のどが渇くのは、糖の水を引き寄せる性質による

正常なHbA1cは5.5%以下

CGMの一種としてFGMがあるととらえるほうが良さそう。

本当のCGMはSMBGによる校正が必須。

Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation Potential Conflicts of Interest: None

PUNCHLINE Endothelial ANGPTL4 drives diabetic kidney fibrosis by disrupting cellular metabolism, triggering inflammation, and damaging the vasculature.

BACKGROUND Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide, affecting millions and placing a growing burden on healthcare systems. While the disease is characterized by progressive scarring and vascular damage in the kidneys, the root causes remain incompletely understood. Emerging evidence suggests that subtle shifts in how kidney endothelial cells generate and use energy may play a central role in disease progression. The renal vasculature does more than transport blood; it regulates communication with surrounding cells and helps maintain metabolic balance. In diabetes, this balance is disrupted, leading to endothelial dysfunction, inflammation, and fibrotic remodeling. ANGPTL4, a protein involved in lipid metabolism and vascular homeostasis, has been implicated in kidney injury, but its specific role in the endothelium has remained unclear. This study investigates whether targeting ANGPTL4 in endothelial cells can break the cycle of metabolic dysfunction and fibrotic signaling in diabetic kidneys.

KEY QUESTION ADDRESSED Can reprogramming the metabolism of endothelial cells by deleting ANGPTL4 interrupt the cascade of vascular dysfunction, inflammation, and fibrosis that drives diabetic kidney disease?

SUMMARY This study uses a mouse model of endothelial-specific ANGPTL4 deletion to demonstrate that ANGPTL4 is a key upstream mediator of diabetic kidney pathology. In diabetic settings, endothelial ANGPTL4 promotes glycolysis and de novo lipogenesis while suppressing fatty acid oxidation—triggering mitochondrial damage, cGAS-STING–mediated inflammation, and vascular leakage. These metabolic shifts contribute to fibrosis through endothelial-to-mesenchymal transition (EndMT) and paracrine signaling to tubular epithelial cells. Mice lacking ANGPTL4 in the endothelium are protected from albuminuria, glomerulosclerosis, and fibrotic remodeling. ANGPTL4-deficient endothelium also displays a favorable switch from VEGFR1 to VEGFR2 signaling, downregulation of DPP-4/β1-integrin pathways, and upregulation of the anti-inflammatory metabolic regulator SIRT1. These protective effects are recapitulated by pharmacological inhibition of lipogenesis, glycolysis, or STING signaling, supporting a broader therapeutic strategy targeting endothelial metabolism. While direct ANGPTL4 inhibitors are not yet clinically validated, modulators of FASN, STING, and SIRT1 are further along in development, suggesting nearer-term translational opportunities.

KEY RESULTS ANGPTL4 is upregulated in diabetic kidney endothelium and correlates with increased vascular permeability, glycolysis, EndMT, and mitochondrial dysfunction (Fig. 1).

Endothelial-specific ANGPTL4 knockout mice (Angptl4^emut^) show protection from DKD, with reduced fibrosis, glomerular damage, and albuminuria despite persistent hyperglycemia (Fig. 2).

ANGPTL4 loss reprograms endothelial metabolism, enhancing fatty acid oxidation and suppressing glycolysis and lipogenesis (Figs. 2–3).

ANGPTL4-deficient endothelium avoids mitochondrial DNA release, blunting cGAS-STING activation and cytokine-driven inflammation (Fig. 4).

Pharmacologic inhibition of STING or FASN reproduces the protective effects, supporting a causal role for metabolic-immune crosstalk (Figs. 3–4).

ANGPTL4 deletion shifts VEGF signaling (VEGFR1→VEGFR2) and blocks downstream mesenchymal signaling to tubules via DPP-4/β1-integrin (Fig. 5).

SIRT1 expression is upregulated in ANGPTL4-deficient endothelium, potentially linking metabolic rewiring to anti-fibrotic resilience (Supp. Figs. S11–S12).

STRENGTHS Utilizes cell-type–specific genetic tools to dissect endothelial contributions in a robust diabetic kidney model.

Provides mechanistic insight into how metabolic alterations drive inflammation and fibrosis.

Combines in vivo models with molecular assays, metabolic flux analyses, and histopathology.

Demonstrates therapeutic relevance through complementary pharmacologic interventions.

Supports a conceptual shift in DKD from a purely metabolic or hemodynamic condition to a vascular-metabolic disorder.

FUTURE WORK & EXPERIMENTAL DIRECTIONS Elucidate how ANGPTL4 regulates SIRT1 expression and activity in endothelial cells.

Investigate ANGPTL4’s role in fibrotic progression across other diseases, such as aging-related or hypertensive kidney injury.

Explore sex-specific responses and long-term outcomes in ANGPTL4-deficient models.

Evaluate the therapeutic efficacy of ANGPTL4 inhibition or SIRT1 activation in vascularized human kidney organoids or ex vivo human kidney tissues with preserved endothelial architecture.

Examine interactions between endothelial cells, podocytes, and immune cells in diabetic nephropathy.

RELEVANCE TO RECENT LITERATURE This work builds on the authors’ prior study in Science Advances (2024), which showed that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys. It strengthens the case that DKD is not simply a byproduct of hyperglycemia but an actively regulated process involving endothelial metabolic stress, immune signaling, and fibrogenesis. Similar to prior reports on glycolysis suppression and SIRT1 enhancement as anti-fibrotic strategies, this study identifies ANGPTL4 as a critical mediator linking lipid metabolism, mitochondrial damage, and endothelial inflammation. It underscores a growing consensus that endothelial metabolism governs kidney health and positions ANGPTL4 as a novel, actionable target for therapeutic intervention in DKD.

AUTHORSHIP NOTE This review was drafted with the assistance of ChatGPT (OpenAI) to organize and articulate key insights. Dr. Angela Andersen reviewed the final content for accuracy and clarity.

FINAL TAKEAWAY This preprint reframes diabetic kidney disease as a vascular-metabolic disorder driven by ANGPTL4-mediated metabolic reprogramming in endothelial cells. By connecting mitochondrial dysfunction, immune activation, and fibrotic signaling, it clarifies a central mechanism in DKD progression and highlights promising new therapeutic strategies targeting endothelial metabolism.

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How to Control Blood Glucose Levels

Deepti Gurdasani. (2022, January 10). Lots of people dismissing links between COVID-19 and all-cause diabetes. An association that’s been shown in multiple studies- whether this increase is due to more diabetes or SARS2 precipitating diabetic keto-acidosis allowing these to be diagnosed is not known. A brief look👇 [Tweet]. @dgurdasani1. https://twitter.com/dgurdasani1/status/1480546865812840450

Su, Y., Yuan, D., Chen, D. G., Ng, R. H., Wang, K., Choi, J., Li, S., Hong, S., Zhang, R., Xie, J., Kornilov, S. A., Scherler, K., Pavlovitch-Bedzyk, A. J., Dong, S., Lausted, C., Lee, I., Fallen, S., Dai, C. L., Baloni, P., … Heath, J. R. (2022). Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae. Cell, 0(0). https://doi.org/10.1016/j.cell.2022.01.014

Kamrath, C., Rosenbauer, J., Eckert, A. J., Siedler, K., Bartelt, H., Klose, D., Sindichakis, M., Herrlinger, S., Lahn, V., & Holl, R. W. (2022). Incidence of Type 1 Diabetes in Children and Adolescents During the COVID-19 Pandemic in Germany: Results From the DPV Registry. Diabetes Care, dc210969. https://doi.org/10.2337/dc21-0969

Geddes, L. (2021, September 28). Covid can infect cells in pancreas that make insulin, research shows. The Guardian. https://www.theguardian.com/society/2021/sep/29/covid-can-infect-cells-in-pancreas-that-make-insulin-research-shows

Blakemore, E. (n.d.). New diabetes cases linked to covid-19. Washington Post. Retrieved February 11, 2021, from https://www.washingtonpost.com/health/2021/02/01/covid-new-onset-diabetes/

Mansfield, K. E., Mathur, R., Tazare, J., Henderson, A. D., Mulick, A., Carreira, H., Matthews, A. A., Bidulka, P., Gayle, A., Forbes, H., Cook, S., Wong, A. Y., Strongman, H., Wing, K., Warren-Gash, C., Cadogan, S. L., Smeeth, L., Hayes, J. F., Quint, J. K., … Langan, S. M. (2020). COVID-19 collateral: Indirect acute effects of the pandemic on physical and mental health in the UK. MedRxiv, 2020.10.29.20222174. https://doi.org/10.1101/2020.10.29.20222174

Müller, J.A., Groß, R., Conzelmann, C. et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab (2021). https://doi.org/10.1038/s42255-021-00347-1

(2020) COVID-19 and diabetes: a co-conspiracy? The Lancet Diabetes & Endocrinology. Retrieved from: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30315-6/fulltext

I found a study on acai and blood sugar, but they used healthy overweight subjects. The relative reduction in postprandial glucose was substantial. However, since the subjects' baseline fasting glucose was normal, the drop was not significant. We have every reason to think that fasting blood sugar would be reduced in diabetic subjects.

I was unable to find a study on baobab on diabetes or metabolic syndrome. However, given the effectiveness of amla, curcumin, and acai, it is likely effective. There is also some evidence for many other antioxidant sources, which backs up the idea that any source will do.

I've found one study on sumac for type 2 diabetes. There seems to be two separate write-ups on the same data.

Oddly, 3 grams sumac did not perform as well as 3 grams amla. I can think of several possible explanations. The most likely explanation is that they used the whole grain rather than the bran. I assume the grain is what's used traditionally, but I'm having difficulty finding information about this. The bran has over 3 times the ORAC compared to the whole grain. It's likely that the bran is both hard to find and expensive.

This backs up the two studies on fasting glucose in diabetes and per-diabetes. It is also a higher quality study (crossover design).

Killerby. M. E., (2020) Characteristics Associated with Hospitalization Among Patients with COVID-19 — Metropolitan Atlanta, Georgia, March–April 2020. Centers for Disease Control and Prevention. Retrieved from: https://www.cdc.gov/mmwr/volumes/69/wr/mm6925e1.htm

Endocrinology, T. L. D. &. (2020). Obesity and COVID-19: Blame isn’t a strategy. The Lancet Diabetes & Endocrinology, 0(0). https://doi.org/10.1016/S2213-8587(20)30274-6

Stokes, E. K. (2020). Coronavirus Disease 2019 Case Surveillance—United States, January 22–May 30, 2020. MMWR. Morbidity and Mortality Weekly Report, 69. https://doi.org/10.15585/mmwr.mm6924e2

Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., Barnaby, D. P., Becker, L. B., Chelico, J. D., Cohen, S. L., Cookingham, J., Coppa, K., Diefenbach, M. A., Dominello, A. J., Duer-Hefele, J., Falzon, L., Gitlin, J., Hajizadeh, N., Harvin, T. G., … Zanos, T. P. (2020). Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. https://doi.org/10.1001/jama.2020.6775

T1DM children

• annual flu vaccine
• pneumoccocal vaccine

immediate (same-day) referral to a specialist for

• adults diagnosed with T1DM
• children and young people with suspected type 1 diabetes

Serious hypoglycaemia = endocrinology referral

• Active foot problem = podiatry ferral within 1 day

• Longest CVOT in dpp4. - 6 years
• only active comparator CVOT
• 77 % relative risk reduction in hypoglycaemia in Lina
• early diabetics studied

This could be interesting as well. Metabolic issues run through chronic illness. As do circadian dysfunctions, diabetes susceptibility,

ADA-EASD Consensus Report reflects current treatment recommendations as endorsed by the ADA and the PPC.

On October 5, 2018, the consensus report “Management of Hyperglycemia in Type 2 Diabetes: ADA-EASD Consensus Report 2018” was published. The consensus report was developed by a writing group consisting of representatives from the ADA and EASD. The consensus report addresses approaches to glycemic management in adults with type 2 diabetes with the goal of reducing complications and maintaining quality of life in the context of comprehensive cardiovascular risk management and patient-centered care. The ADA Professional Practice Committee (PPC) was involved in the review and approval of the final consensus report. The consensus recommendations and approach to glycemic management in adults with type 2 diabetes presented within the report reflects the current view of the ADA. Please find a link to the consensus document here: http://dx.doi.org/10.2337/dci18-0033

Reference:

Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB: Management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care Oct 2018; DOI: 10.2337/dci18-0033

Rationale/Reason for Change:

Management of Hyperglycemia in Type 2 Diabetes: ADA-EASD Consensus Report 2018 reflects current treatment recommendations as endorsed by the ADA and the PPC.

Annotation published: October 5, 2018. Annotation approved by PPC: September 20, 2018.

Suggested citation: American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018 [web annotation]. Diabetes Care 2018;41(Suppl. 1):S73–S85. Retrieved from https://hyp.is/1p2zesvFEeioRdNqCoou5A/clinical.diabetesjournals.org/content/36/1/14

This is likely do to the reduced carbohydrate intake rather than increased fat intake. Since carbohydrates generally insulin sensitivity, it's likely that this additional insulin resistance is acting as a confounder (as well as, presumably, a standard deviation widener). Thus, I would expect similar results during hypocaloric carbohydrate restriction.

A visual exploration of the link between statin use and the risk of Diabetes in a subpopulation of patients with subclinical hypothyroidism.

This is an interactive graph created with Biovista Vizit; nodes and links can be further explored to view supporting bibliography and molecular mechanism of action.

The first note in Biovista Vizit the free unbiased visual pubmed search tool using hypothes.is

Here is an example graph (click to go to the live graph)

Very good explanation!

Wow, this is a very interesting application!

This reminds me of the diabetes and heart disease epidemic. If through forced choice you can engender a species of people to change the make up of their blood through outside chemicals and OVER FEEDING everyone sugar rendering most people diabetic you can in essence control the emerging medical needs of a society dependent on new forms of health care and medicines. The obama care state.