -
Nature Communications May 2024The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic...
The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
Topics: Animals; Insulin-Secreting Cells; Receptors, Interleukin; Female; Humans; Male; Insulin; Mice; Homeostasis; Glucose; Mice, Knockout; Insulin Secretion; Mice, Inbred C57BL; Interleukin-22; Glucose Intolerance; Interleukins; Aging
PubMed: 38811550
DOI: 10.1038/s41467-024-48320-2 -
Proceedings of the National Academy of... Jun 2024Patients with type 1 diabetes mellitus who are dependent on an external supply of insulin develop insulin-derived amyloidosis at the sites of insulin injection. A major...
Patients with type 1 diabetes mellitus who are dependent on an external supply of insulin develop insulin-derived amyloidosis at the sites of insulin injection. A major component of these plaques is identified as full-length insulin consisting of the two chains A and B. While there have been several reports that characterize insulin misfolding and the biophysical properties of the fibrils, atomic-level information on the insulin fibril architecture remains elusive. We present here an atomic resolution structure of a monomorphic insulin amyloid fibril that has been determined using magic angle spinning solid-state NMR spectroscopy. The structure of the insulin monomer yields a U-shaped fold in which the two chains A and B are arranged in parallel to each other and are oriented perpendicular to the fibril axis. Each chain contains two β-strands. We identify two hydrophobic clusters that together with the three preserved disulfide bridges define the amyloid core structure. The surface of the monomeric amyloid unit cell is hydrophobic implicating a potential dimerization and oligomerization interface for the assembly of several protofilaments in the mature fibril. The structure provides a starting point for the development of drugs that bind to the fibril surface and disrupt secondary nucleation as well as for other therapeutic approaches to attenuate insulin aggregation.
Topics: Humans; Amyloid; Insulin; Models, Molecular; Hydrophobic and Hydrophilic Interactions; Diabetes Mellitus, Type 1; Protein Conformation; Magnetic Resonance Spectroscopy
PubMed: 38809711
DOI: 10.1073/pnas.2401458121 -
PloS One 2024Attempts to subtype, type 2 diabetes (T2D) have mostly focused on newly diagnosed European patients. In this study, our aim was to subtype T2D in a non-white Emirati...
BACKGROUND
Attempts to subtype, type 2 diabetes (T2D) have mostly focused on newly diagnosed European patients. In this study, our aim was to subtype T2D in a non-white Emirati ethnic population with long-standing disease, using unsupervised soft clustering, based on etiological determinants.
METHODS
The Auto Cluster model in the IBM SPSS Modeler was used to cluster data from 348 Emirati patients with long-standing T2D. Five predictor variables (fasting blood glucose (FBG), fasting serum insulin (FSI), body mass index (BMI), hemoglobin A1c (HbA1c) and age at diagnosis) were used to determine the appropriate number of clusters and their clinical characteristics. Multinomial logistic regression was used to validate clustering results.
RESULTS
Five clusters were identified; the first four matched Ahlqvist et al subgroups: severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), and a fifth new subtype of mild early onset diabetes (MEOD). The Modeler algorithm allows for soft assignments, in which a data point can be assigned to multiple clusters with different probabilities. There were 151 patients (43%) with membership in cluster peaks with no overlap. The remaining 197 patients (57%) showed extensive overlap between clusters at the base of distributions.
CONCLUSIONS
Despite the complex picture of long-standing T2D with comorbidities and complications, our study demonstrates the feasibility of identifying subtypes and their underlying causes. While clustering provides valuable insights into the architecture of T2D subtypes, its application to individual patient management would remain limited due to overlapping characteristics. Therefore, integrating simplified, personalized metabolic profiles with clustering holds greater promise for guiding clinical decisions than subtyping alone.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Blood Glucose; Glycated Hemoglobin; Body Mass Index; Cluster Analysis; Adult; Aged; Insulin; Insulin Resistance; United Arab Emirates
PubMed: 38805513
DOI: 10.1371/journal.pone.0304036 -
Frontiers in Endocrinology 2024Psychological insulin resistance (PIR), which refers to the reluctance of diabetic patients to use insulin, is a frequently encountered clinical issue. Needle-free... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Psychological insulin resistance (PIR), which refers to the reluctance of diabetic patients to use insulin, is a frequently encountered clinical issue. Needle-free injection (NFI) offers advantages in terms of expediting insulin absorption and mitigating adverse reactions related to injection. To evaluate the effects of subcutaneous injection of insulin aspart 30 with NFI on PIR and insulin dosage in patients with type 2 diabetes mellitus (T2DM).
METHODS
Sixty-four patients with T2DM participated in this randomized, prospective, open, crossover study. Insulin aspart 30 was administered subcutaneously to each subject via QS-P NFI and Novo Pen 5 (NP) successively. The effects of NFI on PIR were analyzed. Differences in insulin dosage, glycemic variability, and injection safety were compared at similar levels of glycemic control.
RESULTS
After the administration of NFI, the insulin treatment attitude scale score decreased (53.7 ± 7.3 vs. 58.9 ± 10.7, p<0.001), the insulin treatment adherence questionnaire score increased (46.3 ± 4.9 vs. 43.8 ± 7.1, p<0.001), and the insulin treatment satisfaction questionnaire score increased (66.6 ± 10.5 vs. 62.4 ± 16.5, p<0.001). At the same blood glucose level, NFI required a smaller dosage of insulin aspart 30 compared with that of NP (30.42 ± 8.70 vs. 33.66 ± 9.13 U/d, p<0.001). There were no differences in glycemic variability indices (standard deviation, mean amplitude of glycemic excursion or coefficient of variation) between the two injection methods. Compared with NP, NFI did not increase the incidence of hypoglycemia (17.2% vs. 14.1%, p=0.774), and it decreased the incidence of induration (4.7% vs. 23.4%, p=0.002) and leakage (6.3% vs. 20.3%, p=0.022) while decreasing the pain visual analog scale score (2.30 ± 1.58 vs. 3.11 ± 1.40, p<0.001).
CONCLUSION
NFI can improve PIR in patients with T2DM and be used with a smaller dose of insulin aspart 30 while maintaining the same hypoglycemic effect.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/, identifier ChiCTR2400083658.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Cross-Over Studies; Hypoglycemic Agents; Insulin Resistance; Injections, Subcutaneous; Insulin Aspart; Aged; Prospective Studies; Insulin; Blood Glucose; Adult; Insulin, Isophane
PubMed: 38803476
DOI: 10.3389/fendo.2024.1379830 -
Andes Pediatrica : Revista Chilena de... Apr 2024Hypertriglyceridemia (HTG)-induced acute pancreatitis (AP) secondary to insulin deficiency following the onset of type 1 diabetes mellitus (T1DM) is a rare but serious...
UNLABELLED
Hypertriglyceridemia (HTG)-induced acute pancreatitis (AP) secondary to insulin deficiency following the onset of type 1 diabetes mellitus (T1DM) is a rare but serious complication in children.
OBJECTIVE
To describe the diagnosis and treatment of severe HTG and to emphasize the need for timely diagnosis of T1DM.
CLINICAL CASE
A 15-year-old female adolescent with a history of overweight presented with a two-weeks history of fever, anorexia, and diffuse abdominal pain. Laboratory tests revealed triglycerides of 17,580 mg/dL, lipase of 723 U/L, and blood glucose of 200 mg/dL. An abdominal CT scan showed an enlarged and edematous pancreas. She was hospitalized with a diagnosis of AP and severe HTG, which progressed to acute necro-hemorrhagic pancreatitis. Treatment included continuous intravenous insulin infusion until triglyceride levels decreased. Upon discontinuation of insulin, fasting hyperglycemia (206 mg/dL) and metabolic acidosis recurred, therefore DM was suspected. Upon targeted questioning, a history of polydipsia, polyuria, and weight loss during the last 3 months stood out. Glycated hemoglobin was markedly elevated (14.7%). Insulin therapy was optimized, achieving stabilization of laboratory parameters after 15 days of treatment and complete anatomical resolution of pancreatic involvement at one year of follow-up.
CONCLUSIONS
The presence of severe HTG in pediatrics compels us to consider its secondary causes, such as the onset of T1DM. It is crucial to improve the ability to diagnose T1DM early, as it may present with infrequent and high-risk presentations for the patient.
Topics: Humans; Adolescent; Diabetes Mellitus, Type 1; Female; Hypertriglyceridemia; Pancreatitis; Acute Disease; Insulin; Severity of Illness Index; Hypoglycemic Agents
PubMed: 38801367
DOI: 10.32641/andespediatr.v95i2.4967 -
Andes Pediatrica : Revista Chilena de... Apr 2024Diabetic ketoacidosis (DKA) is one of the most serious complications of type 1 diabetes mellitus. Its treatment requires fluid and electrolyte replacement and insulin.... (Observational Study)
Observational Study
UNLABELLED
Diabetic ketoacidosis (DKA) is one of the most serious complications of type 1 diabetes mellitus. Its treatment requires fluid and electrolyte replacement and insulin. Hypophosphatemia as a complication of treatment has been scarcely evaluated.
OBJECTIVES
To estimate the incidence of hypophosphatemia in children with DKA, treated with subcutaneous regular insulin (IRS), and to explore factors associated with this complication.
PATIENTS AND METHOD
Prospective, observational study. Patients diagnosed with DKA hospitalized in the general care ward were included. Data on phosphatemia, glycemia, acid-base status, and IRS amount (U/kg) received were recorded at baseline and after 24 h of treatment. Hypophosphatemia was defined as values below 2.5 mg/dl. The correlation between initial phosphate and at 24 h of treatment was evaluated; the incidence of hypophosphatemia at 24 h was expressed as a percentage of the total number of patients.
RESULTS
30 patients were included, 15 were female, mean age 11.4 ± 3.2 years. At 24 h of treatment with IRS, 36.7% (95%CI 22-55%) presented hypophosphatemia, mean value 1.9 ± 1.5 mg/dl. Initial bicarbonate < 10 mmol/L acted as a predictor of hypophosphatemia (OR 7.5; 95%CI 1.4-39.8%; p = 0.01). No patient required intravenous phosphate correction, and no associated clinical complications were observed.
CONCLUSION
In the group studied, the incidence of hypophosphatemia reached 36.7% at 24 hours of treatment. Initial bicarbonate lower than 10 mmol/L was significantly associated with hypophosphatemia. No complications associated with hypophosphatemia were observed.
Topics: Humans; Female; Hypophosphatemia; Male; Diabetic Ketoacidosis; Child; Prospective Studies; Insulin; Adolescent; Injections, Subcutaneous; Prevalence; Hypoglycemic Agents; Diabetes Mellitus, Type 1; Incidence
PubMed: 38801366
DOI: 10.32641/andespediatr.v95i2.4924 -
Journal of Diabetes Research 2024Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients...
Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1 (SDF-1)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.
Topics: Animals; Islets of Langerhans Transplantation; Diabetes Mellitus, Experimental; Myoblasts, Skeletal; Mice; Male; Insulin; Neovascularization, Physiologic; Hepatocyte Growth Factor; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A; Islets of Langerhans; Chemokine CXCL12; Blood Glucose; Diabetes Mellitus, Type 1; Signal Transduction; Insulin Secretion; Cell Differentiation
PubMed: 38800586
DOI: 10.1155/2024/5574968 -
Nutrients May 2024Mounting evidence indicates a complex link between circulating saturated fatty acids (SFAs) and cardiovascular disease (CVD) risk factors, but research on erythrocyte...
Mounting evidence indicates a complex link between circulating saturated fatty acids (SFAs) and cardiovascular disease (CVD) risk factors, but research on erythrocyte membrane SFA associations with metabolic markers remains limited. Our study sought to investigate the correlations between erythrocyte membrane SFAs and key metabolic markers within glycemic and lipid metabolism in a Chinese population of 798 residents aged 41 to 71 from Guangzhou. Using gas chromatography-mass spectrometry, we assessed the erythrocyte membrane saturated fatty acid profile and performed multiple linear regression to evaluate the relationship between different SFA subtypes and metabolic markers. Our findings revealed that the odd-chain SFA group (C15:0 + C17:0) exhibited negative associations with fasting blood glucose (FBG), homeostatic model assessment for insulin resistance (HOMA-IR), and triglycerides (TG). Conversely, the very-long-chain SFA group (C20:0 + C22:0 + C23:0 + C24:0) exhibited positive associations with fasting insulins (FINS), HOMA-IR, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Furthermore, there was no evidence supporting an association between the even-chain group (C14:0 + C16:0 + C18:0) and metabolic markers. Our findings suggest that different subtypes of SFAs have diverse effects on glycemic and lipid metabolic markers, with odd-chain SFAs associated with a lower metabolic risk. However, the results concerning the correlations between even-chain SFAs and very-long-chain SFAs with markers of glycemic and lipid metabolism pathways are confusing, highlighting the necessity for further exploration and investigation.
Topics: Humans; Middle Aged; Male; Cross-Sectional Studies; Fatty Acids; Female; Aged; Blood Glucose; Biomarkers; Erythrocyte Membrane; Adult; China; Insulin Resistance; Lipid Metabolism; Asian People; Triglycerides; Insulin; East Asian People
PubMed: 38794744
DOI: 10.3390/nu16101507