Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets

Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results from increased Foxo1 protein degradation, due to hyperacetylation of Foxo1 from increased nutrient turnover. To understand the mechanisms of Foxo1-related beta cell failure, we performed genome-wide analyses of its target genes, and identified putative mediators of sub-phenotypes of cellular dysfunction. Chromatin immunoprecipitation analyses demonstrated a striking pattern of Foxo1 binding to the promoters of a cluster of aldo-ketoreductases on chromosome 13: Akr1c12, Akr1c13, Akr1c19. Of these, Akr1c19 has been reported as a marker of Pdx1-positive endodermal progenitor cells. Here we show that Akr1c19 expression is dramatically decreased in db/db islets. Thus, we investigated whether Akr1c19 is involved in beta cell function. We performed gain- and loss-of-function experiments in cultured beta cells and generated Akr1c19 knockout mice. We show that Foxo1 and HNF1a cooperatively regulate Akr1c19 expression. Nonetheless, functional characterization of Akr1c19 both using islets and knockout mice did not reveal abnormalities on glucose homeostasis. We conclude that reduced expression of Akr1c19 is not sufficient to affect islet function.

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

Beta-cell failure rather than insulin resistance is the major cause of abnormal glucose tolerance in Africans: insight from the Africans in America study

IntroductionUncertainties exist on whether the main determinant of abnormal glucose tolerance (Abnl-GT) in Africans is β-cell failure or insulin resistance (IR). Therefore, we determined the prevalence, phenotype and characteristics of Abnl-GT due to β-cell failure versus IR in 486 African-born blacks (male: 64%, age: 38±10 years (mean±SD)) living in America.Research design and methodsOral glucose tolerance test were performed. Abnl-GT is a term which includes both diabetes and prediabetes and was defined as fasting plasma glucose (FPG) ≥5.6 mmol/L and/or 2-hour glucose ≥7.8 mmol/L. IR was defined by the lowest quartile of the Matsuda Index (≤2.98) and retested using the upper quartile of homeostatic model assessment of insulin resistance (HOMA-IR) (≥2.07). Abnl-GT-IR required both Abnl-GT and IR. Abnl-GT-β-cell failure was defined as Abnl-GT without IR. Beta-cell compensation was assessed by the Disposition Index (DI). Fasting lipids were measured. Visceral adipose tissue (VAT) volume was obtained with abdominal CT scan.ResultsThe prevalence of Abnl-GT was 37% (182/486). For participants with Abnl-GT, IR occurred in 38% (69/182) and β-cell failure in 62% (113/182). Compared with Africans with Abnl-GT-IR, Africans with Abnl-GT-β-cell failure had lower body mass index (BMI) (30.8±4.3 vs 27.4±4.0 kg/m2), a lower prevalence of obesity (52% vs 19%), less VAT (163±72 vs 107±63 cm2), lower triglyceride (1.21±0.60 vs 0.85±0.42 mmol/L) and lower FPG (5.9±1.4 vs 5.3±0.6 mmol/L) and 2-hour glucose concentrations (10.0±3.1 vs 9.0±1.9 mmol/L) (all p<0.001) and higher DI, high-density lipoprotein (HDL), low-density lipoprotein particle size and HDL particle size (all p<0.01). Analyses with Matsuda Index and HOMA-IR yielded similar results. Potential confounders such as income, education, alcohol and fiber intake did not differ by group.ConclusionsBeta-cell failure occurred in two-thirds of participants with Abnl-GT and may be a more frequent determinant of Abnl-GT in Africans than IR. As BMI category, degree of glycemia and lipid profile appeared more favorable when Abnl-GT was due to β-cell failure rather than IR, the clinical course and optimal interventions may differ.Trial registration numberNCT00001853.

A multi-scale in silico mouse model for insulin resistance and humanoid type 2 diabetes

Insulin resistance (IR) causes compensatory insulin production, which in humans eventually progresses to beta-cell failure and type 2 diabetes (T2D). This disease progression involves multi-scale processes, ranging from intracellular signaling to organ-organ and whole-body level regulations, on timescales from minutes to years. T2D progression is commonly studied using overfed and genetically modified rodents. However, rodents do not exhibit human T2D progression, with IR-driven beta-cell failure, and available multi-scale data is too complex to fully comprehend using traditional analysis. To help resolve these issues, we here present an in silico mouse model. This is the first mathematical model that simultaneously explains multi-scale mouse IR data on all three levels – cells, organs, body – ranging from minutes to months. The model correctly predicts new independent multi-scale validation data and provides insights into non-measured processes. Finally, we present a humanoid in silico mouse exhibiting disease progression from IR to IR-driven T2D.

A Case of Possible SARS-COV-2 Induced Beta-Cell Failure

Background: There are several known viral triggers of ketosis-prone diabetes, including SARS-1 and HHV-81,2. SARS-COV-2 can bind ACE-2 receptors on the beta-cell causing destruction and acute impairment of insulin secretion3. There is accruing evidence to suggest that COVID-19 infection can worsen preexisting diabetes or induce new disease4. Clinical Case: A 40-year-old Hispanic male presented to the ER complaining of fatigue, polyuria, and polydipsia. A screening COVID-19 PCR was positive but he denied URI symptoms. His admission labs were notable for hyperglycemia (434 mg/dL; n 71–99), metabolic acidosis (pH 7.1 [n 7.35–7.45]; HCO3 3 mmoL/L [n 21–32]), increased anion gap (27 mmoL/L; n &lt; 12) and elevated HbA1c (7.9%; n &lt; 5.7%). The patient’s fructosamine was also high (464 umol/L; n 200–285) and discordant from his HbA1c. There was no evidence of pancreatitis, lactic acidosis, renal impairment or hepatic dysfunction. The patient had no known medical problems, did not drink alcohol to excess, and reported good access to nutrition. He had a strong family history of T2DM, but his BMI (23.3 kg/m2) and lipid panel were normal. The DKA was managed in the medical ICU using fluids and IV insulin per protocol. The patient required 180 units of IV insulin/24-hours (2.5 units/kg/day) to maintain blood glucose 180–250 mg/dL. After 48-hours of IV insulin, he was transitioned to subcutaneous insulin and prescribed multiple daily injections at discharge. There were concerns about possible T1DM and/or glucose toxicity leading to further diagnostics. His GAD-65 (&lt;5 [IU]/mL; n 0–5 [IU]/mL) and IA-2 (&lt;5.4 U/mL; n &lt;5.4 U/mL) antibodies were negative but his c-peptide was suppressed (0.64 ng/mL; n 0.8–3.85). The patient was reevaluated at three months post-discharge. His glycemic control and insulin requirements had improved but repeat c-peptide level was undetectable. He was thought to have beta-cell failure and referred to a diabetologist. Conclusion: This is a case of absolute insulin deficiency persisting for at least three months most likely attributable to acute COVID-19 infection. References: 1. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47(3):193–199.2. Sobngwi E, Choukem SP, Agbalika F, et al. Ketosis-prone type 2 diabetes mellitus and human herpesvirus 8 infection in sub-saharan africans. Jama. 2008;299(23):2770–2776.3. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637.4. Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020;8(6):546–550.

Hyperglycemia in Acute COVID-19 is Characterized by Adipose Tissue Dysfunction and Insulin Resistance

COVID-19 has proven to be a metabolic disease resulting in adverse outcomes in individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality compared to those who do not develop hyperglycemia. Nevertheless, the pathophysiological mechanism(s) of hyperglycemia in COVID-19 remains poorly characterized. Here we show that insulin resistance rather than pancreatic beta cell failure is the prevalent cause of hyperglycemia in COVID-19 patients with ARDS, independent of glucocorticoid treatment. A screen of protein hormones that regulate glucose homeostasis reveals that the insulin sensitizing adipokine adiponectin is reduced in hyperglycemic COVID-19 patients. Hamsters infected with SARS-CoV-2 also have diminished expression of adiponectin. Together these data suggest that adipose tissue dysfunction may be a driver of insulin resistance and adverse outcomes in acute COVID-19.

Nutritional Biomarkers for Predicting Pancreatic Beta Cell Failure in Central Obesity

BACKGROUND: There is a continuous rise in the prevalence of central obesity and become a pressing health problem in the world. Central obesity followed by many metabolic disorders especially Type 2 Diabetes Mellitus (T2DM). The pathogenesis started from overnutrition signal that force pancreatic beta cells to produce a large number of insulin. Low-grade chronic inflammation that occurred also affects the organs sensitivity against insulin and caused beta cells to compensated this situation and at the end become exhausted and loss its function.CONTENT: Along compensation mechanism, certain nutrients were support the beta cells to maintain their mass and function to produce insulin. Short chain fatty acids (SCFAs) are gut microbiota fermentation product that act as nutrient and give an advantage to the proliferation and survivability of the beta cells. Zinc (Zn) also plays an important role in every step of insulin production. Moreover, these nutrients protecting pancreas against inflammation and oxidative stress through certain mechanism. Most of patients with central obesity are unaware of the presence of this disturbance at early stage. Whereas, at molecular level there is a magnitude of SCFAs and Zn level in the blood that would become an early signal and predict the damage of beta cells.SUMMARY: Quantification of these two nutrients in the blood expected to provide an early warning tool to maintain insulin adequacy and predict the possibility of beta cell failure in central obesity with promising performance.KEYWORDS: central obesity, T2DM, SCFAs, Zinc, beta cell failure