Hypertension, A Comorbid Condition in Type 1 Diabetes Increases Risk of Neuropathy

Foot Amputation is Common in Patients with Diabetes Neuropathy

Neuropathy Signs are Verified Using Pinprick or Even Temperature Control

There are millions of people affected by diabetes, millions affected by hypertension and also million others who have a combination of diabetes and hypertension leading their lives. Hypertension is a comorbid condition very commonly seen in up to 75% diabetic patients depending on their obesity, age and lifestyle. It usually presents as a metabolic syndrome of insulin resistance that includes central obesity and dyslipidemia as well. Such comorbid presence of hypertension increases the risk of microvascular and macrovascular complications. Macrovascular complications include coronary artery disease, myocardial infarction, stroke, congestive heart failure and peripheral vascular disease and microvascular complications generally include retinopathy, nephropathy and neuropathy. Microvascular conditions are generally linked to hyperglycemia but hypertension too is a valuable risk factor for these conditions.

Diabetic Peripheral Neuropathy (DPN)
Diabetic Peripheral Neuropathy (DPN) is damage to nerves that sit near the skin and is a very common effect of diabetes that almost 50% people with type 2 diabetes and 20% people with type 1 diabetes suffer from it! It is most commonly nerve damage (to two types of nerves) caused to the hands and feet. While researchers still question how diabetes kills nerve cells, they have come up with other important causes such as high cholesterol, obesity and high blood pressure as major contributing factors. A British report in a study conducted more than a decade back on 37,000 people with type 2 diabetes for almost 9 years showed that high blood pressure increased risk of neuropathy by 11-65% in these participants. The explanation given here is that metabolic changes due to diabetes increases number of free radicals that attack cell DNA thereby killing antioxidant compounds that help in protecting the cell from free radicals and inflammation. Also, the nerve fibers rely on blood vessels for nutrients and oxygen supply and high blood sugar/blood pressure levels damage these blood vessels preventing any supply to the nerve fibers.

DPN affects almost 70% people with diabetes and exists as the leading cause of foot amputation. It usually is the result of prolonged diabetes in individuals and is associated with metabolic derangements such as increased polyol flux, accumulation of advanced glycosylation end products, lipid derangements and oxidative stress. Extremely stringent measures to control blood sugar levels is recommended for controlling DPN but this also only helps in preventing progress of the disease in type 1 diabetes mellitus (T1DM) patients but shows no benefits in individuals with type 2 diabetes mellitus (T2DM). There are numerous clinical and experimental studies showing that hypertension exists as an independent risk factor for DPN in patients with T1DM or T2DM. Hypertension mostly affects the myelinated fibers and studies in hypertensive rats with diabetes show a reduction in sciatic nerve blood flow along with a reduction in motor and sensory nerve conduction velocity and myelinated fiber density but no loss of intraepidermal nerve fibers. In a hypertensive T2DM model a reduction in sensory nerve conduction velocity and increased matrix metalloproteinase was witnessed at sites of myelin thinning. In nondiabetic rats affected by hypertension impaired epineural arteriolar function led to reduced endoneurial perfusion and neuropathy. But a combination drug helped in preventing and reversing nerve conduction and nerve abnormalities in type 2 diabetes rats. Elaborated below is a detailed study helpful in exactly identifying the impact of hypertension on both large and small fiber measures of DPN in patients with T1DM.

Effect of Blood Pressure on Type 1 Diabetes Patients with Neuropathy
Participants with T1DM and controls without diabetes were chosen based on multiple exclusion criteria which included hypothyroidism, corneal surgery in the last 6 months or so, vitamin B12 deficiency, neuropathy from nondiabetic causes, corneal trauma and diabetes or impaired glucose tolerance in the control group. BP measurements were taken in sitting position after a rest period of 5 minutes on 2 occasions. Systolic blood pressure readings ≥140 mm Hg or subjects on antihypertensive treatment were defined as suffering from Hypertension. Each of the participants were measured for their body mass index (BMI), glycated hemoglobin (HbA1c), cholesterol and triglycerides. Each of the participants were declared to be suffering from DPN or not based on certain criteria such as neuropathy symptoms or neuropathy signs and an abnormality of NCS or some known measure of small fiber neuropathy. Neuropathy symptoms included unsteadiness in walking, neuropathic pain, paresthesia and numbness each of which was given scores up to 4. A score ≥1 indicated the presence of a neuropathic symptom. The signs of neuropathy were verified using a pinprick on the tip of the large toe, temperature perceptions in the dorsum of the feet and the presence or absence of ankle reflexes. Any score >2 of 10 was confirmed to be a sign of neuropathy.

Corneal confocal microscopic images from the subbasal nerve plexus in the central cornea was noted for each eye. Corneal nerve fiber density (CNFD) and length of nerve fibers (CNFL) were measured. Skin biopsy was taken and cardiac autonomic neuropathy was evaluated. Assessment of Sural sensory nerve action potential (SNAP), sural nerve conduction velocity (SNCV), tibial compound motor action potential (TCMAP), tibial motor nerve conduction velocity (TMNCV), peroneal compound motor action potential (PCMAP) and peroneal motor nerve conduction velocity (PMNCV) was done in the right lower limb by a consultant neurophysiologist. On the whole, 58 normotensive controls, 20 hypertensive controls, 30 normotensive and 40 hypertensive T1DM participants were involved. Systolic and diastolic blood pressure were comparably higher in the hypertensive compared to the normotensive groups. While hypertensive controls exhibited higher blood cholesterol levels compared to normotension controls values of HbA1c, triglycerides and BMI were comparable. Hypertensive T1DM participants expressed higher triglycerides and BMI compared to normotensive T1DM participants but HbA1c and cholesterol were comparable. Results showed that:
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1. Prevalence of DPN (53.8% vs. 51.7%) and painful DPN (38.5% vs. 23.3%) was comparable between patients with T1DM with and without hypertension
2. There was no difference in the prevalence of DPN (10% vs. 7%) and painful DPN (5.3% vs. 1.8%) between hypertensive and normotensive controls
3. Hypertension-present T1DM group had a lower CNFD and CNFL compared to the normotensive group but there was no difference in corneal nerve branch density and intraepidermal nerve fiber density between normotensive and hypertensive T1DM groups.
4. There was no difference in deep breathing heart rate variability (DB-HRV) between T1DM and control participants with and without hypertension.
5. Vibration perception threshold (VPT) was significantly higher in hypertensive participants compared to normotensive patients with T1DM
6. T1DM patients with hypertension had a significantly lower SNAP, TCMAP and PCMAP but in the control group, only SNAP was significantly lower in the hypertensive group compared to the normotensive group
7. While it was initially seen that all measures of DPN including CNFD, CNFL, HRV, SNAP, SNCV, TCMAP, PCMAP, PMNCV and VPT were all linked to SBP in patients with T1DM after adjusting for certain factors such as age, gender and diabetes it was seen that only TCMAP and TMNCV were independently linked to SBP.
   
   

This study clearly shows that hypertension is associated with nerve conduction abnormalities in T1DM but has no impact on those participants with diabetes.

In another study on 467 participants aged between 45 and 64 done by the University of Toronto in 2015 almost half of those with prediabetes or newly diagnosed type 2 diabetes showed early signs of peripheral neuropathy. Higher the blood sugar levels likelier are the chances of nerve damage. Diagnosis of patients with type 1 diabetes usually happens at an early stage and about 20% of them have peripheral neuropathy after 20 years. While age does seem to be a contributing factor for people with DPN there are cases of even small kids and young adults with type 1 and type 2 diabetes who show signs of peripheral neuropathy. Also, nerve damage is irreparable causing great loss in the ability to feel and move irrespective of however the nerves could get damaged.
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Damage Control
You might suffer from any form of diabetes but if you don’t have nerve damage it is highly possible to avoid suffering from neuropathy if you control blood sugar levels and pursue other healthy steps. If you suffer from T1DM tight glucose control can eliminate DPN risk by 78% while for those with T2DM it reduces the risk by 5-9%. This vast variation in risk control might be due to the diagnosis stage. T1DM is usually diagnosed earlier preventing most nerve damages while T2DM patients might lead a life with the disease for years together before diagnosis. Such prolonged existence of T2DM without medications and sugar level control leads to nerve damage even from the prediabetes stage and this indicates ample irreparable nerve damage that is caused before a diagnosis is made. There is nothing that can be done about nerve damage that has already happened but we can prevent further damage by taking good care of our health.

References
Hypertension Contributes to Neuropathy in Patients with Type 1 Diabetes: https://academic.oup.com/ajh/article/32/8/796/5477297

The Comorbidities of Diabetes and Hypertension: Mechanisms and Approach to Target Organ Protection: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746062/

Diabetic Neuropathy: Causes and Symptoms: https://www.endocrineweb.com/guides/diabetic-neuropathy/diabetic-neuropathy-causes
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Treatment of Hypertension in Adults with Diabetes: https://care.diabetesjournals.org/content/26/suppl_1/s80

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