Diabetes is the most common cause of end-stage renal disease, also called kidney failure. The link between the renal artery receptor angiotensin II type I (AT1R) and endothelin-1 (ET-1), involved in vasoconstriction, oxidative stress, inflammation and kidney fibrosis (collagen) in diabetes-induced nephropathy with and without metformin incorporation has not been previously studied. Diabetes (type 2) was induced in rats and another group started metformin (200 mg/kg) treatment 2 weeks prior to the induction of diabetes and continued on metformin until being culled at week 12. Diabetes significantly (p < 0.0001) modulated renal artery tissue levels of AT1R, ET-1, inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and the advanced glycation end products that were protected by metformin. In addition, diabetes-induced inflammation, oxidative stress, hypertension, ketonuria, mesangial matrix expansion, and kidney collagen were significantly reduced by metformin. A significant correlation between the AT1R/ET-1/iNOS axis, inflammation, fibrosis and glycemia was observed. Thus, diabetes is associated with the augmentation of the renal artery AT1R/ET-1/iNOS axis as well as renal injury and hypertension while being protected by metformin.

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.

Lower extremity arterial disease (LEAD) is a major risk factor for amputation in diabetic patients. The advanced glycation end products (AGEs)/endothelin-1 (ET-1)/nitric oxide synthase (NOS) axis-mediated femoral artery injury with and without metformin has not been previously investigated. Type 2 diabetes mellitus (T2DM) was established in rats, with another group of rats treated for two weeks with 200 mg/kg metformin, before being induced with T2DM. The latter cohort were continued on metformin until they were sacrificed at week 12. Femoral artery injury was established in the diabetic group as demonstrated by substantial alterations to the femoral artery ultrastructure, which importantly were ameliorated by metformin. In addition, diabetes caused a significant (p < 0.0001) upregulation of vascular tissue levels of AGEs, ET-1, and iNOS, as well as high blood levels of glycated haemoglobin, TNF-α, and dyslipidemia. All of these parameters were also significantly inhibited by metformin. Moreover, metformin treatment augmented arterial eNOS expression which had been inhibited by diabetes progression. Furthermore, a significant correlation was observed between femoral artery endothelial tissue damage and glycemia, AGEs, ET-1, TNF-α, and dyslipidemia. Thus, in a rat model of T2DM-induced LEAD, an association between femoral artery tissue damage and the AGEs/ET-1/inflammation/NOS/dyslipidemia axis was demonstrated, with metformin treatment demonstrating beneficial vascular protective effects.

We present the case of a woman who was found to have severe hypercalcaemia, staghorn calculus formation and renal impairment from the long-standing ingestion of calcium carbonate antacids from a supermarket outlet. The dosage was reported to be approximately 1,800 mg of elemental calcium each day which would constitute only a marginal increase on the recommended intake for daily elemental calcium. Furthermore, she was concomitantly taking a prescribed anti-hypertensive medication that may have exacerbated the hypercalcaemia and subsequent renal calcification. While calcium-alkali syndrome is well documented, it can be overlooked by clinicians as the predominant cause of hypercalcaemia, especially if a thorough drug history is not actively sought. This is particularly important as calcium carbonate products are increasingly being purchased as over-the-counter remedies for dyspepsia management as well as osteoporosis prevention. Explicit product labelling regarding limiting duration usage, potential drug interactions and risk of calcification is therefore recommended.

Adult inherited metabolic disorders

Background and Objective: Familial chylomicronaemia syndrome (FCS) is a rare disease characterised by persistent fasting chylomicronaemia and severe hypertriglyceridaemia, predisposing individuals to recurrent episodes of acute pancreatitis. Treatment strategies focus on a fat-restricted diet to lower triglycerides and reduce the risk of pancreatitis. However, even with excellent dietary adherence, chylomicronaemia and risk of pancreatitis persists. This review outlines the biological basis of FCS and evaluates emerging therapeutic strategies, with emphasis on apolipoprotein C3 (apoC3) directed precision treatment. Methods: A literature search was conducted using PubMed/MEDLINE and Google Scholar from date of inception to June 2026. Titles and abstracts were screened for relevance, and the reference lists of included articles were also reviewed to identify additional relevant studies. Non-English language publications were excluded. Key Content and Findings: Maintaining an ultra-low-fat diet remains the cornerstone of management in FCS and there is only a limited role for traditional lipid-lowering therapies. ApoC3 inhibition with the antisense oligonucleotide (ASO), volanesorsen, demonstrates substantial chylomicronaemia reduction and importantly, reduced pancreatitis risk. Next generation GalNAc₃-conjugated therapies (olezarsen and plozasiran) targeting apoC3 provide comparable efficacy to volanesorsen with improved safety and tolerability. Therapies targeting angiopoietin-like proteins (ANGPTLs) and microsomal triglyceride transfer protein (MTTP) show emerging potential for triglyceride and chylomicronaemia reduction. Advances in gene-editing technology shows promise as a future treatment strategy. Conclusions: Recent advances in technologies targeting apoC3 inhibition represent a significant breakthrough in the management of FCS providing effective and durable reductions in triglycerides and pancreatitis risk. Emerging molecular and gene-editing approaches hold promise for further advances in precision treatment.