A large proportion of the damaging chemical changes which occur in the body’s cells due to diabetes and obesity could be prevented by a naturally occurring molecule, a new study suggests.
Scientists at Nottingham Trent University investigated how this “metabolic stress,” resulting from prolonged exposure to high levels of glucose and fat, damages proteins in the blood and cells and prevents them from working properly.
The researchers, writing in the journal Free Radical Biology and Medicine, also studied the effect of “carnosine,” a molecule found in human skeletal tissue and consumed in the diet through meat and fish. It can also be taken as a nutritional supplement.
While further studies are required, it could pave the way for the potential development of new classes of drugs related to carnosine that would be able to help tackle this previously untreated aspect of type 2 diabetes.
The study involved using mass spectrometry – the process of weighing and separating molecules – to identify proteins in patient blood samples damaged by raised levels of glucose and fatty acids.
Further laboratory work then investigated the extent to which carnosine was able to prevent similar damaging protein modifications in cells and tissues linked to the control of glucose.
The researchers found that carnosine prevented 65–90% of these damaging chemical changes and protected the functional properties of affected cells.
The researchers say that despite the cells being compromised, carnosine was able to preserve cellular function by soaking up the toxic molecules.
The team has previously shown the potential of carnosine in controlling blood sugar levels, but now understand exactly which proteins are damaged.
“The regulation of blood glucose is vital for the human body to ensure that the energy requirements of vital organs are met,” said Dr. Mark Turner, a senior researcher in Nottingham Trent University’s School of Science and Technology.
He said: “In patients with type 2 diabetes certain molecules become less effective and so can’t do their job properly when it comes to regulating glucose in the body. After identifying these molecules in patient groups, we wanted to see the role that carnosine could play in preventing these damaging changes.
“While further studies are required, this work has confirmed our hypothesis that carnosine could offer significant therapeutic potential against type 2 diabetes.”
It occurs when the pancreas does not release enough insulin, or the cells of the body do not react to insulin.
Type 2 diabetes continues to grow at an alarming rate, with the projected figure rising from an estimated 451 million adults worldwide in 2017, to 693 million by 2045.
Diabetic nephropathy is the leading cause of chronic kidney disease (CKD), and the foremost cause of end stage renal disease (ESRD) [1]. The standard treatment for diabetic nephropathy includes controlling glycemia and blood pressure and reducing albumin leakage in urine using angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) [2]. These can reduce the number of patients receiving renal replacement therapy which eventually reduces cost of treatment for patients with diabetic nephropathy.
Hyperglycemia induces an abnormal activation of glucose-dependent pathways. i.e., the polyol pathway, hexosamine pathway and protein kinase C pathway in producing multiple substances, including transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), interleukine-1 (IL-1), interleukine-6 (IL-6) and tissue necrosis factor (TNF) [3, 4].
Increased urinary TGF-β level among patients with diabetes stimulates the canonical pathway (ALK 5, Smad 2/3) and alternate pathway (ALK 1, Smad 1/5) [5]. The activation of the canonical pathway induces extracellular matrix accumulation at the glomerular basement membrane (GBM) and mesangium.
In addition, the activation of the alternate pathway induces podocyte injury causing foot process effacement. Therefore, TGF-β and activation of the metabolic pathway are important factors in developing diabetic nephropathy [6]. Treatment to reduce TGF-β level in the urine may be able to slow the deterioration of diabetic nephropathy [7].
Carnosine is an amino acid found in nature, synthesized from L-histidine and beta-alanine (carnosine synthase) and degraded by the enzyme carnosinase [8]. Carnosine has many biological qualities that can slow CKD progression and prevent diabetic nephropathy from developing [9, 10]. One of the proposed mechanisms is that it inhibits the synthesis of TGF-β [11].
It has been hypothesized that individuals with two copies of the CNDP1 Mannheim have lower activity of plasma carnosinase, leading to higher plasma carnosine concentrations and a lower risk of diabetic nephropathy [11]. One study has shown that oral carnosine supplementation could reduce albuminuria and urinary alpha-1 microglobulin level in type 1 diabetes [12].
Presently, no studies have yet been conducted among adult type 2 diabetes mellitus (T2DM) patients with diabetic nephropathy. The study aimed to assess the effect of oral carnosine supplementation on levels or urinary TGF-β and albumin in patients with T2DM.
reference link: https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-021-02434-7
More information: Charlie Jr Lavilla et al, Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress, Free Radical Biology and Medicine (2021). DOI: 10.1016/j.freeradbiomed.2021.08.233
