Diabetic Skin: targeted soothing and support

Introduction

In 2014, the prevalence of diabetes-linked pathologies was estimated to be of the order of 420 million worldwide, up from 108 million in 1980 ⁽¹⁾. That is to say that one person out of sixteen is suffering from a diabetic pathology. In particular, the prevalence of diabetes in adults over 18 years of age has nearly doubled (8.5% in 2014, up from 4.7% in 1980) and remarkable prevalence peaks, twice as much as the world average, are observed in the Eastern Mediterranean regions.

It is well known that the skin of diabetic patients presents specific pathological symptoms and needs careful and specifically targeted treatments. As a matter of fact, soothing diabetic skin is relevant both from the esthetic as well as from the functional point of view. Successful treatments can be delivered whenever the diagnostics allows an accurate classification of the different manifestations of the disease. As usual, prevention is to be preferred to the repairing intervention, particularly so because of the hyper-reactivity of the cutaneous structures involved in the process.

In this paper we will not discuss the systemic consequences of the diabetic pathology and we will address only the cutaneous aspects of diabetes seen as the outcome of a generalized meiopragic status. In spite of our focus, we feel that it is not unnecessary to maintain that the primary pathology needs to be treated with the appropriate medical therapies and must be accompanied by fitting physical activities under medical control and by an accurate organization of one’s lifestyle to avoid behaviors that might worsen the effects of the disease. As a matter of fact, in diabetic patients glucose metabolism is altered and this leads to protein glycation, impairing of enzymatic activities, micro-angiopathy, atherosclerosis, neuronal degeneration and life threatening necrotic phenomena.

The most frequently observed cutaneous modification in diabetic patients is accelerated skin aging, ranking from moderate to severe. This is likely to be the consequence of a disorganization of the dermal extracellular matrix, affecting mainly collagen and fibronectin. This is the consequence of the increased activities of collagenases such as Matrix Metallo Proteinases MMP-1 and MMP-2 (gelatinase A), and of Lysil Oxydase (LOX) that catalyzes the cross-linking of collagen microfibrils and it is believed that the increased activity of these enzymes be the consequence of the impaired glucose metabolism ⁽²⁾.

This is in keeping with what is observed in diabetic skin: fragmentation and disorganization of the scaffold of the dermal structures with concomitant loss of the typical dermal characteristics such as resistance to deformation, resilience after deformation and elasticity. The epidermis of the diabetic does not present with direct structural damage visible in microscopy. Yet it is affected by the damages and by a de-structured dermis that slow down the transport of water as well as the nutritional support needed to correctly perform the keratinization process The consequence of this is the aged and withered aspect of the epidermis ⁽³⁾.

In this paper we shall describe the cutaneous phenomenology in the diabetic and we shall discuss topical interventions for diabetic skin. Appropriate interventions will consist of excipients and active ingredients that are non-toxic to cutaneous enzymes, non-oxidant, non-irritant, with chemical affinities to sebum and that are devoid of negative effects on the biochemical and physiological pathways pertaining to skin structure and functions.

Diabetic Skin

Cutaneous manifestations are known to accompany both insulin-dependent and insulin-independent diabetes mellitus. Often, the clinical observation of one of these manifestations can be of help for the diagnosis of diabetes. These manifestations can be classified into ten major categories ⁽⁴⁾. These categories are: Necrobiosis lipoidica diabeticorum, Acanthosis nigricans, Diabetic dermopathy, Diabetic bullae, Yellow skin and nails, Diabetic ulcers, Diabetic cutaneous infections, Perforating dermatosis, Eruptive Xanthomas, and a broader category Other Dermatoses. The etiology of these manifestations is unknown and no established therapy is at hand.

In recent years, the hypothesis has been put forward that the accumulation of advanced glycation endproducts (AGE) might play a major role in the onset of the pathology of diabetic complications^{(5, 6)}.

AGEs are the result of the non-enzymatic glycation, i.e. of the “spontaneous” binding of sugar molecules to free amino groups in proteins. Because of the elevated levels of serum glucose, the rate of formation of AGE can be expected to be larger in diabetic patients than in healthy individuals. The physiological consequences of this binding are manifold.

On the one hand, glycated proteins could have impaired enzymatic activities, i.e. when the glycation occurs in the active site, the enzyme might not be able to perform its catalytic activities at the normal rate. On the other hand, glycation can affect the structural role of fibers by introducing steric distortions in otherwise well-organized structures, and the extracellular matrix might lose its structural functions and properties. Last but not least, glycated proteins acquire a pro-inflammatory status ⁽⁷⁾ and therefore trigger the recruitment of immune cells from the blood vessels, the consequent oxidative steps and the degradation of dermal elastic fibers by activated matrix metallo-proteinases and myeloperoxidases and are associated to an increased rate of skin
aging^{(8, 9)}. Glycation phenomena in diabetic skin have been recently summarized⁽¹⁰⁾ and the effect of protein glycation and of Advanced Glycation Endproducts on skin aging is being consistently confirmed⁽¹¹⁾.

The phenomena that can be expected to arise because of accumulated AGE are in keeping with the observed large disorganized collagen bundles in the thickened dermis of diabetic scleroderma as well as with the destruction of the anchoring fibrils and the cleavage of the lamina lucida observed in diabetic bullae.

Last but not least, AGE accumulation can account for both the thickening of the vascular walls and the longitudinal fraying and splitting of elastic fibers and of their disruption into small fragments in the skin of diabetics^{(12, 13)} that are reminiscent of the structural changes observed during skin aging⁽¹⁴⁾.

The accumulation of AGE in diabetic skin has been reported since the end of last century(15, 16). The formation of pentosidine, an Advanced Glycation Endproduct, most likely the first of chemically characterized AGEs, has been shown to correlate with the severity of the diabetic complications in individuals with insulin dependent diabetes mellitus for more than 17 years⁽¹⁷⁾.

It was subsequently pointed out that skin auto-fluorescence correlates quantitatively with the accumulation of AGE⁽¹⁸⁾ and several clinical observations have been reported indicating a correlation between high skin auto-fluorescence and the severity of diabetes-accompanying manifestations such as retinopathy⁽¹⁹⁾ or nephropathy⁽²⁰⁾ or diastolic functions⁽²¹⁾.

These observations seem to point out a causative relationship between the presence of AGE in the skin and the manifestations in diabetes.

The observation that injections of Streptozotocin can induce diabetes in rats⁽²²⁾ opened a path to the experimental exploration of the mechanisms involved in the onset of the cutaneous manifestations that accompany diabetes and to test the hypothesis that the accumulation of AGE is causally linked to the appearance of these manifestations, or of part of them. Indeed, it had been reported that the accelerated accumulation of advanced glycation end products in diabetic rats was prevented by oral administration of curcumin, as was the formation of cross links in the collagen of the tail tendon⁽²³⁾.

Studies on endogenous skin lesion in artificially diabetic rats show that 12 weeks after receiving intraperitoneal streptozotocin, male Sprague Dawley rats exhibited decrease of skin thickness, disappearance of the multilayer skin epithelium structure, degenerescence of skin collagen fibers and an increase in infiltration of inflammatory cells⁽²⁴⁾.

This seems to indicate that the formation of AGE is a crucial mechanism of diabetes-induced early-stage endogenous skin damage since it was known that treatment with insulin improved latent skin lesions in Streptozotocin-induced diabetic rats⁽²⁵⁾.

It thus appears that diabetic skin is subjected to an accelerated accumulation of AGE, and that this triggers the mechanisms leading to the cutaneous manifestations associated to diabetes. It seems therefore plausible to try and treat diabetic skin with specific soothing agents able to reduce the rate of formation and accumulation of Advanced Glycation Endproducts, as well as to improve the loss of elasticity and of moisture that are observed in this pathology.

Possible effective interventions

AGE occur in different tissues of the human body. The ones occurring within blood vessels and arteries have been investigated with particular emphasis because of their potential harmful role in the onset of atherosclerosis, with the aim of finding drugs able to undo the AGE and restore sclerotic arteries to the statu quo ante. As of today the therapeutically acceptable removal of Advanced Glycation Endproducts has proven impossible.

To preserve and prolong health in the organs of the human body, and particularly of the skin, against the threat of glycation it is therefore necessary to devise a multi-prong strategy, to avoid the onset of the mechanisms leading to the consequences described above. This strategy could consist of topical treatments to prevent the formation of Schiff bases between free sugars and free amino-groups of skin proteins, and their conversion to Amadori products and eventually to AGE, together with anti-inflammatory substances, agents able to stimulate the production of the Natural Moisturizing Factor and the synthesis of the collagens in the basement membrane.

A panoply of substances are known to hinder the process of glycation. Their mechanisms of action can be as different as the scavenging of reactive Oxygen species, the chelation of transition metals, the reduction of the concentration of free sugars, the destabilization of the Schiff bases etc. Several vegetal derivatives inhibit the glycation of proteins in vitro and in vivo⁽²⁶⁾ and oral curcumin was shown to have such an activity in diabetic rats⁽²³⁾. A new candidate is LR-9, a methylene bisphenylureido derived compound. It scavenges dicarbonyl intermediates and chelates transition metals that catalyze the production of AGE. It inhibits AGE formation when orally administered to rats⁽²⁷⁾. Another possible route to reduce the rate of glycation could be the topical application of oligo-peptides with free amino groups (such as oligo-lysine) that could bind free sugar and therefore decrease the concentration of free sugar and therefore reduce the rate of glycation of skin proteins. Other ingredients are endowed with the capability of hindering or inhibiting the formation of AGE, such as the following, which can be successfully used for this purpose thanks to their remarkable anti-lipoperoxidant and bio-regulating actions:

Filagrinol^®, a mixture of pollen extract and of unsaponifiable fractions from soybean oil, olive oil and wheat germ oil with a strong protective action against oxidation, Salycuminol^®, a local cutaneous modulator of skin inflammatory response with antilipoperoxidant and keratoplastic action, Trioxene-LV^®, an anti-free radicals and anti-lipid peroxidation ester of citric acid and ACS-AntiCytoStressor^®, a fractional phytoderivative, physiological bioregulator of stress hormones.

Since AGE-carrying proteins have been shown to be pro-inflammatory ⁽⁷⁾ and since the micro-inflammatory pathway has been pointed out to be the single most efficient mechanism of skin
aging^{(8, 9)}, the topical application of anti-inflammatory substances is expected to alleviate the onset of the inflammation-derived cutaneous manifestation in diabetes. Appropriate inflammation response modulators can be formulated for topical treatments targeting the oversized inflammatory response met in diabetic skin, such as Salycuminol^®.

Another aspect of the cutaneous manifestation in diabetes is skin dryness. This could be the consequence of random glycation of the proteolytic enzymes whose action is necessary to the degradation of filaggrin and the consequent production of the Natural Moisturizing Factor. It is known that the topical application of Filagrinol, (an activator of the production of filaggrin) has significant effects on the level of hydration and comfort of the skin⁽²⁸⁾.

Hydrating products such as Hyaluramine-S^®, an active precursor of hyaluronic acid improving deep moisturization, Dermonectin^®, a low molecular weight precursor of fibronectin, cutaneous moisturization functionalizer and Filagrinol^®, increasing the NMF-Natural Moisturizing Factor, that can be used at an advantage to temperate the dryness of diabetic skin.

Last but not least, it is known that diabetic skin has a brittle aspect (not to be confused with brittle diabetes!) and this may be the consequence of impaired structural functions of glycated collagen IV and VII in the basement membrane. The turnover of collagen IV and of collagen VII is quite rapid and the time for half renewal of Collagen VII in mice is of the order of a few weeks⁽²⁹⁾. It is therefore not unreasonable to envision a strategy to increase the rate of production of these collagens to accelerate the removal of glycated molecules and therefore reducing the time of persistence of glycated collagens in the basement membrane and concomitantly improve the elasticity of the epidermis. Enhancers of the synthesis of collagens can be used to partially restitute resilience and elasticity to diabetic skin.

Among these enhancers one finds Collagenon^®, a low molecular weight precursor of collagen that supports, renews and restructures collagen structure and Aminoefaderma^®, a balanced mixture of poliproline and E.F.A. with elasticizing and eutrophic effects that promotes the development of new collagen fibrils to improve skin resiliency,

In addition, it is known that diabetic skin is prone to bacterial infections, is sensitive to abrupt temperature changes, is hypersensitive to solar radiation and is subjected to photo-toxicity, and also that it is susceptible to hyperpigmentation and permissible for lipid accumulation, in particular of B-carotene. For these manifestations too, appropriate ingredients are at hand⁽³⁰⁾.

The table hereunder displays the dermal pathologies associated with diabetes, their anatomical sites of manifestation, the type of associated lesions, the structural and physiological consequences of the pathology as well as the suggested ingredients for topical application.

References

1. Global Reports on Diabetes, 2016

2. Argyropoulos AJ, Robichaud P, Balimunkwe RM, Fisher GJ, Hammerberg C, Yan Y, Quan T (2016) Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged‐Appearing Skin, PloS One 11, 2016 April 22, e0153806

3. Sakai S (2017) Dry Skin in Diabetes Mellitus and in Experimental Models of Diabetes. in : MA Farage, KW Miller, HI Maibach (Editors) Textbook of Aging Skin, Springer, 2017 pages 991-1002

4. Chakrabarty A, Norman RA, Phillips, TY (2002). Cutaneous Manifestations of Diabetes. Wounds: 14 (8)

5. De Groot J (2004) The AGE of the matrix: chemistry, consequence and cure. Curr Opinions in Pharmacol. 4:301-305

6. Ahmed, N (2005) Advanced Glycation Endproducts - role in pathology of Diabetic Complications. Diabetes Res and Clin Pract, 67:3-21

7. Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, Stern D. (1995) Advanced Glycation Endproducts interacting with their endothelial receptor induce expression of V-CAM 1 in cultured human endothelial cells and in mice. J. Clin. Invest. 96 : 1395-1403

8. Giacomoni PU, D’Alessio P (1996) Skin Ageing: The Relevance of Antioxidants. In: Rattan S and Toussaint O (Editors) Molecular Gerontology: Research Status and Strategies. Plenum Press, New York, London, Pages 177-192

9. Giacomoni PU, Rein G (2017) Skin Aging: A Generalization of the Microinflammatory Hypothesis in: MA Farage, KW Miller, HI Maibach (Editors) Textbook of Aging Skin, Springer, 2017 pages 1289-1298

10. Pageon H (2017) Glycation and Skin Aging, in: MA Farage, KW Miller, HI Maibach (Editors) Textbook of Aging Skin, Springer, 2017 pages 1247-1270

11. Gkogkolou P (2017) Advanced Glycation Endproducts (AGE): Emerging Mediators of Skin Aging, in: MA Farage, KW Miller, HI Maibach (Editors) Textbook of Aging Skin, Springer, 2017 pages 1675-1686

12. Braverman IM, Keh-Yen A (1984) Ultrastructural abnormalities of the Microvasculature and Elastic Fibers in the Skin of Juvenile Diabetics. J Invest Dermatol 82:270-274

13. Hanna W, Friesen D, Bombardier C, Gladman D, Hanna A (1987) Pathologic features of diabetic thick skin. J Am Acad Dermatol 16 : 546-553

14. Vazquez F, Palacios S, Aleman N, Guerrero F (1996) Changes of the basement membrane and type IV collagen in human skin during aging. Maturitas 25:209-215

15. Marova I, Zahejsky J, Sehnalova H (1995) Non-enzymatic glycation of epidermal proteins of the stratum corneum in diabetic patients. Acta Diabetol. 32:38-43

16. Freitas JP, Filipe P, Guerra Rodrigo F (1997) Glycosylation and lipid peroxidation in skin and in plasma of diabetic patients. C R Seances Soc Biol Fil. 191:837-843

17. Sell DR, Lapolla A, Odetti P, Fogarty J, Monnier VM (1992) Pentosidine formation in skin correlates with the severity of complications in individuals with long standing IDDM. Diabetes 41:1286-1292

18. Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, Thorpe SR, Baynes JW, Gans ROB, Smit AJ (2004) Increased accumulation of skin advanced glycation end products precedes and correlates with clinical manifestation of diabetic neuropathy Diabetologia 47:1324-1330

19. Hirano T, Iesato Y, Imai A, Chiba D, Murata T (2014) Correlation between diabetic retinopathy severity and elevated skin auto-fluorescence as a marker of advanced glycation endproducts accumulation in type 2 diabetic patients. J Diabetes Complic 28:729-734

20. Chabroux S,Canoui-Poitrine F, Reffet S,Mills-Joncour G,Morelon E, Colin C, Thivolet C (2010) Advanced Glycation Endproducts assessed by skin auto-fluorescence in type 1 diabetics are associated with nephropathy, but not retinopathy. Diabetes Metab 36:152-157

21. Willemsen S, Hartog JW, Hummel YM, van Ruijven MH, van der Horst IC, van Veldhuisen DJ, Voors AA (2011) Tissue advanced glycation endproducts are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients. Eur J Heart Fail 13:76-82

22. Vedere per esempio Akbarzadeh A, Norouzian D, Mehrabi MR, Jamshidi Sh, Farhangi A, Allah Verdi A, Mofidian SMA, Lame Rad B (2007) Induction of Diabetes by Streptozotocin in Rats. Indian J Clin Biochem
    22 : 60-64

23. Shajithlal GB, Chithra P, Chandrakasan G (1998) Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats. Biochem Pharmacol 56:1607-1614

24. Chen XF, Lin WD, Lu SL, Xie T, Ge K, Shi YQ, Zou JJ, Liu ZM, Liao WQ (2010). Mechanistic study of endogenous skin lesions in diabetic rats. Exp Dermatol. 19:1088-1095

25. Chen XF, Lin WD, Lu SL, Zhang LB, Zhang H, Liu ZM (2005). Amelioration of latent skin lesions in streptozotocin-induced diabetic rats by insulin. Zhonghua Yi Xue Za Zhi 85:3176-3180

26. Sadowska-Bartoz I, Bartosz G (2015) Prevention of protein glycation by natural products by natural Compounds. Molecules 20:3309-3334

27. Figarola JL, Scott S, Loera S, Tessler C, Chu P, Weiss L, Hardy J, Rahbar S. (2003) LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats. Diabetologia. 46:1140-1152. Epub 2003 Jul 5

28. Giacomoni PU (2015) Human Stratum Corneum homeostasis: the relevance of Filaggrin and of inducers of Filaggrin production

29. Kühl T, Mezger M, Hausser I, Guey LT, Handgretinger R, Brucker-Truderman L, Nyström A (2016) CollagenVII Half Life at the Dermal Epidermal Junction Zone: Implication for Mechnaisms and Therapy of Genodermatoses. J. Invest. Dermatol. 136:1116-1123

30. Lexicon Vevy n 2, 2003

Issues Archive

• Year 2023
• Year 2020
• Year 2018
• Year 2017
• Year 2016
• Year 2009
• Year 2008
• Year 2004
• Year 2001
• Year 2000
• Year 1999
• Year 1998
• Year 1997
• Year 1996
• Year 1995
• Year 1994

Latest Editorials

• Physiologic efficacy and harmlessness in cosmetic hair lotions
• The risks associated with herbalism
• COSMETIC ACTIVES FROM VEGETABLE SOURCE
• Diabetic Skin and Cosmetic Treatments
• Interaction between drugs and foods

Latest Healthy Chemistry

• Keratin and keratinocytes
• Safe and effective lipids for new mineral oil- and lanolin-FREE formulations
• Skin and Stress, Stress and Skin: a new Basic Experimental Acquisition
• L’acide a-linolénique dans la peau: nourissant ou antinourissant?
• La fatigue d'éclaircir les difficultés