53
Chapter IX
MEDICAL POLYTHERAPY FOR DIABETIC FOOT
 MEDICAL MANAGEMENT OF PERIPHERAL NEUROPATHY
 MEDICAL MANAGEMENT O...
54
Detecting Heat, Cold, Heat Pain and Cold Pain Thresholds are particularly useful
where clinical evidence of neuropathy ...
55
cause for improvement. (Sugimoto K, 2002.) The reader is requested to study these
references in detail and understand t...
56
also considered as epileptic equivalents. The drugs that have been found clinically
useful and have adequate evidence t...
57
and changes NADH / NAD+ & GSH GSSG ratios. Currently a large trial in USA is
going on. (Ziegler et al, 1995, 1997, 1999...
58
which will also serve for hyperglycemia. The other reversible motor neuropathy is
the cranial third nerve palsy due to ...
59
1. Since the diabetic patient has to off load the affected foot his exercise schedule gets
completely disturbed. Theref...
60
7. Dressing material should be selected carefully taking into account the cost, duration,
availability, accessibility e...
61
The paradox occurs when hemodynamic stability is achieved, blood pH is brought to
a reasonable level but the blood gluc...
62
Insulin is the definitive replacement therapy for all types of diabetes. By definition,
'diabetes mellitus' implies the...
63
numbers that came out of the paper corresponded with DCCT and by adopting these
criteria we can confer, what the author...
64
References for Halting or Reversing the Neuropathic Changes:
1. Vinik AI, Erbas T, Stansberry KB, Pittenger GL. Small f...
65
14. Calcutt, Tomlinson et al, Unpublished data.
15. Johansson BL, et al Diabetologia, 1996 : Johansson BL, Borg K, Fern...
66
9. Apfel SC, Kessler JA, Adornato BT et al. Recombinant human nerve growth factor
in the treatment of diabetic polyneur...
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1363266951 9 chapter9

  1. 1. 53 Chapter IX MEDICAL POLYTHERAPY FOR DIABETIC FOOT  MEDICAL MANAGEMENT OF PERIPHERAL NEUROPATHY  MEDICAL MANAGEMENT OF AUTONOMIC NEUROPATHY  MANAGEMENT OF INSENSATE FEET AND PAINFUL FEET  HALTING/REVERSING THE PROGRESSION OF NEUROPATHY NEW EVIDENCE AND EXPERIMENTAL THERAPIES  REFERENCES FOR FURTHER READING  TREATING MOTOR AND AUTONOMIC NEUROPATHY  MEDICAL MANAGEMENT OF PERIPHERAL VASCULAR DISEASE  MEDICAL MANAGEMENT OF DIABETIC FOOT INFECTIONS  MANAGEMENT OF HYPERGLYCEMIA AND INFECTION  PREPARING AN INFECTED FOOT FOR SURGERY  SAFETY OF ANESTHESIA  AMPUTATION AND RELATED PSYCHOLOGICAL ISSUES  INSULIN WITH A FOCUS ON NEUROPATHY Medical management of Diabetic foot involves many aspects as shown below: Clinical and Laboratory Assessment to delineate the problems a diabetic foot has - These problems could be categorized broadly as relating to: Sensory, Motor and Autonomic Neuropathy Drug therapy Insulin administration and Integrity of Nerve Fiber Peripheral Arterial Disease Deformities, Ulcers, Infection Management of hyperglycemia and co morbidities Physical and Psychological issues associated with amputations Rehabilitation Medical Management of Sensory Neuropathy Problems: Insensate Feet: Medically it is important that an insensate foot is diagnosed to decide clinically the depth of anesthesia not only to pain but to touch, pressure and proprioception. These modalities are related to thickly myelinated fibers and significant loss of function relates to the risk level of ulceration. Simple modalities of investigation like monofilament and Vibration Perception thresholds go a long way in convincing the patient about his serious losses of sensation, thereby motivating him to follow the preventive advice that can be given.
  2. 2. 54 Detecting Heat, Cold, Heat Pain and Cold Pain Thresholds are particularly useful where clinical evidence of neuropathy is not convincing in a person with diabetes. There is adequate evidence to show that these small unmyelinated fibers are lost or become dysfunctional earliest. So far there was no easy way to detect these sensations but that issue does not exist now. Easily operable simple programs are available. We also believe that if we take measures like controlling hyperglycemia aggressively including early initiation of insulin and treating other co morbidities at this stage we should have a fair success in halting or even reversing the progression of neuropathy. As will be shown subsequently in this part insulin is one of the important agents to preserve the integrity of the nerve fibers. It is important to recognize that other unmyelinated fibers of the autonomic system are also likely to get affected with the small C fibers. This finding would call for more aggressive measures to control hyperglycemia on part of the treating physicians. Halting the Progression or Reversal of Neuropathy: Ref. 1-17 The discussion below emphatically underlines the role insulin sufficiency predominantly plays in tight control of hyperglycemia and the different clinical settings in which it helps mitigate the progression or reverse the neuropathy. DCCT in 9 years with intensive back up showed 50% reduction in intensive group, 3% of primary prevention group at the end showed minimal impairment versus 10% in conventional treatment group. Secondary prevention groups showed 56% reduction. (DCCT Research group 1993) Pancreas transplantation with establishment of normoglycemia prevents progression as seen in a series of 115 transplants. The motor & sensory NCV significantly increased, clinical signs and autonomic tests showed slight improvement. (Navarro et al 1997) C peptide seems useful in halting / reversing Type 1 neuropathy. Close to 100% Type 1 develop Diabetic Polyneuropathy, they are totally deficient in C peptide. It is not so in type 2 who have some C peptide. Decidedly T1 and T2 have different pathologic changes. 3 hour infusion or 3 months of injections of C peptide, improved autonomic nerve function (RR variations), as shown by Johansson BL, et al Diabetologia, 1996. 3 months subgroup analysis showed improved thermal discrimination threshold due to stimulation of Na-K-ATPase activity, better electrolyte balance, enzyme activity, endoneurial blood flow and Nitric Oxide release. Insulin therapy alone did not achieve this. (Johansson BL, et al, 2000) Double blind placebo controlled study by Ekberg et al, 2003 showed significant improvement in Sural NCV (80%), and vibration perception threshold as compared to insulin only treated group, the benefit was more marked for greater deficits at baseline, but the Peroneal motor nerve did not improve. A possible mechanism suggested is the dorsal root ganglion which is rich in Insulin Receptors, secrets cytoskeletal proteins, that flow along the axons. It is speculative whether this is a
  3. 3. 55 cause for improvement. (Sugimoto K, 2002.) The reader is requested to study these references in detail and understand the designs etc to know the promise and limitations before attempting to undertake these therapies. Experimental and only animal studies for reversing neuropathy: Following is a brief description of various studies and ideas under experiments on animals. PKC beta inhibitors in streptozotocin induced diabetic rats (STZ rats) show some promise. DAG, Sorbitol, glycation in concert finally activate the PKC beta subunit which is supposed to be the detrimental element for the development of microvascular complications. This drug has entered the phase 2 trials. Could the Receptors for Advanced Glycation End products blocked? Attempts are on to inhibit accumulation of glycation products within the axon as it increases glycation of Axonal cytoskeletal proteins like tubulin, neurofilament and actin, which may contribute to axonal degeneration and slowing of axonal transport (Ryle C et al, 1997,). Glycation of lamilin, a major constituent of Schwann cells and basal lamina, important in sprouting of nerves may cause impaired regeneration as suggested by Federoff et al, 1993. Myelin basic and proteolipid proteins also glycate and are scavenged by macrophages via RAGE leading to segmental demyelination. Nerve growth factors or NGFs: It has the disadvantage of administration by injections. Different nerve fibers have different selectivity for NGFs for particular types. Diabetes induces abnormalities in NGF receptors. Gene therapy in rats have shown some promise. Alternative approach has been attempted by using small molecules of prosapsoin derivatives acting as ligands for NGF receptors stimulating growth.(Calcutt, Tomlinson et al, Unpublished data). TX14, a similar derivative, has acute anti allodynic action in 30 minutes and 48 hours. Vasodialation or preventing vasoconstriction by Endothelin 1 antagonist in STZ rats by Cameroon and Cotter, 1996 and vasodialation by Cilostozol appear impressive in rat data. The Na+ K+ ATPase channels activity improves, improves structural myelin, improves the ratio of endoneurial and vascular area, improves Motor Nerve Conduction Velocity and cAMP activity. (Inada et al, 1996, Ushera et al, 1997, Suh et al, 1999). No human trials yet on neuropathy have been initiated. Painless Painful Feet: The symptoms have been delineated elsewhere. It is highlighted here that the pain could be present even in an otherwise insensate foot. The medical management will consist of simple analgesics like paracetamol but it does not serve for long. Other opioid analgesics that act centrally like codeine are useful but will entail a risk of addiction. Therefore caution is exercised. It is recommendation that it should not be with held in case of severe neuropathy. Bowel evacuation regimens are necessary as constipation is significant.1 One of the most frequent presentations in diabetic neuropathy is hyperesthesia and tingling. Sometimes the symptoms have a lancinating severity. These sensations are
  4. 4. 56 also considered as epileptic equivalents. The drugs that have been found clinically useful and have adequate evidence to justify their use are detailed below. It is necessary to recognize the need for multiple drugs, prolonged treatment durations and partial successes. Amitriptiline: The effective dose will generally be in the range of 75 to 150 mg per day. The anticholinergic effects are quick to develop but get ameliorated as the drug treatment progresses. Thus it is desirable to start the therapy with low doses like 10 mg at HS and increase / double the dose depending upon the tolerance of the side effects. It would normally take about 4 to 6 weeks to reach the dose of 75 to 150 mg. The treating physician will have to make the patient understand the reasons for slow process, the need for patience, the likely result of partial to substantial to full benefit, the possibility of having to add more drugs and the generally frustrating nature of the treatment of painful neuropathy.2 It is also necessary to recognize the frequently associated depression with long durations of painful neuropathy, many failed attempts for control or cure, a possibility of the lack of consistent efforts in a systematic manner. Amitriptiline has an advantage in having antidepressant potential. Reduced depression can allow greater tolerance of the syndrome. As much as drug therapy the psychological support the physicians can give can go a long way in coping with the symptoms. Nortriptiline and desipramine are alternatives with fewer sedative side effects. Fluoxetine and other selective serotonin reuptake inhibitors are not helpful. The other drugs found useful are Phenytoin, Carbamazepine, Gabapentin and Alpha Lipoic Acid. The profession has the longest and best experience with Phenytoin and Carbamazepine. These drugs may be needed in antiepileptic doses and the principle of starting with low dose and building the dosage schedule gradually will hold for both phenytoin and carbamazepine as in case of Amitriptiline. The character of pain where these drugs are most useful is the lancinating kind of pain or with electrical quality.2 Gabapentine in a dose of 300 mg up to three times a day is often used and is found to be useful. It has a more favorable side effect profile and virtually no drug interaction. Cost of gabapentine could be an issue.3 Mexiletine administered in a dose of up to 675 mg daily was associated with a significant reduction of sleep disturbances and night pain. The evidence appears strong for using it for this condition. Cardiac disease is however a contraindication. Alpha Lipoic Acid 600 mg daily as an IV infusion for three weeks has been shown to be effective in improved symptoms of pain, burning, parasthesias, and numbness in a placebo controlled double blind randomized trial.4 The mechanisms by which it is supposed to act are - Alpha lipoic acid is a thiol replenishing and redox modulating agent, has a metal chelating activity, reactive oxygen species are scavenged, endogenous antioxidants like glutathione, Vit C & E, are regenerated and repair of proteins, DNA and lipids is also helped. It stimulates skeletal muscle glucose uptake
  5. 5. 57 and changes NADH / NAD+ & GSH GSSG ratios. Currently a large trial in USA is going on. (Ziegler et al, 1995, 1997, 1999, Roy et al, 1997) There is fairly good evidence that Gamma Linolenic Acid over six months have been shown to improve the NCV and the quantitative sensory tests.5 It serves as an important constituent of neuronal membrane phospholipids, serves as a substrate of PGE2. PGE2 helps preserve blood flow to the nerves. Multi-center double blind placebo controlled trial by Keen et al, 1993, has showed significant improvement in clinical and electrophysiologic testing. Vitamin E is a powerful antioxidant in pharmacologic doses. It is the most efficient antioxidant in lipid phase - (Vinik). Pharmacologic doses of Vit E may improve defective motor nerve conduction in persons with diabetes. It reduces endoneurial lipid peroxidation that has a tendency to self perpetuate lipid Peroxidation. (Tutuncu et al, 1998) Aldose Reductase inhibitors: These drugs should have theoretically the best results as they reduce the Sorbitol levels in the nerve fiber. All the drugs tried have shown mixed results on small numbers. There is some evidence that it may improve the motor nerve conduction velocity but no other symptoms.6,7 Local Applications of Capsaicin, Lidocaine, prilocaine and non steroidal anti- inflammatory creams have all been tried but there is no consistency in the results.8 Recombinant Nerve Growth Factors have been injected subcutaneously three times a week but after initially encouraging results phase three trials have not shown any benefit.9 Topical Isosorbide dinitrates spray has been tried not as vasodilator, but as a NO donor. Spinal cord stimulation by means of TENS, PENS, NMDA channel blockers has been attempted. Motor Neuropathy: The principal problem motor neuropathy produces is weakness of the interossii and lumbricals. This is the cause of deformity of the foot. Variable weakness will result in the imbalance between these muscles which keep the shape of the foot intact. A deformed foot alters the pressure dynamics on the sole of foot and leads to development of excessively high pressure areas and breakdown of skin. Evidence to show that some reversal of the dysfunction of the various nerve fibers and or its halting / slowing down in progression is possible, there is nothing much that can be done medically for this type of abnormality. There are however the reversible motor neuropathies the physician should be aware. This will help recognize one of the frequent but undiagnosed entities like Diabetic Amyotrophy. In the more acute form it presents like a lumbosacral plexopathy with cachexia, rapidly progressive muscle weakness. The clinical picture may mimic an underlying malignant process. The important point to remember is that it is completely reversible on its own in about 18 months to 2 years. There is some evidence to shift such patients on insulin probably for its protein anabolic effects
  6. 6. 58 which will also serve for hyperglycemia. The other reversible motor neuropathy is the cranial third nerve palsy due to diabetes. Autonomic Neuropathy: The understanding of autonomic neuropathy is necessary for treating a diabetic foot, ulcerated and infected or non ulcerated since it produces a number of changes. Medical management in the form of emollients like coconut oil, Vaseline or white petroleum jelly is needed for ameliorating the dryness of the lower limbs, education to the patient to keep the feet clean since there could be heal cracks, for wearing socks for most time as it traps the moisture and can help keep the foot moist are simple measures which will help avoid ulceration. Autonomic Neuropathy is also associated with dense peripheral neuropathy, insensate foot and loss of heat and cold pain thresholds. It is necessary to instruct the patient of these compounded pathologies present. Autonomic Neuropathy is also associated with Charcot's Joint. There is significant osteopenia and fractures are likely. The surgical treatment of Charcot is complex. Medically, reducing weight bearing, protecting the foot as a high risk foot and bisphosphonate therapy, is an essential part of the management. Reversing / halting the progression of the Autonomic Neuropathy: Chronic Intermittent Intravenous Insulin Therapy has its best known effect on postural hypotension. There was a marked decrease in the intensity and frequency of postural dizziness in all subjects and complete secession of postural dizziness in two months could be achieved. Among other effects it improved circadian BP rhythms with consequent possible effects on distensibility of the arterial tree and diabetic autonomic neuropathy also as demonstrated by Thomas Oki, et al in Diabetes Technology and Therapeutics, Vol 3, Number 1, 2001, Mary Ann Liebert. Peripheral Arterial Disease: Diabetes is now recognized to have high risk of vascular complications and aspirin use is now recommended unless there is a contraindication. In that case other COX 2 inhibitors are used. The evidence in favor of concomitant use of dipyridimol has been contested. Some vascular surgeons similarly do not believe in the use of pentoxiphylline and do not recommend it. There is considerable evidence in favor of using statins in coronary artery disease for the reduction of cardiac events, as well as stabilization of plaques, anti inflammatory effects of statins. Statins are useful in presence of elevated cholesterol as well as in patients with normal cholesterol in reducing cardiac events and the benefits are supposed to be even more in persons with diabetes on sub group analysis. The peripheral arterial disease also probably benefits from statin therapy. Deformities and Ulcers: The management of these two conditions is discussed under other sections. Medical Management of Diabetic Foot Infection: Outcome of the infected foot depends upon how close coordination exists between diabetic foot surgeon, the diabetic nurse, the Bacteriologist, and the diabetologist. The special factors to be considered for the medical management are as follows:
  7. 7. 59 1. Since the diabetic patient has to off load the affected foot his exercise schedule gets completely disturbed. Therefore static isometric exercises involving the upper body and the unaffected limb need to be devised for each patient. This is important because maintenance of blood sugar is very vital for optimal outcome of the therapy. 2. Antibiotic management should be in consultation with the surgeon and the bacteriologist. It is always advisable to follow a standard protocol for each institute. This should include a proper collection of the culture from the depth of the infective tissue. It is also common to have mixed infections and it is possible to grow multiple organisms in cultures. Therefore it is normally advisable to cover with antibiotics active against Gram positive, Gram negative and anaerobic organisms also. 3. It is believed that any serious soft tissue infection of foot should be considered like the infection of Osteomyelitis elsewhere. Hence the antibiotic therapy should be prolonged. The treatment should be continued intravenously for a few days after the signs of infection have disappeared. Antibiotics should be continued orally for some more days and then stopped. Selection of proper antibiotic based on a reliable culture report is of paramount importance. The switch over from IV to oral antibiotics should be cautious. It should be ascertained that the infective pockets are drained and that adequate opening has been left for subsequent drainage to occur. 4. Anorexia, especially after the antibiotics have been discontinued is an important indicator clinically that the infection has not been completely eradicated. The wound should be then explored and fresh debridement and drainage of pus undertaken with fresh cultures and a change of antibiotic to the IV route. 5. Diet consultation: Patients with serious foot infections are in a severe catabolic state. This should be corrected by extra calories and protein. It is not unusual to find caloric deprivation even in hospital setting to keep blood sugars under control. Liberal well spaced adequate or hypercaloric diets, with aggressive insulin therapy alone can correct this state. Development of hypoalbuminimea is a serious and adverse risk factor in any serious infection, wound healing or critical state. In the now famous study of Greet Van Den Bergh the critically ill patients were given an average of 18.7 Kcal / kg diet throughout their stay. From the same study it may be noted that the insulin therapy was aggressive and the blood glucose was kept at 110 mg / dL at all time, irrespective of the patient being known or not diabetic. Insulin therapy was used if the blood glucose was higher than 110 mg / dL. This study also underlined a much less occurrence and early reversal of critical illness neuropathy compared to the less intensively treated group. Compared to the control group Greet study showed a phenomenal reduction of 42% on all cause mortality. Adequate protein supplement with iron therapy and adequate calories need to be monitored. It is necessary to keep optimal caloric intake particularly when patient is unable to take adequate solid food either because of vomiting or due to surgical or anesthesia restriction. This can be achieved by Intravenous hyperalimentation. 6. Many patients have nephropathy hence need to balance the amount of proteins depending upon the degree of renal insufficiency. In significant renal disease .6 grams per kilogram of good quality protein is recommended. In early nephropathy up to .8 gms / kilogram may be given. It is necessary to monitor electrolytes and Creatinine daily and avoid excessively salty food and one containing high concentrations of potassium, depending upon the blood pressure and potassium levels. Monitoring for both Creatinine and potassium is important, particularly if the patient is on Angiotensin Receptor Blockers or ACE inhibitors or both.
  8. 8. 60 7. Dressing material should be selected carefully taking into account the cost, duration, availability, accessibility etc. The newer dressing material like Regranex or Plermin (platelet derived growth factor) or Granulocyte Stimulating Factor (NUPOGEN) are very useful. However they need to be used judiciously. A plethora of dressing material shows that no single dressing material is proven to be useful. Properties and indications of the various dressings is discussed elsewhere. 8. Hemorrheological agents like Pentoxiphylline, Low Molecular Weight Heparin and Aspirin have been shown to be useful in severe vasculopathy, which is not amenable to revascularization. However they are more of palliative or preventive nature. If a definite vascular pathology with foot lesion and low A/B index is present and if revascularization is feasible it should be done without delay. Infrapopliteal pedal bypass has reduced the amputation rate in some of the developed countries. However, in presence of diffused atherosclerosis without open lesion and without severe ischemic pain the hemorrheological agents can be useful to prevent the loss of limb. 9. Management of vascular, neuropathic and to certain extent infective pain is necessary .This can be achieved by analgesics preferably excluding NSAID's. However the choice is limited. The opioids along with Carbamezapine and / or Amitriptiline can significantly control neuropathic and ischemic pain. In case of intractable neuropathic pain continuous epidural or paravertebral block also helps. 10. Various antioxidants are used widely. The large number of preparations available in the market can be confusing. Their usefulness ii controversial. 11. Tissue growth factors: Are currently under investigation and there may be some promise in there use in neuropathy. Management of Hyperglycemia and Infection: This issue is of particular importance when the relief of infection needs extensive surgical procedure. It is an extremely paradoxical situation. Infection in such cases is the cause of destabilization and hyperglycemia, not uncommonly ketoacidosis and or hemodynamic instability. Septicemia may threaten the involvement and failure of other organs and likelihood of death. Infections through greatly increased insulin resistance and inadequate replacement of insulin, rapidly lead to significant and serious hyperglycemia, osmotic diuresis, electrolyte imbalance, and later multiorgan failure with or without disseminated intravascular coagulation. Establishing adequate antibiotic therapy alone does not bring the infection under control especially if it is a deep seated abscess which requires drainage. Aside of the caloric supplementation alluded to above such patients need adequate fluids, electrolytes correction, establishing urine output, controlling acidosis by liberal fluid administration of appropriate composition, often blood. But the most important measure in diabetes or any significant hyperglycemia is the active aggressive insulin administration IV, on the lines advised for Diabetic Ketoacidosis. IV insulin administration should proceed quickly in the initial stages in a setting of DKA, where calories are restricted and saline insulin infusions are given under hourly glucose monitoring and doubling the rate of insulin infusion if there is less than 10% reduction in the level of blood glucose.
  9. 9. 61 The paradox occurs when hemodynamic stability is achieved, blood pH is brought to a reasonable level but the blood glucose does not settle to say less than 200mg / dL. In such situations the pocket of infection is the cause of the difficulties in getting the blood glucose settled. The treatment required to achieve normoglycemia is the drainage of infection. That is of paramount importance irrespective of blood sugar control. This issue becomes the bone of contention between the surgeon, anesthetist and the physician. Unless infection is drained it is virtually impossible for the glucose to settle. Failure to understand that leaves a patient precariously hanging on a thin thread between life and death in continued catabolic infective state, hyperglycemia and the likelihood of progressing again in septicemia, Disseminated Intravascular Coagulopathy and multiorgan failure. It is unfortunate that such situations are not occasional. Safety of a patient for anesthesia: It can be judged by the following parameters. The vitals and laboratory parameters on admission change after the interventions to bring the patient to an acceptable level of anesthesia. These changes are achieved after attempts at correction of dehydration, electrolytes, pH and hyperglycemia. They should be quantitatively assessed. If the heart rate and the respiratory rate are falling towards normal in the face of a more alert patient who has stopped vomiting, dehydration is adequately corrected so that an hourly stable urine out put of .5 ml / kg /min is established, blood pressure has risen, pH has reached 7.3 and the bicarbonates have risen to or reached 15 mm of Hg. The last in particular indicates adequacy of tissue perfusion and correction of tissue hypoxia. At this point the blood glucose in and around or more than 250 mg also does not matter for anesthesia. Safe Anesthesia: Elsewhere a detailed chapter on regional anesthesia and its safety and utility is included where these matters of safety of a patient with hyperglycemia due to infection are given. Psychological issues associated with amputations: Destruction of the self image and the growing sense of loss of freedom and dependency set the stage of depression in amputation and diabetic amputations more frequently. The role of the physician is not only to detect depression and treat it aggressively with drugs but also to support the patient with empathy and encouragement. Treating and alleviating depression is essential as greater morbidity, cardiovascular risks, higher mortality, poor compliance etc are known to be frequent in diabetic depression. Rehabilitation: Much of it is physical methods and orthotics, but a supervisory empathic role of physicians is helpful. Insulin with focus on Diabetic Neuropathy
  10. 10. 62 Insulin is the definitive replacement therapy for all types of diabetes. By definition, 'diabetes mellitus' implies the underlying pathology of inadequate insulin secretion with reference to the insulin requirement. The natural history of diabetes mellitus is characterized by a progressive deterioration in beta-cell function. Beta-cell failure can be accelerated by intracellular deposits of amylin, as reported to occur with sulfonylurea therapy, and can be prevented by exogenous insulin administration, which suppresses beta-cell function and provides rest to beta-cells. It is the only therapeutic agent that controls all grades of hyperglycemia in all cases. Thus there is sufficient evidence to use insulin as the agent of choice in the management of diabetes. Long term studies like DCCT and UKPDS have used intensive insulin therapy in their treatment arms to demonstrate a reduction in diabetes-related complications. However, implicit in these studies has been the assumption that prevention of diabetes-related complications is exclusively an indirect benefit of insulin's actions on glycemia. This, however, may not be the case. There is a possibility that lack of insulin itself and its signaling may play an important role in the development of diabetic complications. This argument is central to the concept of benefits of insulin beyond glycemic control. Insulin has been reported to possess anti-inflammatory and anti-atherogenic properties in the context of cardiovascular complications in persons with diabetes. Studies have also shown that insulin improves endothelial function as compared to oral antidiabetic drugs in persons with diabetes. Insulin has also been shown to influence pulmonary gas exchange. Studies on effects of insulin on diabetic renal complications like microalbuminuria have yielded equivocal results. There are reports in literature on the direct effects of insulin on the integrity of the nerve fibre. This review focuses on the benefits of insulin beyond glycemic control in the context of diabetic neuropathy (DN). Here we will attempt to strike a balance between some basic research and its applied clinical aspects. Incidentally, all of us are familiar with nerve conduction studies that yield information on two parameters the nerve conduction velocity or NCV and the nerve action potential amplitude or NAPA. NAPA is the more variable, but certainly a better index as it tells us more about the Fibre density in DN or diabetic poly- sensorimotor neuropathy (DSP). If we look at the clinical significance of these 2 parameters, cross-sectional and prospective studies in DN over the past decade and a half have focused on ability of risk factors to predict the presence of DSP. But the importance of these parameters was realized when other studies focused on the ability of the very same risk factors to predict the severity of DSP through these parameters of nerve conduction and nerve morphology. Tkac et al (Diabetes Care 1998; 21:17491752) proved that clinicians could also predict the severity of diabetic neuropathy in terms of NCS (Nerve conduction study) parameters based on the degree of glycemic control. They reported on the value of HbA1c in predicting the electrophysiologic severity. The sample size was small, but the analysis was robust. They used different models of severity (5 models in all) and found that HbA1c could predict severity of DN in both univariate and multivariate regression analysis. The significance held true when HbA1c was handled as both a continuous and discrete variable. Their population could be divided into poorly- and well-controlled at an HbA1c cut-off of 9%. Patients with an HbA1c of >9% had lower NCS values. The
  11. 11. 63 numbers that came out of the paper corresponded with DCCT and by adopting these criteria we can confer, what the authors called “a clinically meaningful degree of prevention (of DN)”. A subsequent paper from the same group, Perkins et al (Diabetes Care 2001; 24: 748-752) reported very similar conclusions with nerve morphology (Fiber density). These are very elegant studies that demonstrate glucose-independent effects of insulin. Brussee et al (Diabetes 2004; 53:18241830) demonstrated that Insulin signals neurons at the level of nerve cell bodies (Perikarya, the dorsal root ganglia /DRG neurons) and exert distal axon-protective effects. They proved the trophic nature of insulin in terms of a direct support for neurons and peripheral axons. Also in low doses insulin reversed conduction slowing (abnormal function) and axonal atrophy (abnormal structure). Insulin was used in sub-hypoglycemic doses proving its benefits independent of glycemic control. A second study from the same group: Zochodne et al (Brain Oct 2004) demonstrated that insulin could preserve the integrity of the structural lattice of axons. This group superimposed STZ-diabetes on a neurofilament-deficient mouse to test the hypothesis whether insulin could reverse this phenotype. Diabetic mice lacking neurofilaments showed a decline in NCV and NAPA between 4 and 8 weeks of diabetes. The administration of insulin led to an immediate reversal of the defect. We all know the crucial role of mitochondria in cells affected by diabetes. Huang et al (Diabetes 2003; 52:21292136) showed that Insulin could preserve the integrity of mitochondria in neurons affected by diabetes. The mitochondrial depolarization was measured by special techniques and the increase or decrease of fluorescence triggered by exposure to a substance known as CCCP was monitored. Mitochondria play an important role in calcium intracellular homeostasis thus contributing to the preservation of physiological ionic fluxes. This study showed that while diabetes increased intracellular calcium, insulin reversed the effect. This experiment also proved that the effects of insulin were glucose-independent. Chronic Intermittent Intravenous Insulin Therapy or CIIIT has been tried on the rationale that pulsatile insulin infusions, may improve portal hepatic venous insulin levels, thereby normalizing Respiratory Quotient in persons with Diabetes. The study was conducted by using a biostator. It was argued that conceivably several days of hyperinsulinimic normoglycemic clamp could do the same. Thomas Oki, et al in Diabetes Technology and Therapeutics, Vol 3, Number 1, 2001, Mary Ann Liebert) In the now famous study of Greet van den Bergh in critically ill patients where blood glucose was rigidly controlled to 110 mg / dl in intensive group, critical illness neuropathy developed in less number, and if it occurred it took shorter time to ameliorate and reverse. In summary, insulin signals neurons directly and has distal protective effects. It prevents axonal loss and atrophy through non-neurofilament related actions. It also prevents depolarization of mitochondrial membrane in sensory neurons. All these point towards the benefits of insulin beyond glycemic control in the context of DN.
  12. 12. 64 References for Halting or Reversing the Neuropathic Changes: 1. Vinik AI, Erbas T, Stansberry KB, Pittenger GL. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus Exp Clin Endocrinol Diabetes. 2001; 109 Suppl 2:S451-73. 2. Greet Van Den Bergh, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. 3. Ziegler et al, 1995, 1997, 1999, Roy et al, 1997 : Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 Dec; 38(12):1425- 33. 4. Ziegler et al, 1997: Ziegler D, Gries FA Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997 Sep; 46 Suppl 2:S62-6. 5. Ziegler et al, 1997: Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie.Diabetes Care. 1997 Mar; 20(3):369-73. 6. Ziegler et al, 1999: Ziegler D, Reljanovic M, Mehnert H, Gries FA Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30. 7. Roy et al, 1997 . 8. Inada et al, 1996, Ushera et al, 1997. 9. Suh et al, 1999: Suh KS, Oh SJ, Woo JT, Kim SW, Yang IM, Kim JW, Kim YS, Choi YK, Park IK. Effect of cilostazol on the neuropathies of streptozotocin-induced diabetic rats. Korean J Intern Med. 1999 Jul; 14(2):34-40. 10. Cameron NE, Cotter MA, Comparison of the effects of ascorbyl gamma-linolenic acid and gamma-linolenic acid in the correction of neurovascular deficits in diabetic rats. Diabetologia. 1996 Sep; 39(9):1047-54. 11. Cameron NE, Cotter MA, Interaction between oxidative stress and gamma-linolenic acid in impaired neurovascular function of diabetic rats. Am J Physiol. 1996 Sep; 271(3 Pt 1):E471-6 12. Cameron NE, Cotter MA, Effects of a nonpeptide endothelin-1 ETA antagonist on neurovascular function in diabetic rats: interaction with the renin-angiotensin system. J Pharmacol Exp Ther. 1996 Sep;278(3):1262-8. 13. Thomas Oki, et al in Diabetes Technology and Therapeutics Vol 3, Number 1, 2001, Mary Ann Liebert; Aoki TT, Grecu EO, Arcangeli MA, Benbarka MM, Prescott P, Ahn JH. Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy. Diabetes Technol Ther. 2001 Spring;3(1):111-23.
  13. 13. 65 14. Calcutt, Tomlinson et al, Unpublished data. 15. Johansson BL, et al Diabetologia, 1996 : Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J. C-peptide improves autonomic nerve function in IDDM patients.Diabetologia. 1996 Jun;39(6):687-95. 16. Johansson BL, et al, 2000: Johansson BL, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J, Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus. Diabet Med. 2000 Mar;17(3):181-9. 17. Sugimoto K 2002. 18. Ryle C, Leow CK, Donaghy M. Nonenzymatic glycation of peripheral and central nervous system proteins in experimental diabetes mellitus. Muscle Nerve. 1997 May; 20(5):577-84. 19. Federoff et al, 1993: Federoff HJ, Lawrence D, Brownlee M. Nonenzymatic glycosylation of laminin and the laminin peptide CIKVAVS inhibits neurite outgrowth. Diabetes. 1993 Apr;42(4):509-13. Additional References for Treating Neuropathy and its Symptoms: 1. Kumar D, Marshall HJ. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care, 1997; 20:1702-5. 2. Mcquay H, Caroll D, Jadad AR, et al. Anticonvulsant drugs for management of Pain: a systematic review. BMJ, 1995; 311:1047-52. 3. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic Treatment of painful neuropathy in patients with diabetes mellitus. A randomized controlled trial. JAMA 1998; 280:1831-6. 4. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine study group. Diabetes Care 1997; 20:1594-7. 5. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma- linolenic acid. The Gamma-Linolenic acid multicenter Trial group. Diabetes Care 1993; 16:8-15. 6. Nicolucci A, Carinci F, Cavaliere D, et al. A meta analysis of trials on aldose reductase inhibitors in diabetic peripheral neuropathy. The Italian Study Group. The St.Vincent Declaration. Diabet.Med 1996; 13:1017-26. 7. Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes 1997; 46(suppl.2):S82-9. 8. Donofrio P, Walker F, Hunt V, et al. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Capsaicin study group. Diabetes Care 1992;15:159-65.
  14. 14. 66 9. Apfel SC, Kessler JA, Adornato BT et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF study group. Neurology 1998; 51:695-702.

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