Hair follicle characteristics as early marker of Type 2 Diabetes
Introduction
Type 2 Diabetes Mellitus (DM2) is a continuum of metabolic disorders characterized by hyperglycemia resulting from defects in insulin action [1]. Today, DM2 is the most common endocrine disorder and one of the major causes of worldwide mortality [2] and disability adjusted life-years [3].
As the disease progresses, hyperglycemia injures target cells through multiple pathways, including the effects of aldose reductase, advanced glycation end products, polyol accumulation, oxidative stress, protein kinase C isoforms, growth factors, and atherosclerosis. Endothelial cell damage leads to vascular impairment, which in turn decreases oxygen and nutrients in virtually all organs [1], causing a variety of chronic complications that are responsible for the majority of DM2-related morbidity and mortality [4], [5]. These are classified by the diameter of the impaired arteries in macrovascular complications —including coronary artery disease, peripheral arterial disease, and stroke— and microvascular complications —including diabetic nephropathy, neuropathy, and retinopathy [6], [7].
The current DM2 diagnosis is based on epidemiological studies that showed a higher risk of the development of retinopathy up to eight years after certain biological thresholds are exceeded [8]. The current American Diabetes Association (ADA) thresholds are A1C ⩾6.5%, fasting plasma glucose ⩾126 mg/dL, 2-h plasma glucose ⩾200 mg/dL during an oral glucose tolerance test, and random plasma glucose ⩾200 mg/dL in patients with classic symptoms of hyperglycemia or hyperglycemic crisis [9].
Currently, an important goal in DM2 care is to minimize organ damage by preventing DM2 onset, so a precursor condition called prediabetes was created for people with greater risk of developing DM2 in the next few years, yet this approach is not free from criticism [10]. The ADA thresholds for prediabetes are: A1C from 5.7% to 6.4%, fasting plasma glucose from 100 mg/dL to 125 mg/dL, and 2-h plasma glucose from 140 mg/dL to 199 mg/dL during an oral glucose tolerance test [9]. In general, there are important discrepancies among common tests to diagnose diabetes [11]. In addition, the diagnosis may differ depending on the guidelines followed, e.g. ADA or World Health Organization guidelines [12].
DM2 diagnosis criteria using cut-offs for various glucose-related markers are currently based on thresholds obtained from population data. Yet, DM2 is a continuous process that starts long before these thresholds are surpassed [13], [14], [15]. For example, alterations in fasting glucose, 2-h glucose, HOMA insulin sensitivity and HOMA β-cell function are present at least 13 years before DM2 diagnosis [16]. This suggests a long compensation period in which the insulin resistance is decreasing beta cell function [17], [18]. This compensation period is not equal for all people: complications can start their progression to various end-organ damage and complications earlier or later depending on individual susceptibility [19], [20]. For example, it has been reported that hyperglycemic complications are already present in some newly diagnosed DM2 patients [21]. Also, many complications such as diabetic nephropathy, chronic kidney disease, neuropathies, retinopathy, stroke, and myocardial infarction are already present in the prediabetic phase [13], [22], [23].
To improve the sensitivity of DM2 diagnosis, it has been proposed to lower the diagnostic thresholds [24], but that would increase the rates of false positives, leading to the unnecessary treatment of and associated risks to healthy people. Also, it has been proposed to use a personalized glucose profile that could identify early deterioration in glucose metabolism on an individual level. This is based on the assumption that some people will have a lower baseline glucose level, and increments in this glucose level that are exceptional for those persons are regarded as normal on a population basis [25], [26]. Therefore, in order to minimize organ damage, there is a need for an early risk marker that takes into consideration the patient’s actual level of vascular impairment or organ damage.
As seen, current glucose thresholds used for DM2 diagnosis give a false sense of security to a susceptible group that could develop complications of lower glucose levels. These persons are not treated early, which allows the development of serious complications that could become irreversible when they finally meet the diagnostic criteria [24]. This is described by the metabolic memory theory, which postulates that early hyperglycemia is remembered in end organs, increasing the rate of complications in late interventions, despite adequate subsequent control [27].
The hair follicle, like many other organs, is susceptible to hyperglycemia damage. This can be noted in the relation between hyperglycemia and androgenetic alopecia, and the hair loss of DM2 patients. Therefore, focusing on the hair follicles may provide an entry point to evaluate hyperglycemia organ damage.
Section snippets
The hypothesis
We propose that dysglycemic states produce vascular impairment resulting in early manifestations of injury in the hair follicle even before a DM2/prediabetes diagnosis can be made, reflected in changes in the hair characteristics: either the number of hairs/cm2, linear hair growth, percentage of anagen bulbs, hair diameter, or time to hair regrowth after teloptosis. Thus, these hair follicle manifestations can be translated to an objective, simple, low-cost, minimally- or non-invasive
Organ damage in DM2
Hyperglycemia damages many organs during the DM2 continuum. In order to detect early manifestations of this damage, physicians could evaluate retinopathy [28], nephropathy, neuropathy, endothelial dysfunction [29], artery damage [30], or hair follicle characteristics (Fig. 1).
Hair follicle as an early manifestation of hyperglycemia
The hair follicle could be considered an end organ, with its own complex microenvironment [31]. There are three types of hair follicles: terminal follicles, characterized by thick hair, found on the scalp and in the
Consequences of the hypothesis
If hair characteristics were demonstrated to have a solid link with early phases of hyperglycemia as well as early damage, we would be able to develop various tools to support primary prevention strategies for DM2 and its related complications. This approach could complement an ongoing array of behavioral activities recommended for DM2 such as calorie restriction, diet, weight loss, and regular exercise.
Operationalizing this hypothesis could yield a simple, non-invasive, low-cost technique that
Funding sources
There was no specific funding for this study. JJM is supported by Fogarty International Centre (R21TW009982), Grand Challenges Canada (0335-04), International Development Research Center Canada (106887-001), Inter-American Institute for Global Change Research (IAI CRN3036), Medical Research Council UK (M007405), National Heart, Lung, and Blood Institute (U01HL114180), National Institutes of Mental Health (U19MH098780). JJM, AT-R, JCT, MGG-G, and RR-C are with the CRONICAS Centre of Excellence
Acknowledgements
The authors are indebted to various colleagues who provided valuable comments and feedback to earlier versions of this manuscript. Special thanks to Kasia Lipska, Dean S Morrell, María Lazo Porras, and Katie Sacksteder for their valuable input in earlier versions of the manuscript.
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The ‘bald’ phenotype (androgenetic alopecia) is caused by the high glycaemic, high cholesterol and low mineral ‘western diet’
2021, Trends in Food Science and TechnologyCutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade
2020, Journal of Investigative DermatologyCitation Excerpt :Other factors may influence diabetic wound healing. Abnormalities in hair follicles result in defective hair development and cycling, representing a sign of vascular impairment and organ damage in diabetic patients (Miranda et al., 2016). Efficiency of wound repair is also influenced by the hair follicle cycle; wound healing was found to be accelerated when mice are wounded in the late anagen stage, with enhanced re-epithelialization and angiogenesis and decreased immune cell infiltration (Ansell et al., 2011).
Association of type 2 diabetes with central-scalp hair loss in a large cohort study of African American women
2019, International Journal of Women's DermatologyCitation Excerpt :CCCA presents as loss of hair on the crown or central scalp that progresses toward the periphery (Tanus et al., 2015; Whiting and Olsen, 2008) and can advance to significant scarring (Herskovitz and Miteva, 2016; Olsen et al., 2011). Hair loss may be associated with diabetes (Arias-Santiago et al., 2010; Cakir, 2012; El Sayed et al., 2016; Kyei et al., 2011; Miranda et al., 2016). In a cross-sectional study of 326 AA women, the prevalence of type 2 diabetes was higher among women with severe central hair loss (17.6%) than among those without severe hair loss (5.7%; Kyei et al., 2011).
iNOS inhibits hair regeneration in obese diabetic (ob/ob) mice
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :There are many types of hair loss in patients, and even though the end result of hair loss is the same, the causes vary. Previous studies have suggested that there is an association between obesity and androgenic alopecia [1–3]. However, the detailed mechanism of hair loss in diabetes is not fully understood.
Noninvasive diagnosis of type 2 diabetes mellitus by hair analysis using laser-induced breakdown spectroscopy (LIBS)
2023, Instrumentation Science and Technology