Tirzepatide is a dual agonist of GLP-1 Receptor and the GIP receptor, producing substantial improvement in glycaemic control, weight reduction and insulin sensitivity. Beyond its metabolic effects, incretin signalling has demonstrated neuroprotective and neurotropic properties, including activation of intracellular pathways that enhance neuronal survival and regeneration.

Using tirzapatide for diabetic sensorimotor peripheral neuropathy and assessing with CCM / NCS and BDNF will represent three complementary aspects of nerve regeneration: metabolic control, structural nerve repair and neurotrophic signalling.

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 assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The MNSI questionnaire is self- administered . A score of ≥ 7 was considered abnormal (34)

During the MNSI examination, a health professional inspects each foot for deformities, dry skin, calluses, infections and fissures. Each foot with any abnormality receives a score of 1. Each foot is also inspected for ulcers and each foot with an ulcer receives a score of 1. The ankle reflexes are also elicited. If the reflex is absent, the patient is asked to perform the Jendrassic manoeuver and, if present, the reflex is designated as present withreinforcement and is scored as 0.5. If the reflex is absent with theJendrassic manoeuver, the reflex is designated as absent and is scored as 1.Vibration sensation is then tested in the great toe using a 128-Hz tuningfork. In general, the examiner should be able to feel vibration in his or her hand for 5 s longer than a normal subject can at the great toe. Vibration is scored as present if the examiner senses the vibration on his or her finger. 10 s longer than the subject feels it in the great toe, decreased if sensed for ≥ 10 s (scored as 0.5) or absent (scored as 1). The total possible score is 8 points and, in the published scoring algorithm, a score ≥ 2.5 is considered abnormal (34) Neuropathy is defined as a score >7.0 on the MNSI questionnaire or a score >2.0 on the MNSI examination . Again, controversies are present with the cut-off values for MNSI examination for identifying DSPN. Studies have been carried out to change the cut-off of MNSI examination from 2 to 1.5 , 2.5 , 3, 4 etc. Moghtaderi et al. validated the MNSI examination scores for 1.5, 2.0, 2.5, and 3.0 cut-off values and suggested selecting the cut-off at 2 and reported the reliability of MNSI is 0.81. Previous researches have shown that MNSI examination with cut-off selected at ≥ 2.0 has 80% sensitivity and 95% specificity with good repeatability . Herman et al. showed that MNSI is a simple, non-invasive, and valid measure of DSPN in comparison with nerve conduction studies (NCS) and suggested that it can be used in large clinical trials for assessment of DSPN. (35) Look AHEAD study also demonstrated improvement in MNSI questionnaire over the first couple years in addition to after 9-11 years of dietary weight loss .These results provide stronger justification for using the MNSI questionnaire as a sensitive measure of neuropathy improvement.

ADA recommends that DSPN should be assessed at the starting of diagnosis of type 2 diabetes and 5 years after being diagnosed with type-1 diabetes and should be annually examined after that. Therefore, a reliable MNSI scoring system can be a potential solution for annually screening DSPN in diabetes patients on large scale. (35)

Abnormalities in sudomotor function in diabetes patients were noted to correlate with thepresence of autonomic neuropathy.

The diagnosis of DSPN as well as the severity of DPN can easily be quantified by using Nerve conduction studies. NCV evaluates both the motor as well as sensory large myelinated nerve fibers thus it cannot detect neuropathy in pre -diabetes or recent onset diabetes because these patients have predominantly small fiber dysfunction early in the course. By using NCS as a diagnostic tool in patients with type 2 diabetes mellitus most of the patients with DPN will be missed. Therefore , if initial NCS is normal it is recommended to use other validated measures of small nerve fibers.

Other test that can be used to detect the presence of small nerve fiber dysfunction includes laser Doppler flare imaging studies, corneal confocal microscopy or quantitative sensory thermal thresholds. (31) Although early studies investigating the role of CCM in DPN used a white light-based microscope, most recent studies have used a laser CCM (Heidelberg Retina Tomograph III Rostock Corneal Module, Heidelberg Engineering GmbH, Heidelberg, Germany) due to its superior image quality and rapid acquisition time. The corneal subbasal nerve plexus is normally visible at a corneal depth of 50 to 90 μm, and images can be captured by using section, volume, or sequence mode. During a CCM scan, several images of the subbasal nerve plexus are captured based on the anatomical position, focus, and image quality.(34) The current consensus is that 5 to 8 non overlapping images from the apical cornea and 2 from the inferior whorl of both eyes provide good accuracy to assess DPN Manual expert quantification is the gold standard method for estimation of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), inferior whorl length, and tortuosity based on a set of established criteria. Briefly, CNFD refers to the total number of main nerve fibers in a CCM image (fibers/mm 2 ); CNBD measures the number of branches connected to main nerve fibers (branches/mm 2 ) CNFL is the total length of all nerve fibers and branches (mm/mm 2 ) per image; the tortuosity coefficient provides an estimate of the tortuosity of the main nerve fibers; and inferior whorl length is the length of nerves at the inferior whorl

Although efforts have been made to establish CCM as a tool for monitoring therapeutic response in clinical trials, no such therapy has been approved to date by the Food and Drug Administration (FDA) for diabetic neuropathy. Initially CCM was evaluated in the context of diabetic peripheral neuropathy, often in comparison to nerve conduction studies. Early results were not particularly promising, which likely reflected a basic methodological mismatch: CCM assesses small fiber neuropathy, whereas nerve conduction studies primarily evaluate large myelinated fibers. On the other hand, when CCM was compared to intraepidermal nerve fiber density measured by skin biopsy, currently considered the gold standard for diagnosing small fiber neuropathy, it demonstrated comparable diagnostic efficiency. Later studies examined whether abnormal CCM findings are associated with diabetic autonomic neuropathy, and in particular CAN, which represents a form of small fiber involvement that is associated with increased mortality in people with DM (36)

In a study , The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm 2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN. (37) CCM as a Diagnostic Biomarker of DPN Almost 2 decades ago, the first studies by Rosenberg et al and Malik et al showed that CCM could be used to detect and stratify DPN severity in patients with type 1 diabetes mellitus (T1DM) and T2DM, respectively. Quattrini et al extended these findings by showing a correlation between IENFD with CNFD (r = 0.39; P = 0.001) and CNBD (r = 0.41; P = 0.001). Furthermore, significant corneal nerve pathology was present even in patients without DPN, which led the authors to suggest that CCM was a potentially more sensitive measure of neuropathy. Indeed, Tavakoli et al reported a sensitivity and specificity of 0.82/0.52 for diagnosing DPN and 0.71/0.64 for diagnosing those at risk of foot ulceration. Both studies reported corneal nerve fiber loss in patients without DPN, with reasonable sensitivity but relatively poor specificity. This simply highlights the diagnostic paradox; that is, that despite small fiber damage preceding large fiber involvement, the accepted definition of DPN uses primarily large fiber measures. CCM, which assesses small fibers, will by default detect an abnormality in patients without DPN who have "normal large fiber function. Notwithstanding, Ahmed et al showed that among CCM parameters, a CNFL <14 mm/mm 2 generated an excellent AUC (0.88) and sensitivity/specificity (0.85/0.84) for the diagnosis of DPN. Petropoulos et al reported that a CNFD <18.7 fibers/mm 2 was associated with an AUC of 0.84, sensitivity/specificity of 0.79/0.78, and an odds ratio of 16.5 (95% CI, 7-39.9). In the context of biomarker validation, it is important that CCM performance is compared with the clinical end point that it is intended to substitute (37)

Subclinical corneal nerve loss is clinically meaningful, as for every 1 mm/mm 2 loss in CNFL there is a 0.61°C reduction in cold detection threshold and 1.78% lower heart rate variability.

Furthermore, corneal nerve pathology is not only an early manifestation of DPN but also precedes diabetic retinopathy and microalbuminuria and progresses with the development of retinopathy and microalbuminuria. Indeed, nerve fiber loss occurs in the retina and cornea of pediatric and adult 57 patients with T1DM without evidence of vasculopathy or nephropathy. These results challenge the view that retinopathy is the earliest microvascular complication and has implications for DM screening. (38)

NERVE CONDUCTION STUDIES: PRINCIPLES AND TECHNIQUES The NCS aims to form an important diagnostic device for clinical neurophysiology and to assess the functional integrity of peripheral nerves. These studies work according to the principle of electrically stimulating peripheral nerves . Despite these advantages, NCS are poorly suited to the early detection of DSPN. The technique primarily evaluates large myelinated fibres, while the earliest pathological changes in DSPN typically affect small Aδ and C fibres. As a result, patients may demonstrate normal NCS results even in the presence of significant small fibre dysfunction, contributing to underdiagnosis in the early stages of disease.

Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Weight loss, particularly in cases of severe obesity, significantly helps to stabilize or improve Intraepidermal Nerve Fiber Density (IENFD), reducing small fiber neuropathy. It stops the natural decline of nerve density and improves symptoms like metabolic parameters and neuropathy as assessed by small fibre regeneration demonstrable by corneal confocal microscopy in T2D individual. Beyond its impact on diabetes management, tirzepatide mechanism involving GIP and GLP-1 receptors has raised interest due to its potential neuroprotective effects. (33)In a large database analysis of patients with type 2 diabetes, those taking tirzepatide had a significantly reduced risk for DPN over 2 years compared with their counterparts who were on insulin or other diabetes medications.Tirzepatide cumulatively decreased the risk of developing diabetic peripheral neuropathy over 2 years from 4.8% to 3%.Conversely, the risk consistently increased with insulin use over 2 years, from 4.9% to 6.3%. (44)

EFFECT TIRZEPETIDE ON WEIGHT LOSS In the 72-week SURMOUNT 1 trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to

• 14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and
• 3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with ti In both SURMOUNT-1 and SURMOUNT-4, tirzepatide treatment resulted in shifts to a lower BMI category compared to baseline . In SURMOUNT-1, 81.8 % of participants treated with tirzepatide (pooled 10 mg/15 mg) shifted at least one BMI category lower and the mean BMI change from baseline was -8.90 kg/m 2 in the improved group versus -3.65 kg/m 2 in the not improved group. In SURMOUNT-4, 91.6 % of participants shifted at least one BMI category lower, with a mean BMI change from baseline of -10.47 kg/m 2 in the improved group versus -5.20 kg/m 2 in the not improved group . Participants from the SURMOUNT-4 trial in the improved BMI category demonstrated greater improvement in cardiometabolic risk factors, including waist circumference, fasting serum glucose, fasting insulin, triglycerides, high-density lipoprotein cholesterol (HDL-C), and very-low-density lipoprotein cholesterol, compared to those with no shift or those who shifted to a higher BMI category (not improved BMI category) (Fig. 4). In both SURMOUNT- 1 and SURMOUNT-4, very-low-density lipoprotein cholesterol and triglycerides decreased over 31 % in the improved BMI category, and fasting insulin levels decreased over 53 % in both trial. A post hoc analysis of SURMOUNT-1 by Krumholz et al. showed that blood pressure declined rapidly over the first 24 weeks of tirzepatide treatment and stabilized by Week 72, with significant reductions in both diastolic and systolic values. Overall, non-HDL-C appears to be a more accurate indicator of cardiovascular death risk than low-density lipoprotein cholesterol. Non-HDL-C captures more atherogenic lipid particles, as it contains very-low- density lipoprotein cholesterol or remnants which are more harmful than low-density lipoprotein cholesterol particles. The observed improvements in blood pressure regulation and lipid profile in our analyses offer additional beneficial effects of tirzepatide, alongside its observed effects on body weight reduction.

EFFECT TIRZEPETIDE ON LIPID PROFILE

When dosed at 5 mg, tirzepatide lowered total cholesterol levels more than controls, with a statistically significant mean difference of -4.77% (95% CI,

• 6.43 to -3.10; K [number of pooled cohorts]=9, N [total patients pooled]=6,421). This advantage increased to -5.39% (95% CI, -6.87 to
• 3.91; K=10, N=7,041) for 10 mg and -6.55% (95% CI, -8.26 to -4.84; K=12, N=8,291) for 15 mg doses. When dosed at 5 mg, tirzepatide raised HDL-C levels more than controls, with a statistically significant mean difference of 3.78% (95% CI, 1.83 to 5.74; K=9, N=6,466). This advantage increased to 5.75% (95% CI, 4.11 to 7.40; K=10, N=7,044) for 10 mg and 6.94% (95% CI, 5.15 to 8.74; K=12, N=8,296) for 15 mg doses.

Effect tirzepetide on blood pressure

Tirzepatide significantly lowers both systolic and diastolic blood pressure (BP) in adults with overweight or obesity, acting as a potent cardiometabolic modulator. Clinical trials, such as SURMOUNT-1, show that 24-hour ambulatory systolic blood pressure decreases by an average of over 7 mmHg, with 58% of participants achieving normalized blood pressure by 72 weeks

Effect tirzepetide on inflammatory markers Tirzepatide, a dual GIP and GLP-1 receptor agonist, has shown significant metabolic benefits and weight reduction, but its anti-inflammatory effects have been less studied. .

Compared to placebo, tirzepatide reduced hsCRP (mean difference [MD]: -32.9; 95% confidence interval [CI]: -33.6 to - 32.2; I²=15.3%) and IL-6 (MD: -17.8; 95% CI: -24.3 to - 11.3; I² = 1.6%). Levels of hsCRP were significantly reduced with tirzepatide at 15 mg (MD: - 32.9; 95% CI: -33.6 to - 32.2; I²=4.4%), 10 mg (MD: -33.9; 95% CI: -50.3 to - 17.6; I²=41.8%), and 5 mg (MD: -20.3; 95% CI: -35.2 to - 5.3; I²=0%). Similarly, IL-6 levels were significantly reduced with tirzepatide at 5 mg (MD: -18.8; 95% CI: -32.9 to - 4.6; I²=17.2%), 10 mg (MD: -17.9; 95% CI: -28.2 to - 7.7; I²=2.1%), and 15 mg (MD: -16.8; 95% CI: -31.1 to - 2.6; I²=47.4%). This study demonstrated that tirzepatide use is associated with a significant reduction in inflammatory markers, regardless of the population studied or treatment regimen. B3

Effect tirzepetide on hba1c

. A dose-dependent superiority in lowering HbA 1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71 mmol/mol (-1.62%) to -22.35 mmol/mol (-2.06%) vs placebo, -3.22 mmol/mol (-0.29%) to -10.06 mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66 mmol/mol (-0.70%) to -12.02 mmol/mol (-1.09%) vs basal insulin regimens. B4

Effect tirzepetide on neuroprotection / effect on BDNF Tirzepatide was found to counteract the detrimental effects of high glucose (HG) exposure, which is known to contribute to neurodegeneration. It prevented the HG-induced downregulation of the pAkt/CREB/BDNF signaling pathway, suggesting a protective role against glucose-related neuronal damage. Additionally, tirzepatide reversed the hypermethylation of CREB and BDNF gene promoters and reduced miR-34a expression, which is typically upregulated in aging and neurodegenerative conditions, leading to impaired synaptic plasticity and cognitive decline (Fontanella et al. 2024). Importantly, tirzepatide prevented HG-induced downregulation of key glucose transporters, including glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), and glucose transporter 4 (GLUT4), which are critical for maintaining neuronal glucose uptake and metabolism. . The restoration of these transporters suggests that tirzepatide may counteract hyperglycemia-induced neurodegeneration. These findings highlight tirzepatide's ability to modulate both molecular and epigenetic mechanisms implicated in neurodegenerative diseases (Fontanella et al.

2024). B5

Schwann cell transplantation is emerging as a safe and potentially transformative therapy for peripheral neuropathy and traumatic nerve injuries. (42 ) Immun histochemical stains are valuable tools to differentiate Schwann cells from other cell types.(45) S-100 is a protein unique to neural crest-derived cells, so anti-S-100 antibodies can be used to stain for healthy Schwann cells or nervous tissue neoplasms, such as schwannomas[Myelin basic protein (MBP) neutralizes phospholipid charges on the inner surface of the membrane and is present in Schwann cells but not satellite cells, the other major PNS glial cell. Anti- MBP can be used to differentiate Schwann cells or oligodendrocytes from other glial cells.(45) P0,a peripheral nerve myelin protein, is a transmembrane adhesion protein that promotes the extracellular lamellar apposition that forms the intraperiod lines.

In an RCT comparing inj methylcobalamin versus oral cobalamin in peripheral neuropathy, injection cobalamin im .5 mg/day ) 3 per week versus 1.5 mg oral tablet daily - the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) as secondary outcome while the tablet treatment did not. (46)

Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy .(47) Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy. ( these study in diabetic mice ). empaglifozin has been shown to improve nerve conduction velocity (NCV) from 22.5±2.3 m/s to 35.8±3.1 m/s (p<.01) and increase intra epidermal nerve fiber density by 45%, and reduce oxidative stress markers such as malondialdehyde by over 50%.(47) in a single case report ,there was a progressive improvement in corneal nerve morphology over 12 months of treatment with tirzepatide, with an increase in corneal nerve fiber density (CNFD) by 34% (+10.4 fiber/mm2), corneal nerve branch density (CNBD) by 52% (+21.8 branch/mm2), and corneal nerve fiber length (CNFL) by 22% (+4.2 mm/mm2)(48) Treatment with tirzepatide has been associated with reductions in weight, body fat, and visceral fat and a sustained reduction in and normalization of A1C, with reversal of type 2 diabetes. CGM data have demonstrated 100% time in range and a reduction in glucose variability with an increase in HDL cholesterol and a reduction in triglycerides The earlysmall nerve fiber regeneration detected using corneal confocal microscopy may be attributedto the improvement in risk factors associated with diabetic peripheral neuropathy .There is an evidence of corneal nerve regeneration after pancreas and kidney transplantationin type 1 diabetes and with exenatide once weekly with pioglitazone or basal-bolus insulin intype 2 diabetes, (49) Tirzepatide is associated with improvements in weight, blood lipids and has anti-inflammatory and neurotrophic effects, all of which may contribute to nerve regeneration. We plan to study that tirzepatide effectively improves weight and body composition, normalizes hyperglycemia, and improves hyperlipidemia, with small nerve fiber regeneration.](streamdown:incomplete-link)

Inclusion Criteria:

Eligible participants (≥ 18 years) with diabetes duration of < 10 years, baseline HbA1c between 7% and 10% Signs and symptoms of DSPN based on a Michigan Neuropathy Screening Instrument (MNSI) history composite score of >= 7 OR MNSI examination SCORE >= 2.5 will be enrolled.

BMI >= 27 KG/metre 2.

Exclusion Criteria:

1. participants with untreated hypothyroidism
2. history of leprosy
3. peripheral vascular disease defined by ankle-brachial index (ABI) &lt; 0.9
4. serum B12 levels < 200 pg./mL/ if low will be supplemented
5. history of alcohol excess (>=2 and >= 1 standard drink per day for male and female respectively)
6. any condition affecting corneal nerves (severe dry eyes, severe corneal dystrophies, ocular trauma or surgery in the preceding 6 months or Sjogren&#39;s or sicca syndrome
7. use of oral contraceptives.