Effect of Tirzepatide on Diabetic Peripheral Sensorimotor Neuropathy

589 million adults (20-79 years) are living with diabetes worldwide - 1 in 9 and the total number of adults with diabetes is predicted to rise to 853 million by 2050 - 1 in 8. An estimated 43% of adults living with diabetes (252 million people) are undiagnosed. (1 ). Diabetic peripheral neuropathy (DPN) is particularly prevalent, affecting anywhere from 18.8 to 61.9% of individuals with DM in India (2). The appropriate management of this disturbance is essential if late-stage complications, such as foot ulceration and amputations are to be avoided in these patients. \[3\] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study evaluated the incidence of DPN in type1 DM and illustrated that the incidence of DPN is 33% (4). In Europe, a study found overall prevalence of DPN is 28% (the EURODIAB IDDM Complications Study) (5). The KORA F4/FF4 Study conducted in Germany reported a prevalence of DPN of 25% (6). The ADDITION Demark study reported that the prevalence of DPN was up to 34.8 (7). The pathogenesis of DN is multifactorial and remains poorly understood. DPN is characterized by progressive, nerve-length-dependent loss of peripheral nerve fibers, leading to impaired sensory and autonomic function, pain, numbness, and eventually, complete loss of sensation. (8)Hyperglycemia, dyslipidemia, and insulin resistance activate various metabolic pathways, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and microvascular damage, culminating in neuronal injury, Schwann cell damage, and myelin sheath degeneration. (9,10,11) . Schwann cels serve as the myelinating cell of the PNS and support cells of peripheral neurons. A Schwann cell forms a myelin sheath by wrapping its plasma membrane concentrically around the inner axon. The plasma membrane of Schwanncells has an extremely high lipid content, and cholesterol is particularly important for assembling the myelin sheath. The compact myelin sheath insulates the axon segment, significantly reducing membrane capacitance and increasing conduction velocity .Schwann cells are critical in response to PNS axon damage and axon regeneration. Wallerian degeneration will occur distal to injury site. The distal axon segment dies and Schwann cells, followed by macrophages, clear the dead cell contents and promote axon regeneration. Schwann cells undergo several phenotypic changes at this time ; they activate myelin breakdown, upregulate the expression of cytokines (including TNF\_ alpha ) to recruit macrophages to the injury site, up-regulate neurotropic factors to stimulate axon regeneration and neuron survival, and organize a regeneration pathway along their basal lamina tube to guide axon growth. .Risk factors for diabetic neuropathy include age, duration of diabetes, glycosylated haemoglobin , age and DR while BMI, smoking , total triglycerides, and total cholesterol do not indicate risk of diabetic neuropathy. Despite extensive research, effective treatments capable of halting or reversing progression of diabetic neuropathy remain elusive. Current management strategies primarily focus on alleviating symptoms and controlling pain.(12)Antidepressants, anticonvulsants, and opioids have shown limited efficacy and are associated with various side effects, such as dizziness and nausea.(13,14) Furthermore, no novel therapies have received approval in recent years (12,15). Novel pharmacological agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and have shown promising neuroprotective and pain management effects. (16). GLP1 1 and GIP receptors are expressed in both murine and human adipose tissue and schwann cells . (17) the differential pharmacodynamics property of incretin drugs should be explored further in treatment of peripheral neuropathy. (17) There are different methods to quantify neuropathy including clinical scores based on patients symptoms and neurological assessment electrophysiological tests,intraepithithelial nerve fibre density measurement and quantitative sensory testing each with variable sensitivity.though neurophysiology is consider the gold standard it is less sensitive to detect early diabetic peripheral neuropathy (18) The human cornea is the most densely innervated tissue of the body.. Corneal confocal microscopy (CCM) is a non-invasive imaging technique, which allows us to view the microscopic layers of the cornea. Examination of the cornea with this high-resolution method demonstrates an objective means to assess corneal nerve fibre density (CNFD), corneal nerve fibre length (CNFL), and corneal nerve branch density (CNBD) in persons with diabetes,with high sensitivity and good reproducibility . (19) Corneal Confocal microsccopy (CCM) is a sensitive measure of early small nerve fibre regeneration. A recent 12-week cross-over trial of dapagliflozin and glimepiride showed no differences in measures of cardiac autonomic neuropathy (20) , while another study showed an improvement in multiple measures of diabetic autonomic neuropathy after 24 weeks oftreatment with dapagliflozin (21). We recently demonstrated that dapagliflozin treatment is associated with reduced oxidative stress and small nerve fibre regeneration in patients with DPN as assessed with corneal nerve fiber evaluation in people with diabetes.(22)Jia et al. showed an improvement in corneal nerve parameters in participants who received optimal antidiabetic, antihypertensive and lipid-lowering medications (23). Ponirakis et al. showed that a decrease in HbA1c with either basal-bolus insulin or exenatide and pioglitazone in patients with T2DM will be associated with corneal nerve regeneration, but with no change in vibration perception or sudomotorfunction (24). Here, we show that tirzepatide effectively improves weight and body composition, normalizes hyperglycemia, and improves hyperlipidemia, with small nerve fiber regeneration. These findings highlight its potential as a disease-modifying therapy, warranting randomized controlled trials to assess its efficacy in diabetic neuropathy. Tirzepatide may act as a disease modifying therapy in diabetic neuropathy. Diabetic peripheral neuropathy (DPN) is a chronic, progressive complication of diabetes.affecting upto half of diabetics . Hyperglycemia disrupts normal cellular metabolism, ultimately leading to a vicious cycle in which dysregulated production of reactive oxygen species (ROS), advanced glycation end products (AGEs), and other factors contribute to the poor and progressively neurotoxic environment in diabetes. Increased generation of AGEs leads to their accumulation in the mitochondria, causing considerable strain to the electron transport chain, impaired energy production, and increased ROS generation. (27) Owing to their high metabolic activity, peripheral sensory nerves have a rich blood supply in the skin and are critically dependent on oxygen and nutrients from microvessels surrounding, and within, the nerve for proper functioning. Hyperglycemia and its downstream effects damage the microvasculature (28) . Peripheral artery disease, vasoconstriction, and associated vascular abnormalities restrict blood supply to the periphery .These vascular effects lead to diminished oxygen tension and hypoxia, which in turn contribute to distal nerve fiber damage. A combination of damage, loss, and hyperactivity of peripheral sensory nerve fibers in the diabetic foot underlies the symptoms of painful DPN, which include numbness, burning, and stabbing pain .Experiments using skin punch biopsies show that, as DPN progresses, there is a reduction in the epidermal nerve fiber (ENF) density, as assessed by immunohistochemistry using the pan-neuronal marker protein gene product 9.5 (PGP 9.5).(29) Obesity and dyslipidemia are major metabolic risk factors; a higher body BMI and dyslipidemia promote insulin resistance and metabolic dysfunction, contributing to neuropathy. Future studies using more advanced measure of body fat distribution, such as DEXA scans, are needed to further investigate influence of body fat distribution on neuropathy. Similarly, investigators should define the precise mechanisms by which fat causes neuropathy. Obesity alone has emerged as the second most important metabolic risk factor for neuropathy, following diabetes Obesity and dyslipidemia appear to trigger neuropathy even in the absence of overt diabetes mellitus .In a recent cross- sectional, observational study in obese and normoglycemic individuals with a body mass index (BMI) greater than 35 kg/m 2 , a high prevalence of neuropathy was found compared to lean controls. In a cross-sectional, observational study, the prevalence of polyneuropathy was high in obese individuals, even among those with normoglycemia. Screening at the primary care setting for neuropathy will offer a way for early intervention and stop the disease's development .The early detection of DPN using an objective screening test followed by its appropriate management is important, as up to 50% of diabetic peripheral neuropathies may be asymptomatic. Currently, there is no single gold standard test for objective assessment and early identification of DPN in routine clinical practice , while there is considerable inter-physician variability in judgement and weighing of neuropathic symptoms/signs to draw a clinical diagnosis (32) ADA recommends pinprick and temperature sensation tests for small fiber dysfunction; and lower extremity reflexes (particularly Achilles reflex) and vibration sensation with 128 Hz tuning fork for large fiber dysfunction (33) A simple non-invasive clinical tests that assess symptoms and signs have been developed and used, especially in clinical trials . The MNSI is one such test .The Michigan Neuropathy Screening Instrument (MNSI) is used toassess distal symmetrical peripheral neuropathy in diabetes. It includes two separate asses…