Epidemiology
Diabetes mellitus is characterized by high blood glucose (hyperglycemia) which can be due to: a) decreased production of insulin (called Type I diabetes mellitus) due to destruction of the pancreas on an autoimmune basis or b) decreased peripheral sensitivity to insulin (called type II which also has some decreased production of insulin by the pancreas) associated with obesity and lack of physical activity. Only about 5-10% of the total have type I disease, the rest have type II.
The most recent statistics available (2005) reveal 20.8 million people (7% of the population) with diabetes of which 14.6 million were actually diagnosed leaving 6.2 million unaware of the presence of this serious disease. Moreover, its prevalence has increased 40% in the last decade and is expected to increase by 165% between 2000 and 2005 (figure 1). It has been estimated that fully 1/3 of the population born in 2000 will develop diabetes. In addition to patient suffering and disability, the economic impact in direct and indirect costs is enormous, amounting to $132 billion in 2002 representing 1/10th of all health care costs.
There were 224,092 deaths attributable to diabetes in the USA in 2002 (probably an underestimation). The risk for death in patients with diabetes is twice that for people of the same age without diabetes, and this decreased longevity is due to cardiovascular disease. Diabetes increases the risk of heart disease and stroke 2-4 fold over that for people without diabetes. Its microvascular complications of retinopathy, nephropathy, and neuropathy make diabetes mellitus the leading cause of blindness, end-stage renal disease, and non-traumatic lower extremity amputations in the U.S.A.2 The frequency of the last complication is increasing (figure 2).
Pathogenesis
The macrovascular and microvascular complications of diabetes are closely related to hyperglycemia and oxidative stress, which is when cells fail to detoxify the reactive oxygen species (ROS) produced during metabolism. Four hypotheses have been proposed to explain how hyperglycemia causes complications: 1) increased polyol pathway flux, 2) increased intracellular formation of advanced glycation end-products (AGE), 3) activation of protein kinase C (PKC) isoforms, and 4) increased flux through the hexosamine pathway.
A unifying concept is that hyperglycemia-induced mitochondrial superoxide overproduction activates these 4 pathways. Excess superoxide partially inhibits the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) thereby diverting upstream metabolites from glycolysis to pathways of glucose over-utilization. Superoxide anion achieves this by causing DNA strand breaks that result in activation of poly ADP ribose polymerase (PARP) which in turn ribosylates and deactivates GAPDH. By preventing their metabolism, this process increases energy substrates resulting in increased flux of dihydroxyacetone phosphate (DHAP) to diacylglycerol (DAG), an activator of PKC, and of triose phosphates to methylglyoxol, which is the main intracellular AGE precursor. Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine in the hexosamine pathway increases modification of proteins by O-linked N-acetylglucosamine and increased glucose flux through the polyol pathway consumes the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and depletes GSH (reduced glutathione, a natural potent anti-oxidant).
Several mechanisms have been postulated to explain why increasing the polyol pathway flux is detrimental. These are sorbitol-induced osmotic stress, decreased (Na++K+) ATPase activity, increased cytosolic NADH/NAD+ and decreased cytosolic NADPH.
Activation of the hexosamine pathway results in intracellular glycosylation and donation of N-acetyl glucosamine to serine and threonine residues of transcription factors such as Sp1 resulting in increased production of factors such as plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor beta 1 (TGF-beta 1).5
Production of intracellular AGEs damages target cells by three mechanisms. Intracellular proteins modified by AGEs have altered function (like neurotropism, axonal transport, and gene expression). Secondly, extra-cellular matrix components modified by AGE precursors interact abnormally with other matrix components and with the receptors for matrix proteins (integrins) on cells. Thirdly, plasma proteins modified by AGE precursors bind to AGE receptors (RAGE) on endothelial cells, mesangial cells, and macrophages inducing receptor-mediated production of ROS as a second messenger to activate the nuclear factor kappa B (NF-kappa B), a transcription factor causing pathological changes in gene expression.5
Hyperglycemia-induced activation of PKC has a number of pathogenic consequences by affecting expression of endothelial nitric oxide synthetase (eNOS), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), TGF-beta 1, and PAI-1, and by activating NF-kappa B and NAD(P)H oxidases. Increased eNOS and decreased ET-1 decrease blood flow causing hypoxia. Increased VEGF causes increased vascular permeability and angiogenesis. Increased TGF-beta leads to increased collagen, fibronectin, extra-cellular matrix, and basement membrane resulting in capillary occlusion. Increased PAI-1 decreases fibrinolysis leading to vascular occlusion. Increased NF-kappa B causes an increase in pro-inflammatory gene expression. Increased NAD(P)H oxidase causes increased ROS (resulting in DNA damage, oxidation of polydesaturated fatty acids in lipids, and oxidation of amino acids in proteins). These pathogenic mechanisms can all be characterized as a result of ROS effects on genes and proteins.5
Diabetic Skin
The skin of the diabetic is prematurely aged and is subjected to the problems of neuropathy, macrovascular disease, and microvascular disease. In addition, diabetes is associated with poor wound healing, susceptibility to infection, and decreased cell-mediated immunity. This battle may go on unrecognized to the naked eye and dictates a keen vigilance by both doctor and patient to prevent the dreaded complications of this disease. The struggle is against oxidative stress and inflammation, ischemia and necrosis.
Clinical manifestations
1. Diabetic dermopathy is the most common dermatological manifestation of diabetes and is due to microvascular changes. Because it is associated with but not specific for diabetes mellitus, it serves as a marker for the disease. This dermopathy is most often seen in diabetic men over the age of 50 but may also be seen in euglycemic diabetics and healthy individuals. The lesion is so named because of typical changes in the microvasculature. Irregularly shaped patches of skin with a depressed surface are found primarily over the anterior aspect of the lower legs but may occur on the upper arms and thighs and over bony prominences. The lesions are light brown in color due to extravasated red blood cells and deposition of hemosiderin in histiocytes. They appear in crops and resolve over 12-18 months. Since the lesions are asymptomatic, no specific treatment is required except to protect the area from trauma and secondary infection.
2. The skin of the diabetic foot is usually dry due to decreased sweating as a result of the autonomic neuropathy of diabetes. Sweating normally helps hydrate the stratum corneum, and dry skin is prone to callus formation with cracking and fissuring.
3. The “diabetic foot” is due to neurovascular and ischemic changes. It is a very serious complication of this disease. Loss of sensation means that the diabetic patient is no longer able to sense and avoid injuring agents in the environment. Thermal trauma can have horrific results. Even minor mechanical trauma to the skin of the diabetic foot can result in blisters, sores, and ulcers. This is compounded by motor loss to the intrinsic muscles of the foot leading to deformities including a high plantar arch and “hammer toes.” Bony prominences are created at the heel, toes, and metatarsal heads that become pressure points over which the skin can break down. This can lead to ulceration; infection of skin, soft tissues, and bone (osteomyelitis); gangrene (which can be either “wet” due to necrosis with infection or “dry” due to necrosis without infection); and ultimately amputation. The skin over pressure points can become thickened as a callus or corn or develop blisters that can get infected. The skin between the toes can become macerated which fosters secondary infection by bacteria and fungi. The bones of the feet can degenerate producing fractures (Charcot foot). One dreaded complication from this is a “rocker-bottom foot” that often results in skin breakdown and infection. A “diabetic foot” is usually asymptomatic until late in the game. Special attention is required: the patient should inspect his or her feet daily to avoid the complication, and a physician with expertise in this field is required for optimal results.
Treatment:
Control of hyperglycemia: The first step in controlling hyperglycemia in type II diabetics is diet and exercise. Then oral hypoglycemic agents are added of which there are many. Ultimately, insulin may be required by injection. Insulin is the first therapeutic step in type I diabetics. Unfortunately, control of blood glucose is difficult particularly in type II patients probably related to poor compliance. It is at this level that the patient can be most helpful. Make sure the patient takes control of their blood glucose, exercises, has proper diet, attends to their skin, and uses appropriate medications. Patients should check their blood sugar often and their feet daily. The best results come from treatment based on pathogenesis, and prevention is the name of the game.
Pharmacology
Corneotherapy is made possible by what is known as the 500 Dalton Rule. The 500 Dalton Rule is used in the development of topical drugs and trans-dermal delivery systems. The skin’s barrier is effective in blocking molecules with an atomic weight more than 500 Daltons, but molecules of less weight pass through the skin’s barrier. Topical drugs like cyclosporine, tacrolimus, and ascomycins can be effectively delivered through the skin because the molecules of these drugs are all smaller than 500 Daltons.
While the stratum corneum’s physicochemical barrier resists the penetrations of large molecules, smaller molecules with a molecular weight of less than 500 Daltons pass transcutaneously. Molecular size is an important factor governing passage of substances through the skin, giving substances with higher molecular weights self-limiting properties. Passive delivery of substances, due to their low molecular weight, provides novel delivery opportunities. Included in these low molecular weight substances are vitamins, amino acids, ?-3 and ?-6 essential fatty acids, and antioxidants like hydroxytyrosol.
Instructions for Patients to Prevent Diabetic Foot Problems
You should start taking good care of your feet. Set a time every day to check them. Now is the time for you to play an active role in your health care with these 10 steps:
1.Test your blood glucose often. Work with your health care team to keep your blood glucose in your target range with proper diet and exercise.
2.Avoid foot problems by early detection of changes before they get worse. Look at your bare feet daily for red spots, cuts, swellings, and blisters. If you cannot see the bottoms of your feet, use a mirror or ask someone for help.
3.Get active. Plan your physical activity program with your health care team.
4.Get informed. Ask your doctor about Medicare coverage for special shoes (orthotics).
5.Wash (not soak) your feet every day in lukewarm water and dry them carefully, especially between the toes.
6.Keep your skin soft and smooth. Rub a thin coat of skin cream over the tops and bottoms of your feet, but not between your toes.
7.If you can see and reach your toenails, trim them when needed. Trim your toenails straight across and file the edges with an emery board or nail file.
8.Wear shoes and socks at all times. Never go barefoot. Wear comfortable shoes that fit well and protect your feet. Check inside your shoes before wearing them. Make sure the lining is smooth and there are no objects inside.
9.Protect your feet from hot and cold. Wear shoes at the beach or on hot pavement. Don't put your feet into hot water. Test water before putting your feet in it just as you would before bathing a baby. Never use hot water bottles, heating pads, or electric blankets. You can burn your feet seriously without realizing it.
10.Keep the blood flowing to your feet. Put your feet up when sitting. Wiggle your toes and move your ankles up and down for 5 minutes, two (2) or three (3) times a day. Don't cross your legs for long periods of time. Don't smoke!
Remedy® Description:
Clinical Pharmacology: The active ingredient in these preparations is dimethicone 1.5% that protects the skin. Olivamine® is a patent pending blend of antioxidants and anti-inflammatory agents that helps repair cell membranes and restore cells to a healthy state. Olivamine® contains the following:
Hydroxytyrosol
3,4-dihdroxyphenylethanol (hydroxytyrosol: DOPET) is the major component in the phenolic fraction of olive oil. It is a hydro-soluble and lipid soluble molecule that is an efficient scavenger of peroxyl radicals. Experiments demonstrate that DOPET effectively counteracts the cytotoxic effects of reactive oxygen species (ROS) in various human cellular systems. In studies using DOPET pre-incubated cells, it was found that damage due to oxidative stress, such as lipid peroxidation and alterations of cell permeability, could be prevented and that DOPET exerted a protective effect against H2O2 induced oxidative hemolysis.
Glycine
Altering cellular osmolality to a hyperosmotic state results in a decrease in adenosine triphosphate (ATP) allied with necrosis and resultant necrosis. Glycine is a cytoprotectant against injury by ATP-depletion. Glycine protects ATP-depleted cells by low affinity interactions with multimeric channel protein, stabilization of which may other wise lead to formation of pathological pores. Such porous defects in membranes of ATP-depleted cells have been characterized recently, showing definable exclusion limits for molecules of increasing sizes. Glycine provided during ATP-depletion blocked the development of membranous pores completely. The relationship between necrosis and an extracellular depletion of ATP makes its protection and restoration imperative during the prelethal stages of necrosis or early necrosis.
L-Taurine
L-Taurine can act as a direct antioxidant that scavenges or quenches oxygen free radicals intracellularly to block ROS mediated cell death. The beneficial effects of the ROS-scavenging capacity of L-taurine include attenuation of lipid peroxidation, reduction of membrane permeability, and inhibition of intracellular oxidation in different cells. Taurine prevents high glucose induced apoptosis in endothelial cells thru ROS inhibition and stabilization of intracellular calcium. Apart from its effect on antioxidant defense, L-taurine also functions as a principle modulator of intracellular Ca2+ homeostasis.
N-Acetyl-L-Cysteine
In research conducted by the Department of Microbiology and Immunology, SUNY Buffalo School of Medicine, Buffalo, NY, and the Free Radical & Radiation Biology Program, Department of Radiation Oncology, the University of Iowa, Iowa City, Iowa, we investigated the hypothesis that NAC-induced free radical-signaling delays G0/G1 cells progression to S phase by regulating the cell cycle regulatory protein cyclin D1 and the free radical-scavenging enzyme manganese superoxide dismutase (MnSOD). Treatment with NAC resulted in increased cellular glutathione levels indicating a shift to a more reducing environment. This shift in cellular redox environment was associated with delayed progression from G0/G1 to S. NAC treatment resulted in a decrease in cyclin D1 and an increase in MnSOD protein levels. The absence of NAC-induced G1 arrest in fibroblasts over-expressing cyclin D1 (or a non-degradable mutant of cyclin D1-T286A) indicates cyclin D1 regulates this delay in G0/G1 to S progression. These results support the hypothesis that cellular redox environment regulates cellular proliferation via regulating cell cycle regulatory protein levels. Furthermore, our results also suggest that inclusion of NAC in skin care formulations might help in appropriate wound healing by controlling proliferation and preventing scarring.
L-Proline
DNA synthesis is a vital part of cell life. In studies done in vivo and in vitro, L-proline was found to be the only amino acid that was involved in the stimulation of DNA synthesis. Further, epidermal growth factor (EGF) elicited no response without the addition of L-proline. Proline-deficient media such as Leibovitz’s L-15, Eagle’s minimal essential, and Dulebecco’s modified minimal essential did not induce DNA synthesis. However, using media such as Williams E, McCoy’s 5A and Ham’s F-12, which are rich in L-proline, there was DNA synthesis and marked proliferation. L-Proline is essential for the induction of cellular proliferation in vivo and in vitro through its effect on synthesis of intracellular collagen.
Vitamin B6 (Pyridoxine)
The term vitamin B6 is used to describe all biologically inter-convertible forms of pyridoxine including pridoxine, pyridoxal, pyridoxal 5-phosphate, and pyridoxamine. Vitamin B6 is an essential co-factor in numerous enzymatic reactions involved primarily in amino acid metabolism. In addition, vitamin B6 functions as an antioxidant by interacting with singlet molecular oxygen during oxidative stress.
Vitamin B3 (Niacinamide)
Niacinamide is a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD+) used to generate ATP in the mitochondrial electron-transport chain. Niacinamide is involved in DNA integrity and maintains phosphatidylserine membrane asymmetry to prevent cellular inflammation and phagocytosis. Current research demonstrates that niacinamide prevents the induction of caspase-8, caspase-1, and caspase-2 activities during cellular injury. The cytoprotectant effects of niacinamide are involved in the maintenance and preservation of cellular membranes.
Methylsulfonylmethane (MSM)
Methylsulfonylmethane (MSM) is a naturally occurring organic compound containing 34% elemental sulfur. Sulfur is critical in the formation of collagen. The flexibility of bonds between cells, including skin, is dependent upon sulfur. MSM provides a bioavailable from of sulfur and supports the body’s ability to produce N-acetyl-L-cysteine and L-taurine that are sulfur-containing amino acids. MSM is an important volatile component in the sulfur cycle. Topically applied MSM is keratolytic through the formation of hydrogen sulfide. MSM aids in wound healing via keratin. Compounds containing sulfur are found in all body cells and are indispensable for life. Low levels of MSM are implicated in slow wound healing.
Indications and Usage
Remedy® with Olivamine® temporarily protects and helps relieve chapped or cracked skin in patients with dry skin or diabetes mellitus. It is useful in prevention of skin complications from diabetes.
Contraindications
Do not use products on deep or puncture wounds, animal bites, or serious burns.
Warnings
These products are recommended for external use only.
Precautions
When using this product do not get into eyes. Stop use and ask a physician if the condition worsens, symptoms last longer than 7 days, or symptoms clear up and then return within a few days. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Protect the products from freezing and excessive heat.
Adverse Reactions
An allergic skin rash is possible with any of the components. If redness, itching, or hives occur, stop the product and seek medical care.
Dosage and Administration
Apply cleansing lotion to wet or dry skin and rub gently. Rinse or wipe with a moistened cloth. The cleanser acts without lathering. Apply the cream liberally until the entire area is covered. Both the cleansing lotion and the repair cream can be used as needed.
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